National Agricultural Library
Animal Welfare Information Center
HomeAbout AWICPublicationsWorkshopsServicesNews and EventsHelpContact Us
Search AWIC
Search all of the United States Department of Agriculture
Advanced search
Browse by Subject
Research Animals
Farm Animals
Zoo, Circus and Marine Animals
Companion Animals
Government and Professional Resources
Literature Searching and Databases
Pain and Distress
Humane Endpoints and Euthanasia
You are here: Home / Publications / Bibliographies and Resource Guides / Canine Models in Biomedical Research, 1990-2009  / Pharmacology  Printer Friendly Page
Canine Models in Biomedical Research,  1990-2009
<< Table of Contents << Previous |  Next >>



Albright, A.L. (2007). Long-term intraventricular baclofen infusion in beagles. Journal of Neurosurgery 107(3 Suppl): 225-7. ISSN: 0022-3085.
Abstract: OBJECT: This study was designed to evaluate the clinical and histopathological effects of long-term (3-month) intraventricular baclofen (IVB) infusion in beagle dogs. METHODS: Catheters were inserted stereotactically into the lateral ventricles of nine dogs and were connected to implanted Synchromed II pumps. Saline solution (control animals) and IVB (experimental animals) were infused continuously. The IVB dosages ranged from 100 to 1000 microg/day. RESULTS: An IVB infusion of 135 microg/day or less throughout a 3-month period was associated with no adverse side effects in any animal. Infusion of 150 microg/day produced overt seizures in one dog and produced adverse side effects in another; a reduction in the dosage given to these animals to 135 microg/day was tolerated with no adverse effects. Infusion of IVB at a dosage of 250, 500, or 1000 microg/day caused lethal toxicity within the first 4 days of infusion. Histopathological specimens obtained at necropsy revealed no ventricular or subependymal changes in animals receiving an IVB dosage of 135 microg/day or less. CONCLUSIONS: Intraventricular baclofen infusion in beagles has dose-related toxicity; however, no clinical or neurological toxicity was evidenced at clinically tolerated dosages (< or =135 microg/day) throughout 3 months of infusion.
Descriptors: baclofen toxicity, muscle relaxants, central toxicity, baclofen pharmacology, brain pathology, cerebrospinal fluid metabolism, dogs, dose response relationship, drug, fourth ventricle, infusion pumps, injections, intraventricular, injections, spinal, magnetic resonance imaging, models, animal, muscle relaxants, central pharmacology, time factors.
Notes: Comments: Comment In: J Neurosurg. 2007 Sep;107(3 Suppl):224; discussion 224.

Alkharfy, K.M., R.M. Khan, B.M. Al Hadiya, H.S. Abou Auda, and R.R. Abou Shaaban (2007). Disposition of abouthiouzine: a novel antihyperthyroid drug. Biopharmaceutics and Drug Disposition 28(3): 105-11. ISSN: 0142-2782.
Abstract: Abouthiouzine is a novel antithyroid agent with a profile of fewer reported adverse effects than other currently used drugs. The purpose of this current work was to explore, for the first time, the disposition of abouthiouzine following intravenous and oral administration using an animal model; also, to study its plasma protein binding properties. Abouthiouzine (2 mg/kg intravenously) was administered to healthy male Vole rabbits and Beagle dogs. A dose of 20 mg/kg of the drug was also given orally to another group of Beagle dogs. Abouthiouzine plasma concentrations were measured using an HPLC method, and its pharmacokinetic parameters were determined by non-compartmental analysis. Abouthiouzine plasma protein binding was determined using an ultrafiltration technique. The drug was quickly eliminated from the rabbit and dog systemic circulations with terminal half-lives (T(1/2 lambda)) of 0.7 h and 1.9 h, respectively. The calculated T(1/2 lambda) following the oral administration in dogs was 1.8 h. Total abouthiouzine clearance (CL) in rabbits was 7.84+/-0.87 ml/min/kg, and 4.03+/-0.83 ml/min/kg in dogs. The apparent volume of distribution at steady state (V(ss)) in rabbits and dogs was 360.09+/-63.41 ml/kg and 481.10+/-62.64 ml/kg, respectively. The absolute oral bioavailability in dogs was approximately 16%, which may indicate poor absorption characteristics of the pure drug and/or an extensive first past effect. Protein binding studies have demonstrated that abouthiouzine has moderate-to-high binding properties ( approximately 63%-86%). Further studies are needed to evaluate the route of elimination of abouthiouzine in these animal models including any metabolite formation and the role of enterohepatic recycling in this process. Copyright (c) 2007 John Wiley & Sons, Ltd.
Descriptors: antithyroid agents pharmacokinetics, polyamines pharmacokinetics, pyridines pharmacokinetics, administration, oral, antithyroid agents administration and dosage, area under curve, biological availability, blood proteins metabolism, chromatography, high pressure liquid, dogs, drug evaluation, preclinical, injections, intravenous, models, animal, polyamines administration and dosage, protein binding, pyridines administration and dosage, rabbits, species specificity, tissue distribution, ultrafiltration.

Barros, G.A., M.E. Marques, and E.M. Ganem (2007). The effects of intrathecal administration of betamethasone over the dogs' spinal cord and meninges. Acta Cirurgica Brasileira Sociedade Brasileira Para Desenvolvimento Pesquisa Em Cirurgia 22(5): 361-5. ISSN: 0102-8650.
Abstract: PURPOSE: To determinate the potential clinical and histological changes due the injection of betamethasone, when administered into the canine intrathecal space. METHODS: Twenty one animals were included in a random and blind manner in the study. After general anesthesia, intrathecal puncture was performed and 1 ml of the random solution was injected. The G1 dogs received 0.9% saline solution, the G2 dogs received 1.75 mg betamethasone and the G3 dogs received 3.5 mg of betamethasone. The animals were clinically evaluated for 21 days and then sacrificed. The lumbar and sacral portions of the spinal cord were removed for light microscopy histological analyses. RESULTS: No clinical changes were observed in any of the animals included in this study. No histological changes were observed in G1 animals. Inflammatory infiltration was observed in two dogs, one in G2, another in G3. Hemorrhage and necrosis were also seen in the G2 dog which inflammatory infiltration was detected. In other two dogs, one from G2 and another from G3, there was discreet fibrosis and thickness of the arachnoid layer which was focal in one and diffuse in the other. CONCLUSION: Intrathecal administration of betamethasone caused histological changes in the spinal cord and meninges in some of the dogs involved in this study.
Descriptors: anti inflammatory agents adverse effects, betamethasone adverse effects, meninges drug effects, spinal cord drug effects, analysis of variance, anti inflammatory agents administration and dosage, betamethasone administration and dosage, dogs, fibrosis etiology, inflammation chemically induced, inflammation pathology, injections, spinal, meninges pathology, models, animal, necrosis etiology, random allocation, sodium chloride administration and dosage, spinal cord pathology, spinal puncture.

Bilotta, F., L. Agati, V. Fabbrini, G. Centola, and G. Rosa (2003). Pulmonary transit of levovist(r): a transthoracic echocardiographic study. 2003 Annual Meeting of the American Society of Anesthesiologists, San Francisco, CA, USA; October 11-15, 2003,
Abstract: After intravenous injection in spontaneously breathing patients and anesthetized dogs, ultrasound contrast agents opacify the right ventricle, pass through the lungs, opacify the left ventricle and depict systemic organ perfusion patterns. Contrast ultrasound based intraoperative organ-perfusion studies -- currently limited to intraarterial or intraaortic injection -- require an intravenous ultrasound contrast agent that passes through the lungs during mechanical ventilation in humans. Effective lung transit of ultrasound contrast agents during controlled mechanical ventilation is a prerequisite for ultrasound-based real time systemic organ perfusion studies (myocardium, kidneys, liver and brain) because it allows the contrast agent injected intravenously to reach the systemic circulation. Whether an ultrasound contrast agent passes the lungs during mechanical ventilation depends on many factors, including biochemical interactions with blood gasses, intravascular pressure and shell stability. Mechanical ventilation alters the physiology of the pulmonary microcirculation by increasing intrathoracic pressure and pulmonary vascular resistance. Levovist(R) (Schering AG, Berlin, Germany) is a galactose and palmitic based air-filled ultrasound contrast agent used for organ perfusion studies with intravenous injection in spontaneously breathing patients. In this study, we investigated whether Levovist(R) injected intravenously during intermittent positive pressure ventilation (IPPV) opacifies the right and left ventricular cavities after lung transit. With transthoracic echocardiography we measured the time in cardiac cycles (CC), for contrast to appear in the right ventricle and traverse the lungs; and the intensity of right and left ventricular cavity opacification (RVCO and LVCO). Twenty patients undergoing elective peripheral neurosurgical procedures were prospectively enrolled. All patients received intravenous Levovist(R) 1 g, during spontaneous breathing (baseline), 5 min after the beginning of IPPV, and 5 min and 30 min after extubation. Pulmonary transit time was constant: 7 +- 3 CC at baseline, 6 +- 2 CC during IPPV, and 8 +- 2 CC at 5 min and 7 +- 3 CC at 30 min after extubation. In all patients, each of the four contrast injections achieved high-grade RVCO and LVCO, and remained constant before, during IPPV and at 5 and 30 minutes after extubation. In this study, conducted in patients mechanically ventilated during general anesthesia for peripheral neurosurgical procedures, intravenous injection of Levovist(R) during IPPV opacified the right ventricular cavity, passed physiologically through the lungs and opacified the left ventricular cavity. It did so at an intensity equivalent to that when patients breathed spontaneously. During surgery, especially in high-risk patients, adequate organ blood flow is critical for normal cellular metabolism and tissue preservation. Because hypoperfusion often precedes and causes functional damage, early diagnosis of inadequate tissue perfusion could guide treatment to restore perfusion. In conclusion, Levovist(R) injected intravenously provides physiologic pulmonary capillary transit in patients undergoing peripheral neurosurgical procedures during mechanical ventilation. An ultrasound contrast agent with these properties might make real-time echographic evaluation of organ perfusion patterns possible in patients during IPPV. Anesthesiology 2003; 99: A168.
Descriptors: methods and techniques, pharmacology, surgery, medical sciences, contrast ultrasound, clinical techniques, diagnostic techniques, imaging and microscopy techniques, laboratory techniques, mechanical ventilation, therapeutic and prophylactic techniques, transthoracic echocardiography, cardiac cycles.

Brandt, K.D., G.N.J. Smith, and S.L. Myers (2004). Hyaluronan injection affects neither osteoarthritis progression nor loading of the oa knee in dogs. Biorheology 41(3-4): 493-502. ISSN: 0006-355X.
NAL Call Number: QH505.A1B5
Abstract: We previously reported that intraarticular injections of hyaluronan (HA), administered prophylactically to dogs in whom knee osteoarthritis had been induced by transection of the anterior cruicate ligament, did not significantly modify the intraarticular pathology but decreased the proteogylcan concentration of the articular cartilage by as much as 30%. Because the cartilage proteoglycan concentration is directly related to the stiffness of the tissue, these results raised the possibility that intraarticular HA therapy could exacerbate OA. In the present study, using a different HA formulation, with a longer interval between intraarticular HA injection and examination of joint tissues, we found that neither prophylactic nor therapeutic administration of HA had an effect on the severity of OA pathology, the magnitude of vertical ground reaction forces generated by the unstable hind limb (a surrogate for joint pain), or the cartilage proteoglycan concentration. The data suggest that the suppression of proteoglycan synthesis induced by HA is temporary and fully reversible and that HA injections do not result in overloading of the OA extremity. A significant correlation was noted between the severity of chondropathy and the magnitude of the vertical ground reaction forces generated by the unstable limb.
Descriptors: animal care, pharmacology, skeletal system, movement and support, osteoarthritis, joint disease.

Carballo Jane, E., L.S. Gerckens, S. Luell, A.S. Parlapiano, M. Wolff, S.L. Colletti, J.R. Tata, A.K. Taggart, M.G. Waters, J.G. Richman, M.E. McCann, and M.J. Forrest (2007). Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists. Journal of Pharmacological and Toxicological Methods 56(3): 308-16. ISSN: 1056-8719.
NAL Call Number: QP901.J6
Abstract: INTRODUCTION: GPR109A is the receptor mediating both the antilipolytic and vasodilatory effects of nicotinic acid. In order to develop agonists for GPR109A with improved therapeutic indices we have sought to optimize animal models that evaluate both nicotinic acid-mediated inhibition of lipolysis and stimulation of vasodilatation. The rat and the dog have previously been used to study the antilipolytic effects of nicotinic acid, but no optimal vasodilatation model exits in either species. METHODS: We have developed a vasodilatation model in the rat that measures changes in ear perfusion using laser Doppler flowmetry. In the dog, we have developed a model of vasodilatation measuring changes in red color values in the ear, using a spectrocolorimeter. Effects of GPR109A agonists on lipolysis were measured in both species after oral dosing of compounds, and measuring plasma levels of free fatty acids. RESULTS: In both rat and dog, GPR109A agonists induce dose- and time-dependent vasodilatation, similar to that observed in humans. Vasodilatation is inhibited in both species with cyclooxygenase inhibitors or a specific DP1 receptor antagonist, indicating that, as in man, nicotinic acid-induced vasodilatation in rats and dogs is mainly mediated by the release of PGD(2). DISCUSSION: Our results show that both rat and dog are useful models for the characterization of GPR109A agonists. A therapeutic index for GPR109A agonists can be calculated in either species.
Descriptors: lipolysis drug effects, nicotinic agonists pharmacology, receptors, g protein coupled agonists, vasodilation drug effects, anti inflammatory agents, non steroidal administration and dosage, anti inflammatory agents, non steroidal pharmacology, antilipemic agents administration and dosage, antilipemic agents pharmacology, dogs, dose response relationship, drug, drug evaluation, preclinical methods, drug monitoring methods, fatty acids, nonesterified blood, indomethacin administration and dosage, indomethacin pharmacology, inhibitory concentration 50, injections, subcutaneous, models, animal, niacin administration and dosage, niacin pharmacology, nicotinic agonists administration and dosage, pyrazines administration and dosage, pyrazines pharmacology, rats, rats, sprague dawley, receptors, nicotinic metabolism.

Chen, D., B. Jefferson, S.J. Harvey, K. Zheng, C.J. Gartley, R.M. Jacobs, and P.S. Thorner (2003). Cyclosporine a slows the progressive renal disease of alport syndrome (x-linked hereditary nephritis): results from a canine model. Journal of the American Society of Nephrology 14(3): 690-698. ISSN: 1046-6673.
Abstract: Alport syndrome refers to a hereditary disorder characterized by progressive renal disease and a multilaminar appearance to the glomerular basement membrane (GBM). In a small group of patients with Alport syndrome, cyclosporine A was reported to decrease proteinuria and maintain stable renal function over 7 to 10 yr of follow-up. The present study examined the effect of cyclosporine A on GBM structure and the progression to renal failure in a canine model of X-linked Alport syndrome. Affected male dogs and normal male dogs treated with cyclosporine A underwent serial renal biopsies. Body weight, serum concentrations of creatinine and albumin, and GFR were sequentially determined. Controls consisted of untreated dogs that developed end-stage renal failure by 8 mo of age. Renal biopsies were assessed for glomerulosclerosis and the percent of multilaminar GBM as measured by image analysis. Significant differences were found between treated and untreated affected dogs for weight, serum creatinine, and GFR. There was a significant delay in the progression of multilaminar change to the GBM, although treated affected dogs at termination had attained approximately 100% split GBM as did untreated affected dogs. A significant difference in the number of sclerotic glomeruli was also noted; treated dogs rarely developed obsolete glomeruli during the period studied. Interstitial fibrosis was not significantly affected by cyclosporine A treatment. These findings indicate that cyclosporine A is beneficial in slowing, but not stopping, the clinical and pathologic progression of Alport syndrome. At least part of this beneficial effect comes from a delayed deterioration of GBM structure, which in turn may be related to glomerular hemodynamics altered by cyclosporine A.
Descriptors: genetics, pharmacology, urinary system, chemical coordination and homeostasis, Alport syndrome, X linked hereditary nephritis, congenital disease, genetic disease, urologic disease, glomerulosclerosis, interstitial fibrosis, disease miscellaneous, renal disease, drug therapy, renal failure, image analysis, imaging and microscopy techniques, laboratory techniques, renal biopsy, glomerular filtration rate, body weight, glomerular hemodynamics.

Cho, S., S. Zhang, H. Ureshino, T. Hara, S. Tomiyasu, and K. Sumikawa (2003). Hemodynamic interactions of propofol and dantrolene in chronically instrumented dogs. Anesthesia and Analgesia 96(5): 1369-1373. ISSN: 0003-2999.
Abstract: The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia.
Descriptors: biochemistry and molecular biophysics, cardiovascular system, transport and circulation, pharmacology, malignant hyperthermia, metabolic disease, muscle disease, drug induced, cardiac output, coronary blood flow, drug drug interaction, mean arterial blood pressure.

Coleman, K.M., R. Voigts, D.P. DeVore, P. Termin, and W.P.3. Coleman (2008). Neocollagenesis after injection of calcium hydroxylapatite composition in a canine model. Dermatologic Surgery Official Publication for American Society for Dermatologic Surgery [Et Al.] 34(Suppl 1): S53-5.
Descriptors: biocompatible materials pharmacology, collagen metabolism, durapatite pharmacology, skin drug effects, cosmetic techniques, dogs, injections, intradermal, injections, subcutaneous, models, animal, photometry, pilot projects, skin metabolism, skin pathology, time factors.

Critchley, L., B. Ding, B. Fok, D. Wang, B. Tomlinson, A. James, G.N. Thomas, and J. Critchley (2004). The effects of candesartan and ramipril on adrenal catecholamine release in anaesthetized dogs. European Journal of Pharmacology 489(1-2): 67-75. ISSN: 0014-2999.
NAL Call Number: QP901.E8
Descriptors: angiotensin II type 1 receptor antagonist, angiotensin II converting enzyme inhibitor ramipril, endocrine system, chemical coordination and homeostasis, pharmacology, blood pressure.

Crystal, G.J., M. El Orbany, X. Zhou, M.R. Salem, and S.J. Kim (2008). Hemodilution does not alter the coronary vasodilating effects of endogenous or exogenous nitric oxide. Canadian Journal of Anaesthesia; Journal Canadien D'Anesthesie 55(8): 507-14. ISSN: 0832-610X.
Abstract: Introduction: It is well known that hemoglobin is a scavenger of nitric oxide (NO). The present study used a canine model to test the hypothesis that acute normovolemic hemodilution (ANH) affects NO-mediated coronary vasodilation. METHODS: Studies were performed in 18 open-chest, anesthetized dogs. In Series 1, the contribution of endogenous NO to coronary vasodilatation during ANH with 5% dextran-40 (reduction in hematocrit by 50%) was assessed. This was accomplished by comparing myocardial blood flow (MBF; radioactive microspheres) in the left anterior descending (LAD) region, which was treated with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), to that in the circumflex (control) region. In Series 2, the LAD was perfused via a controlled-pressure extracorporeal system with coronary blood flow (CBF) measured with an ultrasonic, transit-time flow transducer. The dose-dependent increases in CBF caused by acetylcholine (ACh), which releases endogenous NO from the vascular endothelium, and sodium nitroprusside (SNP), which provides exogenous NO, were compared before and during ANH. RESULTS: Acute normovolemic hemodilution caused similar (approximately twofold) increases in MBF (P < 0.01) in the absence and presence of L-NAME, and it did not affect the dose-related increases in CBF caused by ACh and SNP. CONCLUSIONS: Series 1: under baseline conditions, hemoglobin in red blood cells does not limit the coronary vasodilatation resulting from tonic release of NO; NO does not mediate coronary vasodilation during ANH. Series 2: ANH does not influence the coronary vasodilating effects of increased levels of NO, whether due to endogenous release (ACh) or infusion of an NO donor (SNP).
Descriptors: coronary vessels drug effects, hemodilution adverse effects, nitric oxide pharmacology, nitric oxide physiology, nitric oxide synthase antagonists and inhibitors, acetylcholine pharmacology, adenosine pharmacology, blood gas analysis, blood pressure drug effects, coronary vessels radionuclide imaging, dogs, enzyme inhibitors pharmacology, free radical scavengers pharmacology, heart rate drug effects, hemodilution methods, models, animal, ng nitroarginine methyl ester pharmacology, nitroprusside pharmacology, treatment outcome, vasodilator agents pharmacology.

Dane, D.M., X. Yan, R.M. Tamhane, R.L.J. Johnson, A.S. Estrera, D.C. Hogg, R.T. Hogg, and C.C.W. Hsia (2004). Retinoic acid-induced alveolar cellular growth does not, improve function after right pneumonectomy. Journal of Applied Physiology 96(3): 1090-1096. ISSN: 8750-7587.
NAL Call Number: 447.8 J825
Abstract: To determine whether all-trans retinoic acid (RA) treatment enhances lung function during compensatory lung growth in fully mature animals, adult male dogs (n=4) received 2 mgcntdotkg-1cntdotday-1 po RA 4 days/wk beginning the day after right pneumonectomy (R-PNX, 55-58% resection). Litter-matched male R-PNX controls (n=4) received placebo. After 3 mo, transpulmonary pressure (TPP)-lung volume relationship, diffusing capacities for carbon monoxide and nitric oxide, cardiac output, and septal volume (Vtiss-RB) were measured under anesthesia by a rebreathing technique at two lung volumes. Lung air and tissue volumes (Vair-CT and Vtiss-CT) were also measured from high-resolution computerized tomographic (CT) scans at a constant TPP. In RA-treated dogs compared with controls, TPP-lung volume relationships were similar. Diffusing capacities for carbon monoxide and nitric oxide were significantly impaired at a lower lung volume but similar at a high lung volume. Whereas Vtiss-RB was significantly lower at both lung volumes in RA-treated animals, Vair-CT and Vtiss-CT were not different between groups; results suggest uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by RA. We conclude that RA does not improve resting pulmonary function during the early months after R-PNX despite histological evidence of its action in enhancing alveolar cellular growth in the remaining lung.
Descriptors: methods and techniques, pharmacology, respiratory system, respiration, right pneumonectomy, experimental surgical techniques, laboratory techniques, alveolar cellular growth, cardiac output, diffusing capacity for carbon monoxide, lung air, lung function, lung volume, resting pulmonary function, septal volume, tissue volume, transpulmonary pressure.

Dias Junior, C.A., J.T. Sertorio, and J.E. Tanus Santos (2007). Aminoguanidine produces beneficial haemodynamic effects in a canine model of acute pulmonary thromboembolism. Acta Physiologica Oxford, England 191(3): 189-96. ISSN: 1748-1708.
NAL Call Number: QP1 .A2
Abstract: AIM: Activating the nitric oxide (NO)-cyclic guanosine 3',5'-monophosphate (cGMP) pathway improves haemodynamics following acute pulmonary thromboembolism (APT). However, the role of NO synthase (NOS) isoforms in the responses to APT has not been determined. We examined the effects of selective and non-selective inducible NOS (iNOS) inhibition. METHODS: Haemodynamic evaluations were performed in non-embolized dogs treated with saline (control group; n = 4), L-NAME (NAME group; n = 3), or aminoguanidine (AG group; n = 3), and in dogs that received the same drugs and were embolized with 5 mL kg(-1) of clots made with autologous blood (Emb group, n = 9; NAME + Emb group, n = 4 and AG + Emb group, n = 7). The lung concentrations of nitrite/nitrate (NOx) and cGMP were determined by chemiluminescence and ELISA respectively. RESULTS: Acute pulmonary thromboembolism increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 21.4 +/- 1.7 mmHg and by 843 +/- 34 dyn s cm(-5) m(-2), respectively, in Emb group. MPAP and PVRI increased to higher levels in the NAME + Emb group 15 min after APT and all dogs in this group died 15-30 min after APT. Conversely, lower MPAP and PVRI levels were found in the AG + Emb group 2 h after APT compared with the Emb group (both P < 0.05). Higher NOx concentrations were found in the Emb group compared with the other groups (all P < 0.05). Higher cGMP concentrations were found in the Emb and AG + Emb groups compared with the other groups (all P < 0.05). CONCLUSIONS: These results indicate that endogenous NO protects against APT-induced cardiovascular responses. Moreover, iNOS-derived NO possibly produces unfavourable effects, which are counteracted by aminoguanidine. However, non-NO-related mechanisms may also be involved.
Descriptors: guanidines therapeutic use, nitric oxide synthase type ii antagonists and inhibitors, pulmonary embolism drug therapy, acute disease, blood pressure drug effects, cyclic gmp analysis, cyclic gmp metabolism, dogs, lung chemistry, lung metabolism, models, animal, ng nitroarginine methyl ester metabolism, ng nitroarginine methyl ester therapeutic use, nitrates analysis, nitrates metabolism, nitric oxide metabolism, nitric oxide synthase type ii metabolism, pulmonary embolism metabolism, vascular resistance drug effects.

Dong, M.S., Y. Sonoda, H. Konomi, M. Kawamoto, T. Takeda, and M. Tanaka (2003). Total duodenectomy: effects of choecystokinin on the sphincter of oddi motility in conscious dogs. Digestive Disease Week Abstracts and Itinerary Planner: Abstract No. S1160.
Abstract: Objective: Cholecystokinin(CCK) is an important gastrointestinal hormone controlling of the Sphincter of Oddi (SO) motility. The mechanism of CCK action on SO motility is not completely understood. Anatomical and electrophysiological studies suggested direct duodenal neural projections to the SO. However the CCK action via duodeno-SO neural projections under physiological intact animal model has not been reported. The aim of this study is to determine the SO motility response to the CCK via the duodeno-SO neural projections using duodenectomized dogs. Methods: In control group (N=6), Thomas cannula was implanted into the duodenum. In duodenectomy group (N=6), the papilla was sutured to the jejunum and a Thomas cannula implanted opposite to the implanted papilla. In both groups, changes in the SO motility was recorded after intravenous injection of cholecystokinin-octapeptide (20 or 100ng/kg). Results: Injection of 20ng/kg CCK produced initial relaxation followed by contraction in control and no changes in duodenectomy. Injecting of 100ng/kg CCK produced a marked but brief contraction followed by relaxation in controls and only contraction after duodenectomy. Conclusions: (1) Response of SO induced by 20ng/kg CCK was mediated via CCK receptor on the duodenum. (2) The duodenal CCK receptor may be more sensitive to CCK than SO receptor..
Descriptors: digestive system, ingestion and assimilation, methods and techniques, pharmacology, total duodenectomy, clinical techniques, therapeutic and prophylactic techniques, sphincter motility, modulation .

Efrati, O., A. Barak, R. Ben Abraham, D. Modan Moses, M. Berkovitch, Y. Manisterski, D. Lotan, Z. Barzilay, and G. Paret (2003). Should vasopressin replace adrenaline for endotracheal drug administration? Critical Care Medicine. 31(2): 572-576. ISSN: 0090-3493.
Abstract: OBJECTIVE: Arginine vasopressin was established recently as a drug of choice in the treatment of cardiac arrest and in retractable ventricular fibrillation; however, the hemodynamic effect of vasopressin following endotracheal drug administration has not been fully elucidated. We compared the effects of endotracheally administered vasopressin vs. adrenaline on hemodynamic variables in a canine model, and we investigated whether vasopressin produces the same deleterious immediate blood pressure decrease as did endotracheal adrenaline in the canine model. DESIGN: Prospective controlled study. SETTING: Animal laboratory in Tel-Aviv University, Israel. SUBJECTS: Five adult mongrel dogs weighing 6.5-20 kg. INTERVENTIONS: Dogs were anesthetized; each dog was intubated orally, and both femoral arteries were cannulated for the measurement of arterial pressure and for sampling blood gases. Each dog was studied four times, 1 wk apart, by using the same protocol for injection and anesthesia: endotracheal placebo (10 mL NaCl 0.9%,), endotracheal vasopressin (1 units/kg), endobronchial adrenaline (0.1 mg/kg), and endotracheal adrenaline (0.1 mg/kg). Following placebo, vasopressin, and adrenaline instillation, five forced manual ventilations were delivered with an Ambu bag. Each dog was its own control. MEASUREMENTS AND MAIN RESULTS: Following placebo or drug administration, heart electrocardiography and arterial pressures were continuously monitored with a polygraph recorder for 1 hr. Endotracheal vasopressin produced an immediate increase of diastolic blood pressure (from 83 +/- 10 mm Hg [baseline] to 110 +/- 5 mm Hg at 1 min postinjection). This response lasted >1 hr. In contrast, both endotracheal and endobronchial administration of adrenaline produced an early and significant (p <.05) decrease in diastolic and mean blood pressures. The diastolic blood pressure increase from 85 +/- 10 mm Hg to 110 +/- 10 mm Hg took an ill-afforded 55 secs following endotracheal adrenaline. Diastolic blood pressure was significantly (p <.05) higher following vasopressin compared with adrenaline administration in both routes. CONCLUSIONS: Vasopressin accomplishes its hemodynamic effect, particularly on diastolic blood pressure, more rapidly, vigorously, and protractedly and to a significant degree compared with both endotracheal and endobronchial adrenaline. Evaluation of the effects of endotracheal vasopressin in a closed chest cardiopulmonary resuscitation model is recommended.
Descriptors: intubation, femoral artery cannulation, vasopressin, henodynamic effect, diastolic blood pressure.

Ensminger, W., J. Knol, S. Deremer, E. Wilkinson, S. Walker, D. Williams, and J. Maybaum (2004). Effects of dexamethasone or celecoxib on biliary toxicity after hepatic arterial infusion of 5-fluorodeoxyuridine in a canine model. Cancer Research 64(1): 311-315. ISSN: 0008-5472.
NAL Call Number: 448.8 C16
Abstract: Previous work has shown that in humans the dose-limiting toxicity for fluorodeoxyuridine (2-fluoro-5'-deoxyuridine (FdUrd)) when administered by hepatic arterial infusion is biliary sclerosis. The current study was undertaken to attempt to modify this toxicity in a canine model that has been demonstrated to closely mimic the clinical situation. Unlike previous studies using this model, in which animals were sacrificed after extensive fibrosis had already occurred, the current experiments were designed so that observations of pathology were made at an earlier time, when the initial inflammatory injury underlying the fibrotic process was still taking place. Implantable pumps were used to deliver FdUrd into the hepatic artery of animals at a rate of 0.3 mg/kg/day in the presence or absence of 10 mg/week dexamethasone or 100 mg/day of celecoxib for 35 days, at which time the animals were beginning to show signs of toxicity. After evaluation for radiological evidence of biliary obstruction, the animals were sacrificed and portions of their livers were processed for examination of microscopic pathology and 2-bromo-5'deoxyuridine labeling index. Dexamethasone treatment protected the animals from biliary sclerosis determined radiologically, further validating this model as being representative of the response in humans. Similarly the Cox-2 inhibitor, celecoxib, appeared to provide protection against radiological changes of biliary stricture, although possibly to a lesser degree than the resultant from dexamethasone. In addition, FdUrd treatment caused elevation of the DNA 2-bromo-5'deoxyuridine labeling index above control levels in biliary epithelial cells. Dexamethasone and celecoxib each significantly attenuated the FdUrd-induced elevation of DNA labeling index in biliary epithelium. These findings demonstrate the usefulness of this canine model for studying the mechanisms of drug-induced biliary sclerosis and reinforce the hypothesis that blocking inflammation may retard the progression of injury that eventually leads to fibrosis. This study suggests that clinical testing of celecoxib as a preventive for hepatic arterial-FdUrd induced biliary damage could prove valuable.
Descriptors: digestive system, ingestion and assimilation, pharmacology, veterinary medicine, medical sciences, biliary obstruction, digestive system disease, biliary sclerosis, drug induced, colorectal cancer, neoplastic disease, infusaid model 400 implantable pump, drug delivery device.

Fedorov, V.V., G.G. Beloshapko, A.V. Yushmanova, O.F. Sharifov, and L.V. Rosenshtraukh (2003). Effects of a new class iii antiarrhythmic drug nibentan in a canine model of spontaneous atrial fibrillation. European Heart Journal 24(Abstract Supplement): 391. ISSN: 0195-668X.
Descriptors: cardiovascular system, transport and circulation, pharmacology, atrial premature depolarization, heart disease, prevention and control, reentrant arrhythmia, heart disease, prevention and control, spontaneous atrial fibrillation, heart disease, drug therapy, atrial electrical stimulation, clinical techniques, ik potassium current, atrial effective refractory period, basic cycle length, conduction velocity.

Fleischer, S., M. Sharkey, K. Mealey, E.A. Ostrander, and M. Martinez (2008). Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS Journal 10(1): 110-9.
Abstract: There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds. This article provides a summary of the literature pertaining to canine breed differences in physiology, drug response, drug pharmacokinetics, and metabolic idiosyncrasies. The existing knowledge of pedigrees and the known phenotypes and genotypes of dogs provides important information for determining mode of inheritance, penetration, and other major characteristics of heritable traits. Understanding these breed differences will improve canine population predictions (for canine drug products) and may be of value when extrapolating toxicology data from dogs to humans.
Descriptors: dogs genetics, models, animal, pharmaceutical preparations metabolism, pharmacogenetics methods, veterinary medicine methods, drug evaluation, preclinical methods, species specificity.

Forrest, M.J., D. Bloomfield, R.J. Briscoe, P.N. Brown, A.M. Cumiskey, J. Ehrhart, J.C. Hershey, W.J. Keller, X. Ma, H.E. McPherson, E. Messina, L.B. Peterson, W. Sharif Rodriguez, P.K. Siegl, P.J. Sinclair, C.P. Sparrow, A.S. Stevenson, S.Y. Sun, C. Tsai, H. Vargas, M.3. Walker, S.H. West, V. White, and R.F. Woltmann (2008). Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. British Journal of Pharmacology 154(7): 1465-73. ISSN: 0007-1188.
NAL Call Number: 396.8 B77
Abstract: BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.
Descriptors: blood pressure drug effects, cholesterol ester transfer proteins antagonists and inhibitors, oxazolidinones toxicity, quinolines toxicity, adrenal cortex cytology, adrenal cortex drug effects, aldosterone blood, anticholesteremic agents toxicity, corticosterone blood, dogs, drug evaluation, preclinical, macaca mulatta, mice, mice, inbred c57bl, models, animal, muscle, smooth, vascular drug effects, muscle, smooth, vascular metabolism, rats, rats, sprague dawley, species specificity.
Notes: Comments: Comment In: Br J Pharmacol. 2008 Aug;154(7):1379-81.

Francis, R.C., M.S. Reyle Hahn, C. Hohne, A. Klein, I. Theruvath, B. Donaubauer, T. Busch, and W. Boemke (2008). The haemodynamic and catecholamine response to xenon/remifentanil anaesthesia in Beagle dogs. Laboratory Animals 42(3): 338-49. ISSN: 0023-6772.
NAL Call Number: QL55.A1L3
Abstract: The noble gas xenon seems to have minimal cardiovascular side-effects and so may be an ideal anaesthetic agent when investigating cardiovascular physiology. In comparison with standard modern anaesthetics, we investigated the haemodynamic and hormonal effects of xenon in Beagle dogs. After a 30 min baseline period, anaesthesia was induced with propofol and maintained with either (1) 1.2% isoflurane/70% nitrous oxide (N(2)O), (2) 0.8% isoflurane/0.5 microg/kg/min remifentanil or (3) 63% xenon/0.5 microg/kg/min remifentanil (n = 6 per group). Haemodynamics were recorded and blood samples taken before and 60 min after induction. Mean arterial blood pressure (MAP) was higher in conscious dogs than during isoflurane/N(2)O (86 +/- 2 vs. 65 +/- 2 mmHg, mean +/- SEM) and isoflurane/remifentanil anaesthesia (95 +/- 2 vs. 67 +/- 3 mmHg), whereas MAP did not decrease significantly in response to xenon/remifentanil anaesthesia (96 +/- 4 vs. 85 +/- 6 mmHg). Bradycardia was present during isoflurane/remifentanil (54 +/- 2/min) and xenon/remifentanil (40 +/- 3/min), but not during isoflurane/N(2)O anaesthesia (98 +/- 3/min, P < 0.05). Xenon/remifentanil anaesthesia induced the highest reduction in cardiac output (CO) (-61%), and the highest increase in systemic vascular resistance (+120%) among all treatment groups (P < 0.05). A simultaneous increase in endogenous adrenaline and noradrenaline concentrations could only be observed in the xenon/remifentanil group, whereas angiotensin II and vasopressin concentrations increased in all groups. In conclusion, xenon/remifentanil anaesthesia maintains MAP but reduces heart rate and CO and is associated with a considerable stimulation of vasopressor hormones in Beagle dogs. Therefore, xenon/remifentanil exerts a new quality of adverse haemodynamic effects different from volatile anaesthetics and may not perform better during studies of cardiovascular physiology.
Descriptors: anesthetics, inhalation pharmacology, cardiovascular system drug effects, catecholamines blood, dogs physiology, models, animal, piperidines pharmacology, xenon pharmacology, aldosterone blood, atrial natriuretic factor blood, dogs blood, endothelin 1 blood, hemodynamics drug effects, isoflurane pharmacology, nitrous oxide pharmacology, random allocation, renin blood.

Freitas, C.F., R. Faro, D. Dragosavac, M. Clozel, G. De Nucci, and E. Antunes (2004). Role of endothelin-1 and thromboxane a2 in the pulmonary hypertension induced by heparin-protamine interaction in anesthetized dogs. Journal of Cardiovascular Pharmacology 43(1): 106-112. ISSN: 0160-2446.
Abstract: This study aimed to study the role of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. Similar results were obtained with inhaled NO (3 ppm). Plasma TXB2 levels were markedly elevated during the pulmonary hypertension, and this was abolished in indomethacin-treated dogs. Our study shows that interaction of heparin-protamine in anesthetized dogs lead to TXA2- and ET-1-mediated pulmonary hypertension. Drugs that interfere with the synthesis of these mediators as well as inhaled NO may be of beneficial value to control this disorder.
Descriptors: cardiovascular system, transport and circulation, pharmacology, pulmonary hypertension, vascular disease, tachycardia, heart disease, cardiac index, heart rate, heparin protamine interaction, mean arterial blood pressure, mean arterial pulmonary pressure, pulmonary pressure gradient, systemic vascular resistance index.

Fryer, R.M., L. Preusser, S. Calzadilla, Y. Hu, H. Xu, K. Marsh, B. Cox, C.T. Lin, M. Gopalakrishnan, and G. Reinhart (2004). A-278637, a novel atp-sensitive potassium channel opener: hemodynamic comparison to zd-6169, way-133537 and nifedipine in the anesthetized canine. FASEB Journal 18(4-5): Abst. 404.3. ISSN: 0892-6638.
NAL Call Number: QH301.F3
Descriptors: cardiovascular system, transport and circulation, pharmacology, urinary system, chemical coordination and homeostasis, overactive bladder, urinary incontinence, urologic disease, therapy .

Gamez, R., R. Mas, M. Noa, R. Menendez, H. Garcia, J. Gonzalez, Y. Perez, and E. Goicochea (2004). Effects of chronic administration of d-003, a mixture of sugar cane wax high molecular acids, in beagle dogs. Drugs Under Experimental and Clinical Research 30(2): 75-88. ISSN: 0378-6501.
Abstract: D-003 is a mixture of high molecular weight aliphatic primary acids purified from sugar cane wax (Saccharum officinarum, Q with cholesterol-lowering and antiplatelet effects. Previous studies, including a 6-month study conducted in rats, have shown no D-003-related toxicity. The present study was undertaken to investigate the effects of D-003 orally administered for 9 months in beagle dogs. The animals were randomly distributed in three groups: a control group receiving the vehicle only and two groups orally administered D-003 (200 and 400 mg/kg). Body weight gain, food consumption and clinical signs were controlled throughout the study. The effects of D-003 on collagen-induced platelet aggregation, bleeding time (B T) and coagulation parameters (prothrombin time and kaolin-activated thromboplastin time) were also investigated. Most blood biochemistry and hematological parameters were assessed at baseline and after 6 and 9 months of treatment, while total cholesterol (TC), triglycerides, platelet aggregation, B T and coagulation parameters were determined at baseline and after 9 months of treatment. At study completion, the animals were sacrificed. D-003 at a dose of 200 and 400 mg/kg significantly reduced TC (p < 0.05), significantly inhibited platelet aggregation and increased BT compared with levels in controls. Data analyses of body weight gain, food consumption, clinical observations, the remaining blood biochemistry and hematology indicators (including coagulation parameters, organ weight ratios and histopathological findings) showed no trends with D-003 doses or significant differences between control animals and treated groups. In conclusion, D-003 administered for 9 months to beagle dogs induced the expected effects with no evidence of drug-related toxicity.
Descriptors: clinical chemistry, allied medical sciences, pharmacology, toxicology .

Genissel, P., Y. Chodjania, J.L. Demolis, I. Ragueneau, and P. Jaillon (2004). Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers. European Journal of Drug Metabolism and Pharmacokinetics 29(1): 61-68. ISSN: 0378-7966.
Abstract: The pharmacokinetics of immediate (IR) and modified release (MR) trimetazidine (TMZ) in dogs and pigs, have been compared under single dose conditions, then predicted at steady-state under conditions mimicking an actual human pharmacokinetic study. In both animal species, the MR tablet has demonstrated sustained release properties, as assessed by delayed time to peak and increased mean absorption times. Multiple dose simulations in dogs revealed a delayed time to peak (3.0 vs. 1.0 h), a decrease in peak plasma concentration (544 vs. 659 mug/L), an increase in trough concentrations (115 vs. 63 mug/L), a decrease in peak-trough fluctuation (141 vs. 193%), and an increase in plateau time (5.5 vs. 4.9 h). Qualitatively similar changes were simulated in pigs. These properties have then been verified in humans where a TMZ MR 35 mg b.i.d regimen did provide similar total exposure, increased plateau time (11 vs. 4 h), decreased peak-trough fluctuation (86 vs. 121%), a 31% increase in trough concentrations, and no increase in inter-individual variability as compared to a TMZ IR 20 mg t.i.d. regimen. Furthermore, the TMZ MR 35 mg b.i.d. regimen is likely to result in improved patient compliance and better patient anti-ischemic protection in the early morning.
Descriptors: metabolism, pharmacology, drug metabolism.

Georges, G.E., R. Storb, J.M. Zaucha, A.G. Taranova, T. Gooley, and R.A. Nash (2003). Il-2 does not enhance the conversion to complete donor chimerism following nonmyeloablative hematopoietic cell transplantation in dogs. Bone Marrow Transplantation 31(11): 1027-1031. ISSN: 0268-3369.
Abstract: A dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical littermates receive nonmyeloablative total body irradiation before hematopoietic cell transplantation and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Unmodified donor lymphocyte infusion (DLI) into stable mixed chimeras failed to increase donor chimerism, while DLI from donors sensitized to recipient minor-histocompatibility antigens promptly converted all recipients to complete donor chimerism. This established a model for studying approaches to enhance the graft-versus-host (GVH)-effect, a potential surrogate for graft-versus-leukemia activity. We asked if interleukin-2 (IL-2) given after unmodified DLI could result in reliable conversion to complete donor chimerism. IL-2, 4X105 IU/kg/day, was administered to six mixed chimeric dogs for 14 days. Four dogs received unmodified DLI with IL-2. At 20-40 weeks after DLI, all dogs remained mixed chimeras. For the two recipients of IL-2 only, mixed chimerism also remained unchanged. These results show that IL-2 given with DLI after nonmyeloablative transplantation in dogs is not effective in reliably converting mixed to complete donor chimerism.
Descriptors: immune system, chemical coordination and homeostasis, pharmacology, nonmyeloablative hematopoietic cell transplantation, clinical techniques, therapeutic and prophylactic techniques, total body irradiation, laboratory techniques, unmodified donor lymphocyte infusion, complete donor chimerism, graft vs host effect, immunosuppression, mixed donor chimerism.

Guo Zhi Bin , Li Qing , Cao Hong Yu , and Xu Zhi (2003). Comparative study of propafenone and procainamide on canine ischemic ventricular tachyarrhythmias. Zhongguo Yaolixue Yu Dulixue Zazhi 17(5): 360-365. ISSN: 1000-3002.
Abstract: AIM: To observe the electrophysiologic effects of propafenone (Prop) on canine ischemic ventricular tachyarrhythmias and compared with those of procainamide (PA), so as to evaluate the effect and mechanism of Prop on ischemic ventricular tachyarrhythmias. METHODS: A canine ischemic ventricular tachyarrhythmia model was established by the left anterior descending coronary artery occlusion for 2 h and reperfusion. Five to eight days later, open-chest dogs were given programmed electrical stimulation (PES), and electrophysiologic data were measured by electrocardiogram (ECG). RESULTS: Both Prop and PA distinctly lengthened the QTc interval (P<0.01) and effective refractory period (ERP) of normal and ischemic ventricular myocardium respectively (P<0.01), decreased the dispersion of ERP in ischemic myocardium and in left ventricle (P<0.01), and increased the diastolic excitability threshold of normal and ischemic ventricular myocardium remarkably (P<0.01). Prop and PA effectively prevented PES- or ischemia-induced ventricular tachycardia or ventricular fibrillation (P<0.05, or P<0.01). CONCLUSION: The canine model is a worthy and reliable one. Prop and PA may be effective in preventing the onset of ventricular tachycardia or ventricular fibrillation after myocardial ischemic damage. The antiarrhythmic effects of both drugs are similar.
Descriptors: cardiovascular system, transport and circulation, pharmacology, ischemic ventricular tachyarrhythmia, heart disease, myocardial infarction, heart disease, vascular disease, ventricular fibrillation, ventricular tachycardia, electrocardiography, clinical techniques, diagnostic techniques, programmed electrical stimulation, experimental surgical techniques, laboratory techniques, qtc interval, comparative study, diastolic excitability threshold, disease onset, disease prevention, effective refractory period, electrophysiologic data.

Halpenny, M., F. Markos, H.M. Snow, P.F. Duggan, E. Gaffney, D.P. O'Connell, and G.D. Shorten (2001). Effects of prophylactic fenoldopam infusion on renal blood flow and renal tubular function during acute hypovolemia in anesthetized dogs. Critical Care Medicine. 29(4): 855-860. ISSN: 0090-3493.
Abstract: OBJECTIVE: It was hypothesized that fenoldopam mesylate, a selective dopamine agonist, may preserve renal perfusion and decrease tubular oxygen consumption during states of hypoperfusion, such as hypovolemic shock. The objective of this study was to quantify the effects of fenoldopam (0.1 microg x kg(-1) x min(-1)) on renal blood flow, urine output, creatinine clearance, and sodium clearance in pentobarbital anesthetized dogs that had undergone partial exsanguination to acutely decrease cardiac output. DESIGN: Prospective, randomized, controlled experiment. SETTING: University-based animal laboratory and research unit. SUBJECTS: Eight female beagle dogs. INTERVENTIONS: Arterial blood pressure, heart rate, cardiac output, renal blood flow, urine output, creatinine clearance, and fractional excretion of sodium were measured and calculated at four times: a) before infusion of fenoldopam or normal saline; b) during infusion of fenoldopam or normal saline (1 hr); c) during a 90-min period of hypovolemia (induced by acute partial exsanguination), with concurrent infusion of fenoldopam or normal saline; and d) during a 1-hr period after retransfusing the dogs. MEASUREMENTS AND MAIN RESULTS: Administration of fenoldopam (0.1 microg x kg(-1) x min(-1)) was not associated with hemodynamic instability. Renal blood flow and urine output decreased significantly from baseline (p <.01) during the hypovolemic period in the placebo group (72 +/- 20 to 47 +/- 6 mL/min and 0.26 +/- 0.15 to 0.08 +/- 0.05 mL/min, respectively) but not in the fenoldopam group (75 +/- 14 to 73 +/- 17 mL/min and 0.3 +/- 0.19 to 0.14 +/- 0.05 mL/min, respectively). Creatinine clearance and fractional excretion of sodium decreased significantly from baseline (p <.01) in the placebo group during the hypovolemic period (3.0 +/- 0.4 to 1.8 +/- 0.8 mL x kg(-1) x min(-1) and 1.7% +/- 0.9% to 0.4% +/- 0.2%, respectively) but not in the dogs that received fenoldopam (3.0 +/- 1.0 to 2.9 +/- 0.5 mL x kg(-1) x min(-1) and 1.9% +/- 1.1% to 1.7% +/- 2.7%, respectively). CONCLUSIONS: Fenoldopam ablated the tubular prerenal response to profound hypovolemia and maintained renal blood flow, glomerular filtration rate, and natriuresis without causing hypotension. This suggests that fenoldopam may have a renoprotective effect in acute ischemic injury.
Descriptors: animal model, female, beagle dogs, hypovolemia, fenoldopam, blood flow, glomerular filtration rate, natriuresis.

Han, J., J.C. Kim, M.K. Chung, B. Kim, and D.R. Choi (2003). Subacute toxicity and toxicokinetics of a new antibiotic, dw-224a, after single and 4-week repeated oral administration in dogs. Biological and Pharmaceutical Bulletin 26(6): 832-839. ISSN: 0918-6158.
NAL Call Number: QP501
Abstract: The subacute toxicity and toxicokinetics of a new fluoroquinolone antibiotic, DW-224a, were evaluated after single (on the 1st day) and 4-week (on the 28th day) oral administration of the drug at doses of 0 (to serve as a control), 10, 30, and 90 mg/kg/d, to male and female dogs (n = 3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral dose of DW-224a resulted in vomiting, salivation, increased serum cholesterol level, and atrophy of thymus and testes. The target organ was determined to be the thymus and testes. The absolute toxic dose of DW-224a was 30 mg/kg and the level at which no adverse effects were observed was 10 mg/kg for both sexes. There were no significant gender differences in the pharmacokinetic parameters of DW-224a for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DW-224a were dose independent after a single oral administration; the time to reach the peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC0-24 h) were not significantly different among the three doses. The accumulation of DW-224a after 4-week oral administration was not notable at the toxic dose of 90 mg/kg/d. For example, after 4-week administration, the dose-normalized AUC0-24 h value at 90 mg/kg/d (7.69, 7.05 mug h/ml) was not significantly greater than that at 10 mg/kg/d. After 4-week oral administration, the dose-normalized Cmax and AUC0-24 h at 90 mg/kg/d were not significantly higher and greater, respectively, than those after a single oral administration.
Descriptors: pharmacology, veterinary medicine, medical sciences, ophthalmoscopy, clinical techniques, therapeutic and prophylactic techniques, urinalysis, laboratory techniques.

Han, J., H.C. Shin, J.C. Kim, and B. Kim (2004). Subacute toxicity and toxicokinetics of cj-10882, a type iv phosphodiesterase inhibitor, after 4-week repeated oral administration in dogs. Food and Chemical Toxicology 42(3): 373-380. ISSN: 0278-6915.
NAL Call Number: 391.8 F73
Abstract: The subacute toxicity and toxicokinetics of a type IV phosphodiesterase inhibitor, CJ-10882, were evaluated after single (on the 1st day) and 4-week (on the 27th day) oral administration of the drug, in doses of 0 (to serve as a control), 2, 10 and 50 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral doses of CJ-10882 resulted in salivation, vomiting, and atrophy of the thymus. The absolute toxic dose was 50 mg/kg/day and the level at which no adverse effects were observed was 2 mg/kg/day for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of CJ-10882 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of CJ-10882 were dose independent after a single oral administration; the time to reach a peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration-time curve from time zero to 8 h in plasma (AUC0-8 h) were not significantly different among three doses. The accumulation of CJ-10882 after 4-week oral administration was not notable at the toxic dose of 50 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC0-8 h value at 50 mg/kg/day (0.132 mug h/ml) was not significantly greater than that at 10 mg/kg/day (0.131 mug h/ml). After 4-week oral administration, the dose-normalized Cmax and AUC0-8 h at 50 mg/kg/day were not significantly higher and greater, respectively, than those after the single oral administration.
Descriptors: pharmacology, toxicology, salivation, vomiting.

Harris, S.R., J.I. Gedge, A.N.R. Nedderman, S.T. Roffey, and M. Savage (2004). A sensitive hplc-ms-ms assay for quantitative determination of midazolam in dog plasma. Journal of Pharmaceutical and Biomedical Analysis 35(1): 127-134. ISSN: 0731-7085.
NAL Call Number: RS400
Descriptors: methods and techniques, pharmacology, 96 well oasis mcx solid phase extraction plates, laboratory equipment, hplc ms ms assay, high performance liquid chromatography dual mass spectrometry assay, chromatographic techniques, laboratory techniques, spectrum analysis techniques, accuracy, clinical pharmacokinetics, drug interactions, inter assay precision, intra assay precision, pharmacokinetic parameters, specificity .

Hashimoto, N., I. Takeyoshi, H. Tsutsumi, Y. Sunose, M. Tokumine, O. Totsuka, S. Ohwada, K. Matsumoto, and Y. Morishita (2004). Effects of a bradykinin b2 receptor antagonist on ischemia-reperfusion injury in a canine lung transplantation model. Journal of Heart and Lung Transplantation 23(5): 606-613. ISSN: 1053-2498.
Abstract: Background: This study investigated the effects of a bradykinin B, receptor antagonist, FR173657 (FR), on ischemia-reperfusion (I/R) injury in a canine lung transplantation model. Methods: Eighteen pairs of weight-matched dogs were randomly divided into 3 groups. Six pairs were assigned to the FR(D+R) group, in which FR (100 nmol/kg/h) was administered to the transplant donor continuously beginning 30 minutes before ischemia until the onset of ischemia, and FR was administered to the transplant recipient beginning 30 minutes before reperfusion and continuing for 2 hours after reperfusion. Another 6 pairs of dogs were assigned to the FR(R) group, in which FR was administered only to the recipient in the same manner as in the FR(D + R) group. The other pairs were assigned to the control group, in which vehicle alone was administered. Orthotopic left lung transplantation was performed after 12-hour cold storage in Euro-Collins solution. Fifteen minutes after reperfusion, the right pulmonary artery and the right stem bronchus were ligated. The animals were measured for 4 hours after reperfusion for left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (Pao2) and alveolar-arterial oxygen pressure difference (A-aDo2). Lung specimens were harvested for measurement of the wet-to-dry lung weight ratio (WDR), histopathologic studies and polymorphonuclear neutrophil (PMN) count. Results: Compared with the control group, Pao2, A-aDo2, L-PVR and CO were all significantly (p < 0.05) improved and WDR significantly (p < 0.05) lower in both the FR(D+R) and FR(R) groups. Moreover, in the FR-treatcd groups, histologic tissue edema was mild, and PMN infiltration was significantly (p < 0.05) reduced. Conclusions: The bradykinin B, receptor antagonist, FR173657, ameliorates I/R injury in lung grafts, indicating that protection of lung grafts can be achieved by the administration of FR solely to the transplant.
Descriptors: cardiovascular system, transport and circulation, pharmacology, respiratory system, respiration, ischemia reperfusion injury, injury, vascular disease, pathology, histopathologic study, histology and cytology techniques, laboratory techniques, lung transplantation, clinical techniques, therapeutic and prophylactic techniques, orthotopic left lung transplantation, alveolar arterial oxygen pressure difference, arterial oxygen pressure, cardiac output, left pulmonary vascular resistance, wet to dry lung weight ratio.

Hatada, K., L.M. Riou, M. Ruiz, R.L. Lima, A.R. Goode, D.D. Watson, G.A. Beller, and D.K. Glover (2003). Comparison between the myocardial uptake of 99mtcn-dbodc5 and 201ti during vasodilator stress in a canine model of a critical coronary stenosis. Journal of the American College of Cardiology 41(6 Supplement A): 443A. ISSN: 0735-1097.
NAL Call Number: RC681.A1
Descriptors: cardiovascular system, transport and circulation, metabolism, pharmacology, coronary stenosis, heart disease, vascular disease, myocardial blood flow, vasodilator stress

Haushalter, T.M., G.S. Friedrichs, D.L. Reynolds, M. Barecki Roach, G. Pastino, R. Hayes, and A.S. Bass (2008). The cardiovascular and pharmacokinetic profile of dofetilide in conscious telemetered beagle dogs and cynomolgus monkeys. British Journal of Pharmacology 154(7): 1457-64. ISSN: 0007-1188.
NAL Call Number: 396.8 B77
Abstract: BACKGROUND AND PURPOSE: The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure. EXPERIMENTAL APPROACH: Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6 h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose. KEY RESULTS: Dogs: increases in the QT(c) interval reached 56 ms in dogs dosed with 0.3 mg kg(-1) of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The mean C(max) values were 3.35 and 60.15 ng mL(-1) at doses of 0.03 and 0.3 mg kg(-1), respectively. Monkeys: increases in QT(c) intervals reached 40-50 ms after 0.03 mg kg(-1). T-wave changes were observed after 0.03 mg kg(-1) without changes in cardiovascular parameters. The mean C(max) values following oral doses of 0.01 and 0.03 mg kg(-1) were 0.919 ng mL(-1) and 1.85 ng mL(-1), respectively. CONCLUSIONS AND IMPLICATIONS: Despite dofetilide exposure comparable to that in humans, QT(c) responses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QT(c). Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.
Descriptors: anti arrhythmia agents toxicity, long qt syndrome chemically induced, models, animal, phenethylamines toxicity, sulfonamides toxicity, administration, oral, anti arrhythmia agents administration and dosage, anti arrhythmia agents pharmacokinetics, blood pressure drug effects, dogs, dose response relationship, drug, electrocardiography, heart rate drug effects, macaca fascicularis, phenethylamines administration and dosage, phenethylamines pharmacokinetics, species specificity, sulfonamides administration and dosage, sulfonamides pharmacokinetics, telemetry.

Hayashi, K. (2003). Effects of angiotensin ii receptor antagonist on intestinal mucosal oxygenation during canine isovolemic hemodilution with hydroxyethyl starch. Japanese Journal of Anesthesiology 52(6): 603-610. ISSN: 0021-4892.
Abstract: Background: Although isovolemic hemodilution can be used clinically to reduce the need for blood transfusion, the critical hemoglobin level and severe indequacy of tissue oxygenation induced by hemodilution remain unknown. Methods: Anesthetized dogs were submitted to graded hemodilution (20% and 40% blood volume reductions of estimated circulating blood volume) replaced with 10% hydroxyethyl starch. The effect of angiotensin II receptor (AT-II) antagonist, candesartan, on the intestinal mucosal oxygenation was assessed by tonometric method. Results: The splanchnic blood flow, measured by transit-time flow meters, and intestinal mucosal oxygenation were maintained well during 20% blood volume reduction without AT-II antagonist. By severe blood volume reduction, however, inadequate oxygenation was observed without, but not with AT-II antagonist. Conclusions: These results suggest the protective effect of AT-II antagonist on intestinal perfusion during severe isovolemic hemodilution. Further investigation will be needed in patients undergoing major surgery with large anticipated blood loss.
Descriptors: blood and lymphatics, transport and circulation, pharmacology, isovolemic hemodilution, clinical techniques, therapeutic and prophylactic techniques.
Language of Text: Japanese.

Hirata, T., T. Funatsu, Y. Keto, M. Nakata, and M. Sasamata (2007). Pharmacological profile of ramosetron, a novel therapeutic agent for IBS. Inflammopharmacology 15(1): 5-9. ISSN: 0925-4692.
Abstract: Ramosetron is a potent and selective serotonin (5-HT)(3) receptor antagonist that has been shown to affect abnormal colonic function and abdominal pain in animals. Ramosetron (0.3 to 100 microg/kg, p.o.) has been found to significantly suppress abnormal defecation induced by conditioned-fear stress (CFS), restraint stress, corticotropin releasing factor (CRF) and 5-HT in rats and mice, and these effects were more potent than those of alosetron, cilansetron or loperamide. On the other hand, ramosetron (3,000 microg/kg, p. o., once daily for 7 days) did not inhibit normal defecation in dogs while tiquizium significantly inhibited it. Ramosetron (3 to 100 microg/kg, p. o.) also significantly prevented CFS-induced acceleration of colonic transit and CRF-induced abnormal water transport in rats, respectively. Moreover, ramosetron (0.3 to 3 microg/kg, p. o.) significantly suppressed restraint stress-induced decrease in colonic pain threshold, an effect not observed with loperamide. These results indicate that ramosetron produce beneficial clinical effects on IBS symptoms.
Descriptors: benzimidazoles pharmacology, irritable bowel syndrome drug therapy, serotonin antagonists pharmacology, abdominal pain drug therapy, benzimidazoles therapeutic use, defecation drug effects, diarrhea drug therapy, dogs, gastrointestinal transit drug effects, mice, models, animal, rats, serotonin antagonists therapeutic use.

Hirota, K., Y. Hashimoto, T. Sato, H. Yoshioka, T. Kudo, A. Matsuki, and D.G. Lambert (2001). Bronchoconstrictive and relaxant effects of lidocaine on the airway in dogs. Critical Care Medicine. 29(5): 1040-4. ISSN: 0090-3493.
Abstract: OBJECTIVE: Intravenous lidocaine commonly is used to treat ventricular arrhythmias and to attenuate reflex airway constriction and intracranial pressure elevation during airway manipulation in intensive care units. There is much controversy as to the actions of lidocaine on the airway, so the aim of this study was to compare, in detail, the actions of lidocaine with those of bupivacaine and procaine on airway caliber and the associated changes in plasma catecholamine concentrations in the dog. DESIGN: Prospective, randomized, controlled experimental in vivo and in vitro study. SETTING: A university research laboratory. SUBJECTS: Mongrel dogs. INTERVENTIONS: In the first experiment, we evaluated the effects of intravenous local anesthetics--lidocaine 0-10 mg/kg (n = 7), bupivacaine 0-2.5 mg/kg (n = 7), or procaine 0-20 mg/kg (n = 7)--on basal airway tone. In second experiment, histamine (10 microg/kg + 500 microg x kg(-1) x hr(-1), n = 6), serotonin (10 microg/kg + 500 microg x kg(-1) x hr(-1), n = 7), and methacholine (0.5 microg/kg + 300 microg x kg(-1) x hr(-1), n = 7) were infused to determine the effects of lidocaine (0-10 mg/kg) on agonist-induced bronchoconstriction. In addition, the actions of lidocaine on vagal nerve stimulation were examined (n = 7). MEASUREMENTS AND MAIN RESULTS: Bronchial cross-sectional area at the third bronchial bifurcation of dogs was monitored continuously through a fiberoptic bronchoscope. In the first experiment, all local anesthetics produced a dose-dependent decrease in basal bronchial cross-sectional area. In the second experiment, lidocaine significantly potentiated histamine and serotonin-induced bronchoconstriction. In contrast, lidocaine antagonized methacholine- and vagal nerve stimulation-induced bronchoconstriction. CONCLUSION: We have clearly demonstrated that lidocaine may produce direct bronchoconstriction and worsen some agonist-induced bronchoconstriction, but it prevents reflex airway constriction. Therefore, we suggest that this agent be used with caution in asthmatics.
Descriptors: animal model, mongrel dogs, intravenous lidocaine, ventricular arrhythmias, reflex airway constriction, intracranial pressure elevation.

Holm, R., C.J.H. Porter, G.A. Edwards, A. Mullertz, H.G. Kristensen, and W.N. Charman (2003). Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (smedds) containing structured triglycerides. European Journal of Pharmaceutical Sciences 20(1): 91-97. ISSN: 0928-0987.
NAL Call Number: 396.8 P4933
Abstract: The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-CS:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.
Descriptors: equipment apparatus devices and instrumentation, pharmacology, cannulation, clinical techniques, self microemulsifying drug delivery systems, smedds, drug delivery device.

Horais, K., V. Hruby, S. Rossi, D. Cizkova, C. Meschter, R. Dorr, and T.L. Yaksh (2003). Effects of chronic intrathecal infusion of a variant delta opioid agonist in dogs. Toxicological Sciences 71(2): 263-275. ISSN: 1096-6080.
NAL Call Number: RA1190.F8
Abstract: To define the effects of chronic spinal exposure to a highly selective variant delta opioid agonist c(DPen2,DPen5)enkephalin (DPDPE), adult beagles were prepared with chronic lumbar intrathecal catheters. Groups of dogs received intrathecal infusions (100 mul/h) of saline (vehicle), DPDPE 3 mg/ml or 6 mg/ml for 28 days. Over the 28-day period, saline or 3 mg/ml showed minimal changes in neurological function, whereas in the 6 mg/ml animals, prominent hind limb dysfunction evolved over the 28-day interval. Histopathology in control animals displayed a modest pericatheter reaction considered normal for this model. Dogs receiving DPDPE (three of four at 6 mg/ml and one of four at 3 mg/ml) but not saline (zero of four) developed large inflammatory masses (granulomas) in the intrathecal space located proximal to the catheter tip. In these masses, severe chronic inflammatory changes in combination with necrosis and fibrosis was detected. Occasional focal destruction of neuropil was detected also in the adjacent spinal cord parenchyma. These masses contained extensive accumulation of mouse antihuman macrophages (MAC)-positive inflammatory cells expressing tumor necrosis factor-alpha (TNF-alpha), revealing infiltration of macrophages, granulocytes, and monocytes. In separate animals, prepared with dual intrathecal catheters, lumbar CSF was sampled at specified time points following intrathecal bolus (3 mg/ml) and 24 h DPDPE infusion (3 mg/ml and 6 mg/ml). Steady-state cerebrospinal fluid (CSF) DPDPE levels were 18.6 +- 1.0 and 22.6 +- 4.0 mug/ml for 3 mg/ml and 6 mg/ml infusions respectively. These results indicate that this variant delta opioid agonist DPDPE produces a concentration and time-dependent formation of an intrathecal inflammatory mass.
Descriptors: neural coordination, pharmacology, toxicology, hind limb dysfunction, nervous system disease, toxicity, drug induced, intrathecal granuloma.

Humbert, B., P. Nguyen, L. Martin, H. Dumon, G. Vallette, P. Maugere, and D. Darmaun (2007). Effect of glutamine on glutathione kinetics in vivo in dogs. Journal of Nutritional Biochemistry 18(1): 10-6. ISSN: 0955-2863.
NAL Call Number: QP141.A1J54
Abstract: To determine whether glutamine affects glutathione (GSH, gamma-glutamyl-cysteinyl-glycine) metabolism, seven healthy beagle dogs received 6-h infusions of [(15)N]glutamate and [(13)C]leucine after a 3-day fast. Isotope infusions were performed during oral feeding with an elemental regimen, supplemented with either l-glutamine or an isonitrogenous amino acid mixture, on two separate days and in randomized order. Timed blood samples were obtained, and a surgical duodenal biopsy was performed after 6 h of isotope infusion. GSH fractional synthesis rate (FSR) was assessed from [(15)N]glutamate incorporation into blood and gut GSH, and duodenal protein synthesis from [(13)C]leucine incorporation into gut protein. Glutamine supplementation failed to alter erythrocyte GSH concentration (2189+/-86 vs. 1994+/-102 micromol L(-1) for glutamine vs. control; ns) or FSR (64+/-17% vs. 74+/-20% day(-1); ns). In the duodenum, glutamine supplementation was associated with a 92% rise in reduced/oxidized GSH ratio (P=.024) and with a 44% decline in GSH FSR (96+/-15% day(-1) vs. 170+/-18% day(-1); P=.005), whereas total GSH concentration remained unchanged (808+/-154 vs. 740+/-127 micromol kg(-1); P=.779). We conclude that, in dogs receiving enteral nutrition after a 3-day fast: (1) glutamine availability does not affect blood GSH, and, (2) in contrast, in the duodenum, the preserved GSH pool, along with a decreased synthesis rate, suggests that glutamine may maintain GSH pool and intestinal redox status by acutely decreasing GSH utilization.
Descriptors: glutamine pharmacology, glutathione metabolism, dogs, duodenum metabolism, enteral nutrition, erythrocytes chemistry, glutamic acid blood, glutamine blood, glutathione biosynthesis, glutathione blood, intestines metabolism, kinetics, models, animal, oxidation reduction, protein biosynthesis.

Imai, T., T. Nomura, M. Aso, and M. Otagiri (2003). Enantiospecific disposition of pranoprofen in beagle dogs and rats. Chirality 15(4): 312-317. ISSN: 0899-0042.
Abstract: The pharmacokinetic characteristics of pranoprofen enantiomer were examined and compared with the disposition of the corresponding isomer after the administration of racemic pranoprofen to beagle dogs and rats. The plasma levels of (+)-(S)-isomer were significantly higher than those of (-)-(R)-isomer in dogs and rats by either intravenous or oral administration. Although the oral bioavailability and absorption rate constant between the (-)-(R)- and (+)-(S)-form was the same, the elimination rate constant of the (+)-(S)-form was significantly lower than that of the (-)-(R)-form in both dogs and rats. This discrepancy can be explained on the basis of differences in protein binding and the metabolism of the two enantiomers. The (-)-(R)-isomer was predominantly conjugated depending on its higher free plasma level and its faster metabolic rate than the (+)-(S)-form, and thus was excreted more rapidly in the urine and bile in the form of pranoprofen glucuronide. Furthermore, a (-)-(R)- to (+)-(S)-inversion occurred to the extent of 14% in beagle dogs, but not in rats. This chiral inversion might be an important factor in the slow elimination of the (+)-(S)-form in dogs. The most efficient organ for chiral inversion was the liver, followed by kidney and intestine.
Descriptors: metabolism, pharmacology, acyl glucuronidation, chiral inversion, protein binding.

Imanishi, M., Y. Tomishima, S. Itou, H. Hamashima, Y. Nakajima, K. Washizuka, M. Sakurai, S. Matsui, E. Imamura, K. Ueshima, T. Yamamoto, N. Yamamoto, H. Ishikawa, K. Nakano, N. Unami, K. Hamada, Y. Matsumura, F. Takamura, and K. Hattori (2008). Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I. Journal of Medicinal Chemistry 51(6): 1925-44. ISSN: 0022-2623.
NAL Call Number: RS402
Abstract: A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.
Descriptors: adrenergic beta agonists pharmacology, benzoic acids pharmacology, biphenyl compounds chemistry, receptors, adrenergic, beta 3 agonists, administration, oral, adrenergic beta agonists chemical synthesis, adrenergic beta agonists chemistry, anesthesia, benzoic acids chemical synthesis, benzoic acids chemistry, biological availability, blood pressure drug effects, carbachol antagonists and inhibitors, carbachol pharmacology, dogs, drug design, drug evaluation, preclinical, injections, intravenous, models, animal, molecular structure, stereoisomerism, structure activity relationship, time factors.

Ishida, S., A. Takeuchi, T. Azami, K. Sobue, H. Sasano, H. Katsuya, and J.A. Fisher (2007). Cardiac output increases the rate of carbon monoxide elimination in hyperpneic but not normally ventilated dogs. Journal of Anesthesia 21(2): 181-6. ISSN: 0913-8668.
Abstract: PURPOSE: The very high solubility of carbon monoxide (CO) in blood suggests that its elimination depends predominantly on ventilation and not perfusion. Nevertheless, hyperventilation is not used for CO elimination because of the adverse effects of hypocapnia. With isocapnic hyperpnea (IH), ventilation can be increased considerably without hypocapnia. This raises the issue of whether CO elimination is limited by perfusion during IH. We studied the effect of increasing cardiac output on t1/2, the half-time of decline of blood carboxyhemoglobin concentration ([COHb]), during normal ventilation (NV) and during IH. METHODS: After ethics approval was received, 13 pentobarbital-anesthetized ventilated dogs were exposed to CO to increase their [COHb]. They were then ventilated with NV or IH. At each level of ventilation, dogs were randomly assigned to treatment with dobutamine (to increase cardiac output) or to no dobutamine treatment. After the return of [COHb] to control levels, each dog was re-exposed to CO and treated with the same ventilatory mode, but the alternative inotropic treatment. RESULTS: Gas exchange, [COHb], and hemodynamic measures were recorded during the study. Cardiac index values in the IH group were 4.1 +/- 0.5 and 8.2 +/- 1.2 l.min(-1).m(-2) without and with dobutamine infusion, respectively. Dobutamine infusion was associated with a reduction in t1/2 from 20.3 +/- 3.6 to 16.9 +/- 2.4 min (P = 0.005) in the IH group, but no change in the NV group. CONCLUSION: These findings suggest that CO elimination during IH treatment is limited at least partly by pulmonary blood flow and may therefore be further augmented by increasing cardiac output.
Descriptors: carbon monoxide metabolism, carboxyhemoglobin metabolism, cardiac output physiology, hyperventilation physiopathology, respiratory physiological phenomena drug effects, cardiotonic agents pharmacology, dobutamine pharmacology, dogs, models, animal.

Ishizaka, T., A. Takahara, H. Iwasaki, Y. Mitsumori, H. Kise, Y. Nakamura, and A. Sugiyama (2008). Comparison of electropharmacological effects of bepridil and sotalol in halothane-anesthetized dogs. Circulation Journal Official Journal of the Japanese Circulation Society 72(6): 1003-11. ISSN: 1346-9843.
Abstract: BACKGROUND: Bepridil is known to have a multiple ion channel-blocking property in the heart, which has been applied for the treatment of atrial fibrillation and drug-refractory ventricular tachyarrhythmias. In this study, the electro-pharmacological effects of bepridil were compared with those of dl-sotalol, a representative class III antiarrhythmic drug, using the halothane-anesthetized canine model. METHODS AND RESULTS: Cardiovascular and electrophysiological variables were measured under the halothane anesthesia. Intravenous administration of bepridil (0.3 mg/kg, n=4) delayed the intraventricular conduction and prolonged the ventricular effective refractory period, whereas dl-sotalol (0.3 mg/kg, iv, n=4) inhibited atrioventricular conduction and prolonged the atrial and ventricular effective refractory period. The additional administration of 10 times the higher dose of bepridil or dl-sotalol (ie, 3 mg/kg, iv, n=4 for each group) decreased blood pressure, suppressed ventricular contraction and sinus automaticity, and prolonged the atrial and ventricular effective refractory period and monophasic action potential duration, in addition to the effects of the low dose. CONCLUSIONS: The electropharmacological effects of bepridil and dl-sotalol were similar, although their potency for each cardiovascular variable varied significantly. These findings can be useful when selecting these drugs according to the pathophysiological condition of a patient.
Descriptors: adrenergic beta antagonists pharmacology, bepridil pharmacology, heart conduction system drug effects, sotalol pharmacology, vasodilator agents pharmacology, adrenergic beta antagonists blood, anesthetics, inhalation, atrioventricular node drug effects, bepridil blood, bundle of his drug effects, dogs, dose response relationship, drug, electrocardiography drug effects, halothane, models, animal, myocardial contraction drug effects, pacemaker, artificial, sinoatrial node drug effects, sotalol blood, vasodilator agents blood.

Iyer, R.A., B. Malhotra, S. Khan, J. Mitroka, S.J. Bonacorsi, S.C. Waller, J.K. Rinehart, and K. Kripalani (2003). Comparative biotransformation of radiolabeled (14c)omapatrilat and stable-labeled (13c2)omapatrilat after oral administration to rats, dogs, and humans. Drug Metabolism and Disposition 31(1): 67-75. ISSN: 0090-9556.
NAL Call Number: RM301.35.D78
Abstract: Omapatrilat, a novel vasopeptidase inhibitor, is under development for the treatment of hypertension and congestive heart failure. This study describes the comparative biotransformation of radiolabeled (14C)- and stable-labeled (13C2)omapatrilat after administration of single oral doses to rats, dogs, and humans. The metabolites were identified by a combination of methods including reduction, hydrolysis, and comparison of high performance liquid chromatography retention times with those of the synthetic standards. Urinary metabolites were further characterized by liquid chromatography tandem mass spectrometry analysis. Prominent metabolites identified in human plasma, which were also present in rat and dog plasma, were S-methyl omapatrilat and S-2-thiomethyl-3-phenylpropionic acid. Omapatrilat accounted for only a small portion of the extractable radioactivity in plasma in all three species. A portion of the plasma radioactivity was unextractable in all three species (27-53%). The majority of unextractable radioactivity in plasma was characterized after dithiothreitol reduction to be omapatrilat and (S)-2-thio-3-phenylpropionic acid, both apparently bound to plasma proteins by reversible disulfide bonds. The major human urinary metabolites were the amine hydrolysis product, diasteromeric sulfoxide of (S)-2-thiomethyl-3-phenylpropionic acid, acyl glucuronide of S-methyl omapatrilat, and S-methyl omapatrilat. The minor metabolites were acyl glucuronide of (S)-2-thiomethyl-3-phenylpropionic acid, L-cysteine mixed disulfide of omapatrilat, diastereomers of S-methyl sulfoxide of omapatrilat, and S-methyl omapatrilat ring sulfoxide. The metabolic profiles of dog and human urine were qualitatively similar whereas rat urine showed only metabolites arising from hydrolysis of omapatrilat. Unchanged omapatrilat was not found in rat, dog, or human urine samples indicating extensive metabolism in vivo.
Descriptors: pharmacology, comparative biotransformation, rat, dog, human, omapatrilat, novel vasopeptidase inhibitor, hypertension, congestive heart failure.

Jin, L., I.W. Chen, M. Chiba, and J.H. Lin (2003). Interaction with indinavir to enhance systemic exposure of an investigational hiv protease inhibitor in rats, dogs and monkeys. Xenobiotica 33(6): 643-654. ISSN: 0049-8254.
NAL Call Number: QD415.A1X4
Abstract: 1. The use of a beneficial interaction between indinavir and compound A, a potent investigational HIV protease inhibitor to enhance systemic exposure of compound A, was investigated. 2. When administrated alone, compound A underwent extensive hepatic first-pass metabolism in rats and monkeys, resulting in low oral bioavailability. 3. In vitro studies with liver microsomes revealed that compound A metabolism was mediated exclusively by CYP3A enzymes in rats, dogs and monkeys. Indinavir, which also was metabolized predominantly by CYP3A enzymes, extensively inhibited compound A metabolism in microsomes, whereas compound A showed weak inhibitory potency on indinavir metabolism. 4. Consistent with in vitro observations, co-administration of the two compounds resulted in a 17-fold increase in oral AUC of compound A in rats owing to the inhibition of metabolism of compound A by indinavir, whereas compound A did not affect indinavir metabolism as indicated by the unchanged indinavir AUC. Similarly, the systemic exposure of compound A in dogs and monkeys was increased substantially following oral co-administration with indinavir by 7- and > 50-fold, respectively. 5. Enhancement in compound A systemic exposure by indinavir in humans, as predicted based on the in vivo animal and in vitro human liver microsomal data, was confirmed in subsequent clinical studies.
Descriptors: digestive system, ingestion and assimilation, metabolism, pharmacology, extensive hepatic first pass metabolism.

Julian, L.D., Z. Wang, T. Bostick, S. Caille, R. Choi, M. DeGraffenreid, Y. Di, X. He, R.W. Hungate, J.C. Jaen, J. Liu, M. Monshouwer, D. McMinn, Y. Rew, A. Sudom, D. Sun, H. Tu, S. Ursu, N. Walker, X. Yan, Q. Ye, and J.P. Powers (2008). Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model. Journal of Medicinal Chemistry 51(13): 3953-60.
NAL Call Number: RS402
Abstract: We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Descriptors: 11 beta hydroxysteroid dehydrogenase type 1 antagonists and inhibitors, benzamides administration and dosage, benzamides chemical synthesis, enzyme inhibitors administration and dosage, enzyme inhibitors chemical synthesis, 11 beta hydroxysteroid dehydrogenase type 1 chemistry, 11 beta hydroxysteroid dehydrogenase type 1 metabolism, administration, oral, benzamides chemistry, benzamides metabolism, cell line, crystallography, x ray, dogs, enzyme inhibitors chemistry, enzyme inhibitors metabolism, macaca fascicularis, models, animal, models, molecular, molecular structure, rats, structure activity relationship.

Kador, P.F., K. Blessing, and M. Wyman (2003). The results of combretastatin in galactose - fed dogs with diabetes - like proliferative retinopathy. Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, FL, USA; May 04-08, 2003,
Abstract: Purpose: Combretastatin A-4 (CA4P) is a vascular targeting agent that has been reported to be capable of destroying newly formed capillary endothelial cells in growing vessels. The net effect of this drug has been to rapidly shut off blood flow in newly growing vessels and, as a result, regress neovascularization. The purpose of this study was to determine whether retinal neovascularization which results in altered retinal vessel blood flow and retinal permeability in the long-term galactose-fed dog can be halted with CA4P. Methods: All experiments conform to the ARVO Resolution on the Use of Animals in Research and NIH ACUC Guidelines. Eight beagles fed 30% galactose diet for 80-104 months and four age-matched control dogs were surgically made aphakic. Following recovery the dogs were divided into two groups each containing 4 galactose-fed dogs and 2 age-matched controls dogs with each group receiving CA4P either as sub-Tenon's injections administered at the corneoscleral junction or intravitreal injections. Six weeks after initial CA4P treatment all dogs also received systemic (IV) injections of CA4P. The extent of neovascularization and affect of CA4P administration were monitored by fluorescein angiography and color and monochromatic fundus photography at 2-week intervals. Results: Although CA4P was well tolerated by the healthy eyes of the control animals its administration to galactose-fed dogs was associated with corneal edema and increases in IOP after sub-Tenon's and intraocular injections. All galactose-fed dogs demonstrated retinal neovascular lesions and these were not ameliorated by either sub-Tenon's, intravitreal or systemic CA4P administration. Conclusions: Neovascularization in this animal model progresses over a period of years similar to that observed clinically. The failure of CA4P to ameliorate neovascularization suggests that chronic, long-term administration is required to destroy the slowly growing retinal endothelial cells.
Descriptors: cardiovascular system, transport and circulation, metabolism, pharmacology, sense organs, sensory reception, aphakia, eye disease, diabetes like proliferative retinopathy, endocrine disease, pancreas, metabolic disease, retinal blood vessel blood flow, retinal neovascularization.

Kaewsakhorn, T., M. Gower, W. Kisseberth, C. Capen, M. Calverley, and N. Inpanbutr (2004). Effects of calcitriol and medium chain triglyceride (mct) on cell growth of the canine transitional cell carcinoma of the urinary bladder (tcc) in vitro. FASEB Journal 18(4-5): Abst. 68.8. ISSN: 0892-6638.
NAL Call Number: QH301.F3
Descriptors: calcitriol , cell biology, cell proliferation, pharmacology, tumor biology, bladder transitional cell carcinoma, neoplastic disease, urologic disease, therapy, western blot, genetic techniques, laboratory techniques, drug regimen.

Kangasniemi, M., R.J. Stafford, R.E. Price, E.F. Jackson, and J.D. Hazle (2003). Dynamic gadolinium uptake in thermally treated canine brain tissue and experimental cerebral tumors. Investigative Radiology 38(2): 102-107. ISSN: 0020-9996.
Abstract: RATIONALE AND OBJECTIVES: Thermal coagulation of cerebral tumors induces reactive changes within adjacent brain tissue, which appear as Gd-DTPA enhancement in MR images. This makes assessment of therapeutic success difficult to establish radiographically because the reactive changes can mimic residual tumor. Dynamic Gd-DTPA uptake curves in reactive tissue and tumor were investigated to assess the utility of contrast enhanced (CE)-dynamic MRI to distinguish reactive changes from residual tumor in a canine model. MATERIALS AND METHODS: Cerebral thermal necrosis was induced using a 980 nm laser in 11 dogs with intracerebral transmissible venereal tumors (TVTs). A fast spin-echo T1-weighted imaging sequence was used for CE-dynamic MRI. Gd-DTPA uptake data were acquired with 10-second temporal resolution and for untreated TVTs for reactive tissue using a sigmoidal-exponential model. RESULTS: Characteristic gadolinium uptake curves were measured and characterized for reactive brain tissue, and untreated and treated TVTs. Both early and delayed dynamic responses were significantly different in reactive brain tissue compared with TVT. CONCLUSION: Reactive thermal changes in otherwise normal brain tissue can be distinguished from residual tumor after cerebral thermal therapy using CE -dynamic MRI.
Descriptors: nervous system, neural coordination, pharmacology, tumor biology, cerebral thermal necrosis, nervous system disease, intracerebral transmissible venereal tumor, neoplastic disease, radiotherapy, contrast enhanced dynamic magnetic resonance imaging, clinical techniques, diagnostic techniques, imaging and microscopy techniques, fast spin echo t1 weighted imaging, sigmoidal exponential model, mathematical and computer techniques, thermal coagulation therapy, therapeutic and prophylactic techniques, reactive thermal change.

Kast, R., H. Schirok, S. Figueroa Perez, J. Mittendorf, M.J. Gnoth, H. Apeler, J. Lenz, J.K. Franz, A. Knorr, J. Hutter, M. Lobell, K. Zimmermann, K. Munter, K.H. Augstein, H. Ehmke, and J.P. Stasch (2007). Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. British Journal of Pharmacology 152(7): 1070-80. ISSN: 0007-1188.
NAL Call Number: 396.8 B77
Abstract: BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.
Descriptors: cardiovascular system drug effects, diamines pharmacology, protein kinase inhibitors pharmacology, pyrimidines pharmacology, rho associated kinases antagonists and inhibitors, administration, oral, apoptosis regulatory proteins antagonists and inhibitors, apoptosis regulatory proteins genetics, apoptosis regulatory proteins metabolism, binding sites drug effects, blood pressure drug effects, calcium calmodulin dependent protein kinases antagonists and inhibitors, calcium calmodulin dependent protein kinases genetics, calcium calmodulin dependent protein kinases metabolism, cells, cultured, computer simulation, dogs, dose response relationship, drug, injections, intravenous, mice, models, animal, models, molecular, organ culture techniques, phosphorylation, polymerase chain reaction methods, protein kinase inhibitors administration and dosage, protein kinase inhibitors chemistry, rabbits, rats, rats, inbred shr, rats, wistar, recombinant proteins antagonists and inhibitors, recombinant proteins genetics, recombinant proteins metabolism, time factors, vasodilator agents administration and dosage, vasodilator agents chemistry, vasodilator agents pharmacology, rho associated kinases genetics, rho associated kinases metabolism.

Kawase, A., T. Ikeda, K. Nakazawa, T. Ashihara, T. Namba, T. Kubota, K. Sugi, and H. Hirai (2003). Widening of the excitable gap and enlargement of the core of reentry during atrial fibrillation with a pure sodium channel blocker in canine atria. Circulation 107(6): 905-910. ISSN: 0009-7322.
NAL Call Number: RC681.A1 C8
Abstract: Background: This study aimed to assess the effects of pilsicainide, a pure sodium channel blocker, on electrophysiological action and wavefront dynamics during atrial fibrillation (AF). Methods and Results: In a newly developed model of isolated, perfused, and superfused canine atria (n=12), the right and left endocardia were mapped simultaneously by use of a computerized mapping system. AF was induced with 1 to 5 mumol/L acetylcholine. The antifibrillatory actions of pilsicainide on AF cycle length (AFCL), refractory period (RP), conduction velocity (CV), excitable gap (EG), and the core of the mother rotor were studied. The RP was defined as the shortest coupling interval that could capture the fibrillating atrium. The EG was estimated as the difference between the AFCL and RP. At baseline, multiple wavefronts were observed. After 2.5 mug/mL infusion of pilsicainide, all preparations showed irregular activity, and AF was terminated in 2 preparations. The AFCL and RP were prolonged, and CV was decreased significantly. The EG was widened (147%; P<0.01), and the core perimeter was increased (100%; P<0.01). Increasing the dosage either terminated AF (6 preparations) or converted to organized activity (ie, atypical atrial flutter) (4 preparations). On the maps, all "unorganized" AFs were terminated with the excitation of the core of the mother rotor by an outside wavefront, whereas in preparations with atrial flutter, pilsicainide did not terminate its activity. Conclusions: Widening of the EG by pilsicainide facilitates the excitation of the core of the mother rotor, leading to the termination of AF. In some experiments, pilsicainide converts AF to persistent atrial flutter.
Descriptors: cardiovascular system, transport and circulation, pharmacology, atrial fibrillation, heart disease, drug therapy, pathology, electrophysiology, clinical techniques, conduction velocity, cycle length, excitable gap widening, reentry core enlargement, refractory period, wavefront dynamics.

Kent, M.S., B.R. Madewell, G. Dank, R. Dick, S.D. Merajver, and G.J. Brewer (2004). An anticopper antiangiogenic approach for advanced cancer in spontaneously occurring tumors using tetrathiomolybdate: a pilot study in a canine animal model. Journal of Trace Elements in Experimental Medicine 17(1): 9-20. ISSN: 0896-548X.
NAL Call Number: QP534.J68
Abstract: In this pilot study, 13 dogs of various breeds and ages with a variety of advanced tumors were treated with the antiangiogenic copper complexing drug tetrathiomolybdate. Dose escalations were performed to determine the safe and effective dose in dogs. The study was designed to last for a 6-month period for each dog entered. Dogs were examined weekly for the first 3 months and then every other week for the next 3 months. Complete blood count, serum biochemistry panel, and measurement of serum ceruloplasmin (Cp) content were conducted at each visit to monitor response to drug administration. Serum Cp was used as a surrogate marker of copper status. The owner reported toxicity at each visit. The dog was examined for physical abnormalities. Tumor measurements were completed every 2 weeks using direct measurements of the tumor with calipers in three planes or by direct measurements of the tumor using radiographic or ultrasonographic images in two planes. Tumor response was evaluated only after dogs achieved a 4-week reduction in their serum Cp content. Tumor responses were defined as either disease stabilization or reduction in tumor volume. Nine dogs achieved Cp reduction. Of those dogs, five had no response to treatment, whereas four dogs had tumor responses after Cp reduction, characterized as either disease stabilization or reduction in tumor volume, for the remainder of the study period. There was only mild self-limiting toxicity with use of the drug.
Descriptors: pharmacology, veterinary medicine, medical sciences, advanced cancer, neoplasms, neoplastic disease, drug therapy, spontaneously occurring tumor.

Kerbaul, F., B. Rondelet, S. Motte, P. Fesler, I. Hubloue, P. Ewalenko, R. Naeije, and S. Brimioulle (2004). Effects of norepinephrine and dobutamine on pressure load-induced right ventricular failure. Critical Care Medicine 32(4): 1035-40. ISSN: 0090-3493.
Abstract: OBJECTIVE: A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects norepinephrine and dobutamine on RV-PA coupling in this model of RV failure. DESIGN: Prospective, controlled, randomized animal study. SETTING: University research laboratory. SUBJECTS: Twenty-two anesthetized dogs. INTERVENTIONS: Animals underwent transient (90-min) PA constriction to induce persistent RV failure. They were randomly assigned to control, norepinephrine, or dobutamine group. Norepinephrine was administered at 0.1 and 0.5 microg x kg x min or dobutamine at 5 and 10 microg x kg x min. MEASUREMENTS AND MAIN RESULTS: We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We also measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. The transient PA constriction persistently increased PA resistance and elastance, increased Ea from 0.8+/-0.1 to 2.7+/-0.3 mmHg/mL, decreased Ees from 1.1+/-0.1 to 0.5+/-0.1 mm Hg/mL, and decreased Ees/Ea from 1.2+/-0.1 to 0.2+/-0.1. Norepinephrine restored arterial pressure, increased RV contractility, and increased but did not normalize RV-PA coupling and cardiac output. Dobutamine restored arterial pressure, markedly increased RV contractility, and normalized RV-PA coupling and cardiac output. Compared with norepinephrine, dobutamine decreased PA resistance and elastance and increased RV contractility and RV-PA coupling. CONCLUSIONS: A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Dobutamine restores RV-PA coupling and cardiac output better than norepinephrine because of its more pronounced inotropic effect.
Descriptors: animal model, pulmonary arterial (PA) pressure, right ventricular (RV) contractility, cardiac output, norepinephrine, dobutamine.

Kim, J.T., K.Y. Rhee, J.H. Bahk, S.H. Do, Y.J. Lim, H. Ko, and K.H. Lee (2003). Continuous mixed venous oxygen saturation, not mean blood pressure, is associated with early bupivacaine cardiotoxicity in dogs. Canadian Journal of Anesthesia 50(4): 376-381. ISSN: 0832-610X.
Abstract: Purpose: To investigate changes of continuous mixed venous oxygen saturation (cSvO2) and mean arterial blood pressure (MBP) in dogs with bupivacaine-induced cardiac depression. Methods: Bupivacaine was infused into pentobarbital-anesthetized mongrel dogs (n=8) at a rate of 0.5 mgcntdotkg-1cntdotmin-1 until the MBP was 40 mmHg or less (end of bupivacaine infusion; BIE). The infusion time was divided into the early period, first 30 min of bupivacaine infusion and the late period, which was from 30 min of bupivacaine infusion until BIE. cSvO2 was monitored using a fibreoptic pulmonary artery catheter, and MBP and cardiac output (CO) were measured every ten minutes after the initiation of bupivacaine infusion. Arterial blood gas, serum electrolyte and bupivacaine concentration were measured simultaneously. The relationships between CO and cSvO2, and of CO vs MBP were compared by regression analysis in the early and late periods. Results: The Pearson's correlation coefficients between CO and cSvO2 were 0.782 (P=2.1X10-7) in the early period and 0.824 (P=1.3X10-6) in the late period. The correlation coefficients between CO and MBP were 0.019 (P=0.921) in the early period and 0.799 (P=4.8X10-6) in the late period. Conclusions: cSvO2, but not MBP, is associated with CO changes in bupivacaine-induced cardiac depression during the early period of bupivacaine intoxication. Decrease of MBP with low cSvO2 observed during the late period might imply severe cardiac depression induced by bupivacaine infusion.
Descriptors: cardiovascular system, transport and circulation, pharmacology, toxicology, bupivacaine induced cardiac depression, heart disease, toxicity, continuous mixed venous oxygen saturation, bupivacaine induced cardiotoxicity association, mean blood pressure.

Kimura, K., M. Tabo, K. Mizoguchi, A. Kato, M. Suzuki, Z. Itoh, S. Omura, and H. Takanashi (2007). Hemodynamic and electrophysiological effects of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin in a halothane-anesthetized canine model. Journal of Toxicological Sciences 32(3): 231-9. ISSN: 0388-1350.
NAL Call Number: RA1190
Abstract: Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.
Descriptors: blood pressure drug effects, erythromycin analogs and derivatives, gastrointestinal agents toxicity, gastrointestinal motility drug effects, heart rate drug effects, long qt syndrome chemically induced, torsades de pointes chemically induced, ventricular function, left drug effects, action potentials drug effects, anesthesia, general, anesthetics, inhalation, cardiac pacing, artificial, cisapride toxicity, dogs, dose response relationship, drug, electrocardiography, erythromycin administration and dosage, erythromycin blood, erythromycin toxicity, gastrointestinal agents administration and dosage, gastrointestinal agents blood, halothane, infusions, intravenous, long qt syndrome physiopathology, models, animal, risk assessment, time factors, torsades de pointes physiopathology, ventricular pressure drug effects.

Kita, T., K. Kubo, I. Narushima, S. Matsumura, Y. Yonetani, and T. Nakashima (1996). Behavioral effects and role of endothelin in a canine subarachnoid model. Japanese Journal of Pharmacology 71(SUPPL. 1): 91P. ISSN: 0021-5198.
Descriptors: behavior, cardiovascular system, transport and circulation, endocrine system, chemical coordination and homeostasis, nervous system, neural coordination, animal model, basilar artery caliber, behavioral effect, cerebral vasospasm, endocrine system, endothelin 1, meeting poster, meningeal sign, nervous system disease, severe ataxia, subarachnoid hemorrhage, vascular disease

Kucukhuseyin, C. (2003). Cardiovascular effects of intravenous pentazocine and cyclazocine in conscious, curarized-conscious, and anesthetized dogs. Journal of Basic and Clinical Physiology and Pharmacology 14(3): 235-255. ISSN: 0792-6855.
Abstract: The cardiovascular effects of intravenous pentazocine and cyclazocine in dogs were studied under conscious, curarized-conscious (paralyzed by gallamine), and anesthetized states. In the conscious state, blood pressure and heart rate were dose-dependently increased by pentazocine (1, 2, 3 mg/kg) and to a lesser extent by cyclazocine (0.3 mg/kg). In all subsequent experiments on dogs, the results were obtained using 3 mg/kg pentazocine and 0.3 mg/kg cyclazocine. Pentazocine accelerated breathing, peaking at about 10 min, whereas cyclazocine reduced breathing to a minimum in 1 min, followed by a gradual recovery thereafter. In the curarized-conscious state, the blood pressure response to pentazocine was biphasic, namely an initial decrease followed by an increase; chronotrophic activity was stimulated. Pretreatment with either ganglionic or alpha andrenergic blocking agents not only significantly antagonized the pressory responses to the drug but also potentiated the initial decreases in blood pressure and unmasked a bradycardic component, but these parameters were not altered by 0.3 mg/kg naxalone. In open-chest anesthetized dogs, blood pressure, heart rate, contractility, and mean peripheral vascular resistance were simultaneously decreased by both pentazocine and cyclazocine, initially accompanied by increases in aortic blood flow. During the later stages of drug action, only the blood pressure and contractility were increased above control levels (biphasic effect). A comparison of blood pressure and heart rate responses to pentazocine in dogs kept under differing experimental conditions revealed that conscious dogs were more sensitive than curarized conscious and anesthetized animals to pentazocine action. In isolated guinea pig atria, the effect of adrenaline (0.1, 0.3, or 1 mg/mL) on the spontaneous breathing rate was significantly augmented by 10 mg/mL pentazocine (p<0.02 for 0.3 g/mL; p<0.01 for 0.1 g/mL adrenaline). In dogs, however, adrenaline (1 mg/kg)-induced increases in heart contractility, aortic blood flow, and blood pressure remained almost unaltered in the presence of pentazocine. We concluded that the above mentioned cardiovascular responses to pentazocine and cyclazocine are a consequence of the sum of the two following opposing effects: (i) an indirect reflex activation of sympathetic neuromediation in the periphery, and (ii) a direct membrane effect on the heart leading to bradycardia and a depression in myocardial contractility.
Descriptors: cardiovascular system, transport and circulation, pharmacology, curarization, experimental surgical techniques, laboratory techniques, blood pressure, conscious state, heart rate.

Kumagai, K., H. Nakashima, N. Gondo, and K. Saku (2003). Antiarrhythmic effects of jtv-519, a novel cardioprotective drug, on atrial fibrillation/flutter in a canine sterile pericarditis model. Journal of Cardiovascular Electrophysiology 14(8): 880-884. ISSN: 1045-3873.
Abstract: Introduction: A new cardioprotective drug, JTV-519, blocks Na+ current and inwardly rectifying K+ current and inhibits Ca2+ current. However, its role in atrial electrophysiology is unknown. We investigated the antiarrhythmic effects of JTV-519 on atrial fibrillation/flutter in the canine sterile pericarditis model. Methods and Results: In nine dogs with sterile pericarditis, 38 episodes of sustained (>30 sec) atrial fibrillation (8 dogs) and 24 episodes of sustained atrial flutter (7 dogs) were induced by rapid atrial pacing. When atrial fibrillation or atrial flutter was sustained >15 minutes, it was cardioverted and reinduced. The inducibility of atrial fibrillation/flutter, the atrial effective refractory period, and the intra-atrial conduction time were compared before and after the continuous infusion of JTV-519 (0.03 mg/kg/min). JTV-519 significantly decreased the mean number of sustained atrial fibrillation episodes (from 4.2+-2.9 to 0+-0, P<0.01). In contrast, atrial flutter was still inducible in 4 dogs after JTV-519 (from 2.7+-2.5 to 1.6+-2.1, P=NS). JTV-519 significantly prolonged effective refractory period (from 123+-18 to 143+-14 msec, from 127+-18 to 151+-12 msec, and from 132+-13 to 159+-9 msec at basic cycle lengths of 200, 300, and 400 msec, respectively, P<0.01), but it did not affect the intra-atrial conduction time (from 47+-11 msec to 48+-11 msec, P=NS). Conclusion: JTV-519 had significant protective effects on atrial fibrillation in the canine sterile pericarditis model, mainly by increasing effective refractory period, suggesting that it may have potential as a novel antiarrhythmic agent for atrial fibrillation.
Descriptors: cardiovascular system, transport and circulation, pharmacology, atrial fibrillation, heart disease, drug therapy, atrial flutter, heart disease, drug therapy, sterile pericarditis, electrophysiology, clinical techniques, atrial effective refractory period, calcium ion current, intra atrial conduction time, inwardly rectifying potassium ion current, sodium ion current.

Leach, J.K., E. Patterson, and E.A. O'rear (2004). Encapsulation of a plasminogen activator speeds reperfusion, lessens infarct and reduces blood loss in a canine model of coronary artery thrombosis. Thrombosis and Haemostasis 91(6): 1213-1218. ISSN: 0340-6245.
Abstract: In the present study, a polymer-encapsulated plasminogen activator was investigated as an alternative to restore blood flow more effectively than free plasminogen activator. While current fibrinolytic agents have limited efficacy, attributable to delayed onset of sustained reperfusion and bleeding complications, encapsulated plasminogen activators have shown promise in addressing these shortcomings. A polymer-encapsulated plasminogen activator could offer an effective formulation with a prolonged shelf-life. In this study, coronary artery thrombosis was produced in the anesthetized dog by the injection of thrombin + whole blood, and then one of five randomly selected formulations was administered intravenously: saline, blank microcapsules, free streptokinase (FREE SK), streptokinase and blank microcapsules (FREE SK + BLANK), or streptokinase entrapped in polymer microcapsules (MESK). MESK significantly accelerated the time to reperfusion compared to FREE SK or FREE SK + BLANK. Additionally, substantial reductions were observed in residual clot mass, infarct mass, reocclusion episodes, fibrinogen depletion and blood loss with MESK compared to FREE SK. The results of this study demonstrate that MESK accelerates thrombolysis and the restoration of blood flow compared to identical dosages of FREE SK while also reducing systemic fibrinogenolysis and blood loss. Microencapsulation may produce an improved dosage form for restoring arterial blood flow and reducing bleeding complications with thrombolytic therapy.
Descriptors: cardiovascular system, transport and circulation, pharmacology, coronary artery thrombosis, heart disease, vascular disease, therapy .

Lee, B.H., H.W. Seo, and S.E. Yoo (2004). Cardioprotective effects of (2s,3r,4s)-n'-benzyl-n''-cyano-n-(3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2h-benzopyran-4-yl)-guanidine (kr-31372) in rats and dogs. Pharmacology 70(2): 74-82. ISSN: 0031-7012.
NAL Call Number: RM1.P473
Abstract: The cardioprotective effects of (2S,3R,4S)-N'-benzyl-N''-cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) were evaluated against ischemic/reperfusion injury in isolated rat hearts in vitro and in anesthetized rats and dogs in vivo. In isolated perfused rat hearts subjected to a 30-min global ischemia/30-min reperfusion, KR-31372 (1-10 muM) significantly improved severe contracture (end-diastolic pressure and time to contracture), markedly reduced reperfusion lactate dehydrogenase release, and enhanced the recovery of reperfusion contractile function (left ventricular developed pressure and double product) in a concentration-dependent manner compared with the vehicle-treated group. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, intravenous KR-31372 dose-dependently reduced infarct size from 58.6% to 48.5, 48.1 and 39.6% at 0.3, 1.0 and 3.0 mg/kg, respectively (p<0.05). In anesthetized beagle dogs that underwent a 1.5-hour occlusion followed by a 5-hour reperfusion, KR-31372 (2 mg/kg, i.v.) markedly reduced infarct size from 57.0% in controls to 28.0% (p<0.05). The cardioprotective effects of KR-31372 on contractile function in globally ischemic rat hearts and on reperfusion injury in anesthetized rats were significantly reversed by pretreatment with selective adenosine triphosphate-sensitive potassium (KATP) channel blockers, sodium 5-hydroxydecanoate and glibenclamide. Taken together, these results indicate that KR-31372 possesses potent cardioprotective effects in rats and dogs and its effects may be mediated by activation of mitochondrial KATP channels.
Descriptors: cardiovascular system, transport and circulation, pharmacology, ischemia, reperfusion injury, vascular disease, drug therapy, pathology, cardioprotection, double product, end diastolic pressure, left ventricular developed pressure, severe contracture.

Lee, R.S., C.S. Kuhr, G.E. Sale, E. Zellmer, W.J. Hogan, R. Storb, and M.T. Little (2003). Fty720 does not abrogate acute graft-versus-host disease in the dog leukocyte antigen-nonidentical unrelated canine model. Transplantation 76(8): 1155-1158. ISSN: 0041-1337.
NAL Call Number: QP89.T73
Abstract: Background. Acute graft-versus-host disease (GVHD) remains a significant impediment to successful hematopoietic stem-cell transplantation (HSCT). Here, we examined the effectiveness of 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride (FTY720), an immunosuppressant that retraffics activated lymphocytes to secondary lymphoid organs, for the treatment of acute GVHD in an established dog leukocyte antigen-nonidentical unrelated canine HSCT model. Methods. Dogs were given HSCT after conditioning with 920 cGy total body irradiation. The dogs received methotrexate 0.4 mg/kg/day on days 1, 3, 6, and 11 and FTY720 (5 mg/kg/day orally) after developing GVHD. Results. Five of six dogs achieved engraftment, developed acute GVHD, and were treated with FTY720. FTY720 resulted in a profound decrease in lymphocytes and a temporary mitigation of clinical GVHD; however, GVHD recurred in all dogs. Four of five dogs were euthanized because of severe GVHD and the fifth because of severe inanition associated with moderate GVHD. Conclusions. Compared with controls, treatment of GVHD with FTY720 did not control this complication or significantly increase survival.
Descriptors: blood and lymphatics, transport and circulation, methods and techniques, pharmacology, acute graft vs host disease, immune system disease, hematopoietic stem cell transplantation, laboratory techniques, dog leukocyte antigen nonidentical unrelated donor, engraftment .

Lentz, K.A., M. Quitko, D.G. Morgan, J.E.J. Grace, C. Gleason, and P.H. Marathe (2007). Development and validation of a preclinical food effect model. Journal of Pharmaceutical Sciences 96(2): 459-72. ISSN: 0022-3549.
NAL Call Number: 396.8 J825
Abstract: A preclinical canine model capable of predicting a compound's potential for a human food effect was developed. The beagle dog was chosen as the in vivo model. A validation set of compounds with known propensities for human food effect was studied. Several diets were considered including high-fat dog food and various quantities of the human FDA meal. The effect of pentagastrin pretreatment was also investigated. The high-fat dog food did not predict human food effect and was discontinued from further evaluation. The amount of FDA meal in the dog was important in the overall prediction of the magnitude of human food effect. Fed/fasted Cmax and AUC ratios using a 50-g aliquot of the FDA meal in the dog were in the closest qualitative agreement to human data. Pentagastrin pretreatment did not affect the AUC in the fed state, but increased the fasted AUC for weakly basic compounds. Pentagastrin pretreatment and a 50-g aliquot of the FDA meal in the dog predicted the human food effect for a validation set of compounds. This model, which is intended for compound screening, will be helpful for determining food effect as a liability when compounds progress from discovery to clinical development. Copyright (c) 2006 Wiley-Liss, Inc.
Descriptors: dietary fats, drug evaluation, preclinical methods, food drug interactions, models, animal, pentagastrin pharmacology, biological availability, dogs, hiv protease inhibitors pharmacokinetics, hydroxymethylglutaryl coa reductase inhibitors pharmacokinetics, oligopeptides pharmacokinetics, pravastatin pharmacokinetics, pyridines pharmacokinetics.

Lian, X.Y. and J.L. Stringer (2004). Inhibition of aconitase in astrocytes increases the sensitivity to chemical convulsants. Epilepsy Research 60(1): 41-52. ISSN: 0920-1211.
Descriptors: behavior, nervous system, neural coordination, pharmacology, epilepsy, nervous system disease, neuronal damage, injury, nervous system disease, seizure, wet dog shakes, nervous system disease, drug induced, etiology, pathology, immunohistochemistry, immunologic techniques, laboratory techniques, silver staining, genetic techniques, chemical convulsant sensitivity.

Liu, J.C., P.K. Kao, P. Chan, Y.H. Hsu, C.C. Hou, G.S. Lien, M.H. Hsieh, Y.J. Chen, and J.T. Cheng (2003). Mechanism of the antihypertensive effect of stevioside in anesthetized dogs. Pharmacology 67(1): 14-20. ISSN: 0031-7012.
NAL Call Number: RM1.P473
Abstract: Stevioside is a sweet-tasting glycoside isolated from the leaves of Stevia rebaudiana. It has been used as a noncaloric sugar substitute in Japan and Brazil for decades. Previous studies have shown that it lowered blood pressure in spontaneously hypertensive rats by intravenous injection. This study was designed to evaluate the hypotensive effect of stevioside in dogs and to define the underlying mechanism. After nasogastric administration of stevioside powder (200 mg/kg), the blood pressure of healthy mongrel dogs began to significantly decrease at 60 min and returned to baseline level at 180 min. The reduction of blood pressure was more rapid (at 5-10 min) and effective after intravenous injection. However, no significant change of blood pressure was noted after injection through left vertebral artery, implicating that the hypotensive effect is not related to the central nervous system. Stevioside also showed significant hypotensive effects in renal hypertensive dogs, in a dose-dependent manner. In cultured rat aortic smooth muscle cells (A7r5 cell line), stevioside can dose-dependently inhibit the stimulatory effects of vasopressin and phenylephrine on intracellular Ca2+ in a calcium-containing medium. However, no intracellular Ca2+ inhibitory effect was observed in calcium-free medium, implicating that stevioside may inhibit the Ca2+ influx from extracellular fluid. Our present data show that stevioside did not influence the calcium ionophore (A23187) induced Ca2+ influx, indicating that the antagonistic effect was through Ca2+ channels. This study confirmed that stevioside is an effective antihypertensive natural product, and its hypotensive mechanism may be probably due to inhibition of the Ca2+ influx.
Descriptors: cardiovascular system, transport and circulation, pharmacology, hypertension, vascular disease, drug therapy, hypotension, drug therapy, blood pressure, calcium ion influx.

Lurie, F., B. Driessen, J.S. Jahr, R. Reynoso, and R.A. Gunther (2003). Validity of arterial and mixed venous oxygen saturation measurements in a canine hemorrhage model after resuscitation with varying concentrations of hemoglobin-based oxygen carrier. Anesthesia and Analgesia 96(1): 46-50. ISSN: 0003-2999.
Abstract: In this study, we evaluated the validity of saturation measurements in mixed venous and arterial blood during posthemorrhagic anemia and resuscitation with varying levels of hemoglobin-based oxygen carrier (Hemoglobin glutamer-200 (bovine); Oxyglobin(R) (Hb-200)). Nineteen anesthetized, splenectomized, mixed-breed dogs were anesthetized (two were excluded from the data because they did not survive the exsanguination, supporting the validity of the model). Their pulmonary arteries were cannulated with the Abbott QVUE Oximetrix 3 catheter. An 18-gauge catheter was placed in the femoral artery, and a reusable Nellcor probe was applied to the tongue. Mixed venous and arterial samples were drawn at baseline, after 40% hemorrhage (to keep arterial pressure at 50 mm Hg), and postresuscitation with 30 mL/kg of 6% hetastarch in lactated Ringer's solution (n=4), 10 mL/kg of Hb-200, 20 mL/kg of hetastarch (n=6), 20 mL/kg of Hb-200, and 10 mL/kg of hetastarch (n=7). Samples were compared with oxygen content from the LEXO2CON-K oxygen analyzer, and oxygen content was calculated for all values from the monitors. Results were compared by using analysis of variance. There was good correlation (0.97gtoreqrgtoreq0.92) for the measured versus calculated hemoglobin oxygen saturation values at baseline. After resuscitation, the correlation between calculated and measured values of oxygen content was significantly smaller for all tested instruments. The values of oxygen content calculated from the oxygen saturation monitor and from the oximetric pulmonary artery can deviate by as much as 20% from directly measured values. We conclude that the administration of this oxygen therapeutic may interfere with the values of some monitors.
Descriptors: blood and lymphatics, transport and circulation, pharmacology, posthemorrhagic anemia, blood and lymphatic disease, resuscitation, clinical techniques, therapeutic and prophylactic techniques, oxygen saturation, arterial, mixed venous, validity .

Mano, Y., T. Usui, and H. Kamimura (2004). Pharmacokinetics of ym466, a new factor xa inhibitor, in rats and dogs. European Journal of Drug Metabolism and Pharmacokinetics 29(1): 7-13. ISSN: 0378-7966.
NAL Call Number: RM301.E8
Abstract: The pharmacokinetics of YM466, a selective inhibitor for factor Xa, was investigated after single intravenous and oral dosing to rats and dogs. After i.v. dosing, plasma YM466 concentration declined in a bi-phasic manner with a terminal elimination half-life of 1.4 h in rats and 0.8 h in dogs. Total plasma clearance values were 884 and 1212 ml/h/kg in rats and dogs, respectively. After oral dosing, plasma YM466 concentrations reached maximum within 2 h and increased in a dose-proportional manner in rats while increase was nonlinear in dogs. The absolute bioavailability of YM466 was 2.7 - 4.5 % in rats, almost constant regardless of the dose levels investigated, while it was 6.9 - 24.6 % in dogs, indicating nonlinear pharmacokinetics. The plasma protein binding of YM466 was 54.7 - 56.5 % in rats and 45.2 - 49.0 % in dogs and almost constant regardless of the concentration, No metabolism of YM466 was observed in an in vitro liver microsome study. These findings suggest that the low bioavailability of YM466 is attributable to the poor absorption not to the extensive metabolism.
Descriptors: metabolism, pharmacology, drug metabolism, total drug clearance.

Markos, F., B.A. Hennessy, M. Fitzpatrick, J. O'sullivan, and H.M. Snow (2002). The effect of tezosentan, a non-selective endothelin receptor antagonist, on shear stress-induced changes in arterial diameter of the anaesthetized dog. Journal of Physiology 544(3): 913-918. ISSN: 0022-3751.
NAL Call Number: 447.8 J82
Abstract: The effects of changes in the mean (Sm) and pulsatile (Sp) components of arterial wall shear stress on arterial dilatation of the iliac artery of the anaesthetized dog were examined in the absence and presence of the endothelin receptor antagonist tezosentan (10 mg kg-1 I.V.; Ro 61-0612; (5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide)). Changes in shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and stimulation of the left ansa subclavia. An increase in Sm from 1.81+-0.3 to 7.29+-0.7 N m-2 (means+-S.E.M.) before tezosentan caused an endothelium-dependent arterial dilatation which was unaffected by administration of tezosentan for a similar increase in Sm from 1.34+-0.6 to 5.76+-1.4 N m-2 (means+-S.E.M.). In contrast, increasing the Sp from 7.1+-0.8 to a maximum of 11.5+-1.1 N m-2 (means+-S.E.M.) before tezosentan reduced arterial diameter significantly. Importantly, after administration of tezosentan subsequent increases in Sp caused arterial dilatation for the same increase in Sp achieved prior to tezosentan, increasing from a baseline of 4.23+-0.4 to a maximum of 9.03+-0.9 N m-2 (means+-S.E.M.; P<0.001). In conclusion, the results of this study provide the first in vivo evidence that pulsatile shear stress is a stimulus for the release of endothelin from the vascular endothelium.
Descriptors: biochemistry and molecular biophysics, cardiovascular system, transport and circulation, arterial diameter, arterial dilatation, arterial wall shear stress, pulsatile components, endothelium dependent arterial dilatation, shear stress induced changes, stroke volume.

Marsella, R., C.F. Nicklin, S. Saglio, and J. Lopez (2004). Investigation on the effects of topical therapy with 0.1% tacrolimus ointment (Protopic) on intradermal skin test reactivity in atopic dogs. Veterinary Dermatology. 15(4): 218-224. ISSN: 0959-4493.
NAL Call Number: SF901.V47
Abstract: Tacrolimus ointment (TAC) is an effective treatment for atopic dermatitis in humans and dogs. The purposes of the present study were to evaluate the effect of 4 weeks of TAC on intradermal skin testing (IST), and in case of suppression, to investigate if reactivity returned to baseline by 2 or 4 weeks post treatment. Intradermal skin test was performed using saline, histamine, lipopolysaccharide (LPS, 0.4 mg mL-1), house dust (25 PNU mL-1) and house dust mite (1:40 000 w/v) at weeks 0, 4, 6 and 8 on nine dogs enrolled in a blinded, crossover, clinical trial, using 0.1% TAC or placebo once daily for 4 weeks. Reactions were evaluated at 15 min, and at 4 and 6 h. Ointment was applied after the 15-min evaluation on weeks 0 and 4. Data were analysed using the statistical software SAS System for Windows. At week 4, TAC did not affect 15-min IST, but some reactions in the TAC group were suppressed at 6 h compared to baseline. In the TAC group, 4-h IST reactivity was reduced 2 weeks after discontinuation but returned to baseline by 4 weeks. In conclusion, TAC has no effect on immediate reactions but decreased some late-phase reactions. Therefore, no withdrawal is recommended to evaluate only immediate reactions, but a 4-week withdrawal may be necessary for evaluation of late-phase reactions.
Descriptors: atopy, dermatitis, dermatological agents, drug therapy, ointments, pharmacology, skin diseases, skin tests, topical application.
Language of Text: , LS=German; Spanish; French.

Mata Bilbao, M.L., C. Andres Lacueva, E. Roura, O. Jauregui, E. Escribano, C. Torre, and R.M. Lamuela Raventos (2008). Absorption and pharmacokinetics of green tea catechins in beagles. British Journal of Nutrition 100(3): 496-502. ISSN: 0007-1145.
NAL Call Number: 389.8 B773
Abstract: The present study evaluates for the first time in dogs, the kinetics of green tea catechins and their metabolic forms in plasma and urine. Ten beagles were administered 173 mg (12.35 mg/kg body weight) of catechins as a green tea extract, in capsules. Blood samples were collected during 24 h after intake and urine samples were collected during the following periods of time: 0-2, 2-6, 6-8 and 8-24 h. Two catechins with a galloyl moiety and three conjugated metabolites were detected in plasma. Most of the detected forms in plasma reached their maximum plasma concentration (Cmax) at around 1 h. Median Cmax for ( - )-epigallocatechin-3-gallate (EGCG), ( - )-epicatechin-3-gallate (ECG), ( - )-epigallocatechin glucuronide (EGC-glucuronide), ( - )-epicatechin glucuronide (EC-glucuronide), ( - )-epicatechin sulphate (EC-sulphate) were 0.3 (range 0.1-1.9), 0.1 (range 0-0.4), 0.8 (range 0.2-3.9), 0.2 (range 0.1-1.7) and 1 (range 0.3-3.4) micromol/l, respectively. The areas under the plasma concentration v. time curves (AUC0 --> 24) were 427 (range 102-1185) micromol/l x min for EGC-glucuronide, 112 (range 53-919) micromol/l x min for EC-sulphate, 71 (range 26-306) micromol/l x min for EGCG, 40 (range 12-258) micromol/l x min for EC-glucuronide and 14 (range 0.1-124) micromol/l x min for ECG. The values of mean residence time (MRT0 --> 24) were 5 (range 2-16), 2 (range 1-11), 10 (range 2-13), 3 (range 2-16) and 2.4 (range 1-18) h for EGCG, ECG, EGC-glucuronide, EC-glucuronide and EC-sulphate, respectively. In urine, catechins were present as conjugated forms, suggesting bile excretion of EGCG and ECG. Green tea catechins are absorbed following an oral administration and EGC-glucuronide is the metabolic form that remains in the organism for a longer period of time, suggesting that this compound could suffer an enterohepatic cycle.
Descriptors: antioxidants pharmacokinetics, catechin pharmacokinetics, dogs metabolism, tea, administration, oral, biological availability, biotransformation, catechin analogs and derivatives, catechin analysis, catechin chemistry, catechin metabolism, glucuronides analysis, glucuronides metabolism, intestinal absorption drug effects, models, animal, sulfuric acid esters analysis, sulfuric acid esters metabolism, time factors.

Mata Bilbao, M.L., C. Andres Lacueva, E. Roura, O. Jauregui, E. Escribano, C. Torre, and R.M. Lamuela Raventos (2007). Absorption and pharmacokinetics of grapefruit flavanones in beagles. British Journal of Nutrition 98(1): 86-92. ISSN: 0007-1145.
NAL Call Number: 389.8 B773
Abstract: The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites naringenin and naringenin glucuronide, was detected in dog plasma. Blood samples were collected between 0 and 24 h after administration of the extract. Naringin reached its maximun plasma concentration at around 80 min, whereas naringenin and naringenin glucuronide reached their maximun plasma concentrations at around 20 and 30 min, respectively. Maximum plasma concentrations of naringin, naringenin and naringenin glucuronide (medians and ranges) were 0.24 (0.05-2.08), 0.021 (0.001-0.3) and 0.09 (0.034-0.12) micromol/l, respectively. The areas under the curves were 23.16 l (14.04-70.62) min x micromol/for nariningin, 1.78 (0.09-4.95) min x micromol/l for naringenin and 22.5 (2.74-99.23) min x micromol/l for naringenin glucuronide. The median and range values for mean residence time were 3.3 (1.5-9.3), 2.8 (0.8-11.2) and 8.0 (2.3-13.1) h for naringin, naringenin and naringenin glucuronide, respectively. The results of the present study demonstrate the absorption of grapefruit flavanones via the presence of their metabolites in plasma, thus making an important contribution to the field since the biological activities ascribed to these compounds rely on their specific forms of absorption.
Descriptors: citrus paradisi chemistry, flavanones pharmacokinetics, absorption, administration, oral, biological availability, dogs, flavanones administration and dosage, flavanones blood, intestinal absorption, models, animal, plant extracts administration and dosage, plant extracts pharmacokinetics.

Mattiuz, E.L., G.D. Ponsler, R.J. Barbuch, P.G. Wood, J.H. Mullen, R.L. Shugert, Q. Li, W.J. Wheeler, F. Kuo, P.C. Conrad, and J.M. Sauer (2003). Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the fischer 344 rat and beagle dog. Drug Metabolism and Disposition 31(1): 88-97. ISSN: 0090-9556.
NAL Call Number: RM301.35.D78
Abstract: These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride ((-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride) in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F=4%) compared with the high oral bioavailability in dog (F=74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.
Descriptors: metabolism, pharmacology, species differences.

Mc Entee, K., C. Clercx, D. Soyeur, H. Amory, C. Michaux, T. Flandre, E. Jonville, C. Pynnaert, N. Miserque, and M. Henroteaux (2001). Usefulness of dobutamine stress tests for detection of cardiac abnormalities in dogs with experimentally induced early left ventricular dysfunction. American Journal of Veterinary Research 62(3): 448-455. ISSN: 0002-9645.
NAL Call Number: 41.8 Am3A
Abstract: Objective: To determine whether dobutamine stress tests (DST) can be used to detect cardiac dysfunction in dogs with early left ventricular dysfunction (ELVD) induced by rapid right ventricular pacing (RRVP). Animals: 7 adult male Beagles. Procedure: A pacemaker was surgically implanted in each dog at the level of the right ventricular apex. Electrocardiography, Doppler sphygmomanometry, and Doppler echocardiography were performed before and during a DST prior to activation of the pacemaker and every 3 to 4 days during the period of RRVP. Dobutamine stress tests were performed by infusing dobutamine at incremental dosages ranging from 12.5 to 42.5 mug/kg of body weight/min. Results: Clinical signs of congestive heart failure were not observed during the pacing period. However, all dogs developed ELVD associated with significant changes in values for most Doppler echocardiographic variables obtained prior to DST. Adverse cardiac effects were not detected during DST. Most Doppler echocardiographic indices of cardiac function were significantly altered in response to dobutamine infusion during the pacing period, compared with prepacing values. However, a dobutamine-induced 2-fold increase in cardiac output was maintained. Conclusions and Clinical Relevance: Dobutamine stress tests can be safely performed in dogs with experimentally induced ELVD. Dobutamine stress tests may be a sensitive, noninvasive diagnostic method, complementary to standard clinical examinations, for detection of early cardiac dysfunction in dogs asymptomatic for dilated cardiomyopathy.
Descriptors: veterinary medicine, medical sciences, methods and techniques, pharmacology, cardiovascular system, transport and circulation, cardiac abnormalities, heart disease, dilated cardiomyopathy, left ventricular dysfunction, experimentally induced early disease model, dobutamine stress test, detection method, diagnostic method.

Mcverry, B.J., X. Peng, P.M. Hassoun, S. Sammani, B.A. Simon, and J.G.N. Garcia (2004). Sphingosine 1-phosphate reduces vascular leak in murine and canine models of acute lung injury. American Journal of Respiratory and Critical Care Medicine 170(9): 987-993. ISSN: 1073-449X.
NAL Call Number: RC705 .A4
Abstract: Excessive mechanical stress is a key component of ventilator-associated lung injury, resulting in profound vascular leak and an intense inflammatory response. To extend our in vitro observations concerning the barrier-protective effects of the lipid growth factor sphingosine 1-phosphate (Sph 1-P), we assessed the ability of Sph 1-P to prevent regional pulmonary edema accumulation in clinically relevant rodent and canine models of acute lung injury induced by combined intrabronchial endotoxin administration and high tidal volume mechanical ventilation. Intravenously delivered Sph 1-P significantly attenuated both alveolar and vascular barrier dysfunction while significantly reducing shunt formation associated with lung injury. Whole lung computed tomographic image analysis demonstrated the capability of Sph 1-P to abrogate significantly the accumulation of extravascular lung water evoked by 6-hour exposure to endotoxin. Axial density profiles and vertical density gradients localized the Sph 1-P response to transitional zones between aerated and consolidated lung regions. Together, these results indicate that Sph 1-P represents a novel therapeutic intervention for the prevention of pulmonary edema related to inflammatory injury and increased vascular permeability.
Descriptors: pharmacology, respiratory system, respiration, lung injury, injury, respiratory system disease, pulmonary edema, respiratory system disease, drug therapy, pathology, prevention and control, mechanical ventilation, clinical techniques, therapeutic and prophylactic techniques, tomography, diagnostic techniques, imaging and microscopy techniques, laboratory techniques, mechanical stress.

Mealey, K.L., S. Greene, R. Bagley, J. Gay, R. Tucker, P. Gavin, K. Schmidt, and F. Nelson (2008). P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model. Drug Metabolism and Disposition the Biological Fate of Chemicals 36(6): 1073-9.
NAL Call Number: RM300.A1D7
Abstract: P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1Delta) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1Delta dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.
Descriptors: blood brain barrier metabolism, central nervous system depressants pharmacology, loperamide pharmacology, models, animal, p glycoprotein genetics, technetium tc 99m sestamibi cerebrospinal fluid, brain metabolism, dogs, technetium tc 99m sestamibi pharmacokinetics.

Miao, C.H., B. Sun, H. Jiang, Z.G. Xue, and R. Lindwall (2002). Pharmacodynamics and pharmacokinetics of inhaled nitric oxide in dogs with septic acute respiratory distress syndrome. Acta Pharmacologica Sinica 23(3): 278-84. ISSN: 1671-4083.
Abstract: AIM: To evaluate pharmacodynamics and pharmacokinetics of inhaled nitric oxide (iNO) in dogs with acute respiratory distress syndrome (ARDS). METHODS: ARDS, induced after iv injection of endotoxin, was evidenced by reduction of paO2/FiO2 from (62.5 +/- 2.8) to (26 +/- 4) kPa and dynamic lung compliance (Cdyn) from (14.8 +/- 0.7) to (8.6 +/- 0.6) mL.kPa-1 . kg-1, increase of dead space (VD/VT) from (0.14 +/- 0.06) to (0.58 +/- 0.05), intrapulmonary shunting (Qs/Qt) from 4.7 % +/- 1.7 % to 39 % +/- 7 %, and pulmonary vascular resistance index (PVRI) from (16 +/- 4) to (51 +/- 8) kPa.s.L-1 . m-2 (all P < 0.05), along with severe intrapulmonary neutrophil recruitment and peripheral neutropenia. The animals were then treated as either a control or an NO group (n = 6 each, iNO 0.4 - 3.2 micromol/L) for another 10 h. RESULTS: More survival was found in NO group (4/6 vs 0/6, P < 0.05). iNO at 0.8, 1.6, and 3.2 micromol/L (20, 40, and 80 ppm) resulted in > 40 % increase of paO2/FiO2 and Cdyn, a reduction of VD/VT to 0.32, Qs/Qt to < 25 %, and PVRI by > 50 % (30.8 kPa . s . L-1 . m-2) compared to the control. Optimal iNO dose was around 0.8 micromol/L as higher methemoglobin (MetHb, > 3 %) was found at higher NO. iNO had no adverse effects on surfactant phospholipids and lung fluid balance, but attenuated expression of tumor necrosis factor alpha,beta2 integrin CD11b, and interleukin-8 mRNA in the lungs by 22 %, 44 %, and 25 %, respectively (P < 0.05). CONCLUSION: Pharmacodynamics of iNO in this model was related to improvement in gas exchange, Cdyn, PVRI, and suppression of proinflammatory cytokine expression in the lungs, and its adverse effect was mainly confined to MetHb at higher NO dose.
Descriptors: pharmacodynamics, pharmacokinetics, inhaled nitric oxide (iNO), acute respiratory distress syndrome, intrapulmonary neutrophil recruitment, peripheral neutropenia, surfactant phospholipids, lung fluid balance.

Mizutani, T., S. Takahashi, S. Kihara, and H. Toyooka (2001). Repeated administration of protamine does not attenuate circulatory changes caused by protamine reversal of heparin in dogs. Journal of Cardiothoracic and Vascular Anesthesia 15(3): 346-51. ISSN: 1053-0770.
Descriptors: mongrel dogs, nitric oxide, protamine, circulatory changes, haparin, pharmacology.

Morris, T.A., J.J. Marsh, R. Konopka, C.A. Pedersen, and P.G. Chiles (2004). Improved imaging of deep venous thrombi during anticoagulation using radiolabelled anti-d-dimer antibodies. Nuclear Medicine Communications 25(9): 917-922. ISSN: 0143-3636.
Abstract: Objectives Radiolabelled anti-fibrin antibodies have not yet enabled reliable and practical diagnosis of venous thromboembolism. However, previous unsuccessful clinical trials were performed with anti-fibrin P-chain antibodies that do not optimally bind to thrombi during anticoagulation. The current experiments were performed to determine if radiolabelled anti-D-dimer antibodies more reliably allowed nuclear medicine imaging of deep venous thrombi during anticoagulation than anti-beta-chain antibodies. Methods Dogs with pre-existing unilateral femoral vein thrombi were anticoagulated with heparin (300 units-kg bolus followed by 90 .h-1 continuous infusion). They were then allocated to receive one of three 111In labelled antibodies: anti-D-dimer, anti-beta or a non-specific control antibody. Gamma scans of the legs were performed at regular intervals for 24 h. Scans were interpreted in a blinded fashion and the number of gamma counts from the femoral area on the thrombosed side was compared to the contralateral side. Clot/blood isotope density ratios were determined post-mortem. Results Leg thrombi were 100% detectable in the anti-D-dimer group, but only 60% detectable in the anti-beta group. Mean +/- SD relative counts in the thrombosed femoral area was 137 +/- 10% compared to the contralateral side in the anti-D-dimer group, but only 116 20% in the anti-P group. The clot/blood ratio was 24.5 +/- 2.8 in the anti-D-dimer group, but only 7.8 +/- 2.0 in the anti-beta group. Conclusions 111In labelled anti-D-dimer provides superior nuclear medicine images of thrombi during intensive anticoagulation compared to anti-beta. Clinical results with radiolabelled anti-D-dimer may be more promising than those previously observed with other anti-fibrin antibodies. Copyright 2004 Lippincott Williams & Wilkins.
Descriptors: cardiovascular system, transport and circulation, methods and techniques, pharmacology, femoral vein thrombosis, vascular disease, diagnosis, drug therapy, gamma scan, imaging and microscopy techniques, laboratory techniques, indium 111 labelled anti d dimer antibody imaging, clinical techniques, diagnostic techniques .

Mraovic, B., J.G. Krolikowski, P.S. Pagel, D.C. Warltier, and J.R. Kersten (2003). Role of cyclooxygenase during ischemic and pharmacological preconditioning in dogs -- selected for journal symposium. 2003 Annual Meeting of the American Society of Anesthesiologists, San Francisco, CA, USA; October 11-15, 2003,
Abstract: Background: Recent evidence suggests that cyclooxygenase (Cox)-2 antagonists may cause deleterious effects in patients with coronary artery disease. Cox-2 mediates the late phase of ischemic preconditioning (IPC) but the role of Cox to modulate early IPC, anesthetic-induced preconditioning (APC), or pharmacological preconditioning (PPC) are unknown1. We tested the hypothesis that Cox-2 is an essential mediator of IPC, APC, and PPC in dogs. Methods: All experimental procedures conformed to the guidelines of the APS and the NIH and were approved by the Institutional Animal Care and Use Committee. Barbiturate-anesthetized dogs (n = 78) were instrumented for measurement of hemodynamics and left anterior descending coronary artery (LAD) occlusion and reperfusion. The roles of Cox antagonists to modulate IPC, APC or PPC were evaluated in dogs randomly assigned to receive oral aspirin 650 mg, celecoxib 200 mg or acetaminophen 500 mg, respectively, at 24, 12 and 2 h before IPC, APC, and PPC, or during control experiments (without preconditioning stimuli) in 13 separate groups. All dogs were subjected to a 60-min LAD occlusion followed by 3 h of reperfusion. IPC was induced with four 5 min periods of LAD occlusion interspersed with 5 min periods of reperfusion. APC was induced with isoflurane 1.0 minimum alveolar concentration for 30 min and discontinued 30 min before occlusion, and PPC was induced with diazoxide 2.5mg/kg i.v. 30 min before LAD occlusion. Myocardial infarct size and transmural coronary collateral blood flow were measured with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. Statistical analysis of data was performed with ANOVA followed by the Student-Newman-Keuls test. Data were considered statistically significant when P<0.05 (*versus control experiments). Results: No differences in baseline hemodynamics, coronary collateral blood flow or area of the left ventricle at risk for infarction (AAR) were observed between groups. Myocardial infarct size expressed as a percentage of the AAR was 29+-1% (mean+-SEM) in control experiments. In the absence of Cox antagonists IPC, APC and PPC all significantly decreased myocardial infarct size ( 8.6+-1*, 12+-1*, and 10+-1%*, respectively). Celecoxib alone had no effect on infarct size (26+-2%) but abolished IPC (30+-3), APC (30 +-3) and PPC (27+-4%). Aspirin and acetaminophen alone did not alter the extent of myocardial infarction (23+-3 and 29+-2%, respectively), but these Cox antagonists modestly attenuated APC (18+-1* and 18+-1%*, respectively). Conclusions: The results indicate that Cox 2 is an important mediator of IPC, APC and PPC. This finding is consistant with the observation that prostacyclin enhances KATP channel activation and these channels are known to mediate IPC, APC and PPC. Cox 1 and Cox 3 may play a role during preconditioning, although, attenuation of APC by aspirin and acetamenophen may have occurred through non-selective actions of these drugs to antagonize Cox-2. The role of Cox enzymes as obligatory mediators in protection by diverse preconditioning stimuli may have implications in the clinical use of selective and non-selective Cox antagonists..
Descriptors: cardiovascular system, transport and circulation, cell biology, enzymology, biochemistry and molecular biophysics, pharmacology, coronary artery disease, heart disease, vascular disease, ischemia, myocardial infarction, anesthetic induced preconditioning, laboratory techniques, ischemic preconditioning, pharmacological preconditioning, hemodynamics .

Murray, C., F. Markos, H.M. Snow, T. Corcoran, N. Parfrey, and G.D. Shorten (2003). Effects of fenoldopam on renal blood flow and its function in a canine model of rhabdomyolysis. European Journal of Anaesthesiology 20(9): 711-718. ISSN: 0265-0215.
Abstract: Background and objective: Our hypothesis was that fenoldopam, a selective DA1 agonist, would protect against rhabdomyolysis-induced renal injury. Methods: We studied the effects of intravenous fenoldopam (0. 1-1.0 mug kg-1 min-1) or saline on renal blood flow and function in 10 anaesthetized Labrador dogs in whom rhabdomyolysis and myoglobinuric acute renal failure had been induced by administration of glycerol 50% (10 mL kg-1) intramuscularly. Haemodynamic measurements including renal blood flow and derived parameters of renal function including creatinine clearance were recorded before and for the 30 min following glycerol injection, and during the 3 h following commencement of each infusion. Serum malondialdehyde concentrations were measured before and 15 min after glycerol intramuscularly, and 30 and 150 min after commencement of the infusion. Results: In the fenoldopam group, creatinine clearance was less than placebo at 1 and 2 h after commencing the infusion (12.7+-11.5 versus 31.3+-9.9 mL min-1, P=0.04; 8.5+-5.3 versus 20.1+-7.4 mL min-1, P=0.03). A 140-fold increase in serum malondialdehyde concentration occurred in one dog (fenoldopam group). Conclusion: Fenoldopam increased the severity of the renal injury in this canine model of myoglobinuric acute renal failure.
Descriptors: muscular system, movement and support, pharmacology, urinary system, chemical coordination and homeostasis, myoglobinuric acute renal failure, urologic disease, renal injury, injury, urologic disease, rhabdomyolysis, muscle disease, hemodynamics, renal blood flow, renal function.

Nagahara, N., Y. Akiyama, K. Higaki, and T. Kimura (2007). Animal models for predicting potency of oral sustained-release adhesive microspheres in humans. International Journal of Pharmaceutics 331(1): 46-53. ISSN: 0378-5173.
NAL Call Number: RS122.A1I5
Abstract: The sustained-release (SR) adhesive microspheres successfully improved the absorption of furosemide, of which the absorption is limited to the upper small intestine, after oral administration to humans based on the adhesion to the gastric mucosa in our previous study. To develop a new drug using SR-adhesive microspheres, however, some adequate animal models should be needed to predict the potency of the formulation in humans. To find out an adequate animal model, the effect of the SR-adhesive microspheres on furosemide absorption was investigated in rats, dogs and monkeys and the release kinetics of furosemide from SR-adhesive microspheres was also studied. SR-adhesive and SR-non-adhesive microspheres showed very similar characteristics of drug release. The rotation speed did not affect the release kinetics, but higher pH increased the drug release from both microspheres. The absorption of furosemide after SR-adhesive microspheres administration to rats and dogs was significantly higher than that after SR-non-adhesive microspheres administration, which was very similar to the results obtained in humans. On the other hand, in monkeys, SR-adhesive microspheres were not able to improve the absorption of furosemide at all. These findings indicated that rats and dogs were in vivo animal models suitable for predicting the potency of SR-adhesive microspheres in humans.
Descriptors: furosemide chemistry, furosemide pharmacokinetics, intestinal absorption, microspheres, adhesiveness, administration, oral, delayed action preparations, dogs, macaca fascicularis, models, animal, rats, rats, sprague dawley.

Nagasawa, M., T. Ide, M. Suzuki, M. Tsunoda, Y. Akasaka, T. Okazaki, T. Mochizuki, and K. Murakami (2004). Pharmacological characterization of a human-specific peroxisome proliferater-activated receptor alpha (PPAR alpha ) agonist in dogs. Biochemical Pharmacology 67(11): 2057-2069. ISSN: 0006-2952.
NAL Call Number: 396.8 B52
Abstract: Peroxisome proliferator-activated receptor alpha (PPAR alpha ) is a key regulator in lipid metabolism and a potential therapeutic target for lipid-related metabolic diseases. It has been shown that there are species differences between human and mouse in response to several PPAR alpha agonists in a transactivation assay. In the present study, we cloned a full length of dog PPAR alpha and investigated the effects of a novel and potent agonist (KCL) for human PPAR alpha . In a transactivation assay using the full length of PPAR alpha , agonistic activity of KCL for dog PPAR alpha (EC50: 0.007 micro M) was comparable to that for human PPAR alpha (EC50: 0.003 micro M), but not that for rat PPAR alpha (EC50: 11.49 micro M). Similar results were obtained from a transactivation assay using a GAL4/PPAR alpha ligand-binding domain (LBD) chimera. A point-mutation study showed that I272 on PPAR alpha LBD is a major contributor to species differences in response to KCL between human, dog, and rat PPAR alpha . KCL also induced mRNA levels of HMG-CoA synthase in dog hepatocytes. When administered orally to dogs and rats, KCL significantly decreased plasma triglyceride levels in a dose-dependent manner. The triglyceride-lowering effects of KCL in dogs were >100-fold more potent than those in rats. These results suggest that KCL may induce activation of highly potent PPAR alpha in humans as well as dogs, and that dog is a suitable animal model for studying and predicting the biological actions of potent agonists for human PPAR alpha .
Descriptors: animal models, laboratory animals, peroxisomes, pharmacology, potassium chloride, transcription factors, triacylglycerols, dogs, rats, species differences.

Nanri, M., N. Mori, T. Kirimoto, T. Uji, and M. Kiniwa (2004). The effect of propiverine hydrochloride in a canine urinary frequency model associated with bladder hyperactivity. Journal of Pharmacological Sciences 94(Supplement 1): 265P. ISSN: 1347-8613.
Descriptors: pharmacology, urinary system, chemical coordination and homeostasis, veterinary medicine, medical sciences, bladder hyperactivity, urologic disease, lower urinary tract dysfunction, urologic disease, micturition interval

Narisawa, S., M. Nagata, T. Ito, H. Yoshino, Y. Hirakawa, and K. Noda (1995). Drug release behavior in gastrointestinal tract of beagle dogs from multiple unit type rate-controlled or time-controlled release preparations coated with insoluble polymer-based film. Journal of Controlled Release 33(2): 253-260. ISSN: 0168-3659.
NAL Call Number: RS201.C64J68
Abstract: Drug release behaviors from two multiple unit types of controlled release systems were observed in the gastrointestinal (GI) tract of beagle dogs. Factors affecting the in vivo drug release are discussed. The in vivo drug release behaviors were directly predicted by measuring the residual amount of drugs in preparations recovered from the GI tract after oral administration. Theophylline (TP) and propranolol hydrochloride (PPL), which have markedly different solubility, were used as model drugs. A rate-controlled release preparation (porous ethylcellulose film-coated beads) and a time-controlled release preparation (SRS; sigmoidal release system) were examined. Although in vivo TP release from the rate-controlled release beads agreed considerably with in vitro release in the early stages, it was reduced by a lack of fluid in the lower region of the GI tract and the lower water-solublity of the drug. On the other hand, PPL release in vivo was in accord with the in vitro release, and the drug was released almost completely from the beads in the GI tract. In the case of PPL-SRS, although the in vivo release rate was slightly lower than that in vitro, sigmoidal drug release was also observed in the GI tract. TP was not released entirely from the SRS or the porous ethylcellulose film-coated beads in the GI tract. In conclusion, with respect to drug release from controlled release preparations coated with insoluble polymer based-film coating, a good in vitro/in vivo correlation was observed in the early stages of drug release, irrespective of drug properties, but solubility of the drugs was found to be an important factor that affected the drug release in the lower site of GI tract of dogs.
Descriptors: biochemistry and molecular biophysics, digestive system, ingestion and assimilation, pharmacology, drug delivery, ethylcellulose film coating, pharmaceuticals, propranolol hydrochloride, theophylline .

Nolan, E.R., M.B. Bailie, and N.B. Olivier (2008). Effect of autonomic blockade on ventricular repolarization shortening: response to behavioral stimulus in paced dogs. Autonomic Neuroscience Basic and Clinical 140(1-2): 66-71. ISSN: 1566-0702.
Abstract: Autonomic tone has been suggested to be a significant determinant of ventricular repolarization duration with both rate dependent and independent effects. Using the His bundle-paced dog, a model that eliminates the need for QT correction factors, we explored the rate-independent effects of sympathetic and parasympathetic blockade on ventricular repolarization shortening following an excitatory stimulus. Six male His bundle-paced beagle dogs were paced at 80 bpm and fitted with jackets, surface ECG electrodes, and radiotelemeters. Dogs were given propranolol, atropine methyl nitrate, or the appropriate control in a four-period crossover design. Doses were based on literature reviews and unpublished pharmacokinetic/pharmacodynamic modeling to provide efficacious beta- and parasympathetic blockade throughout the data collection period. Data collection began at 11 am and concluded at 11 am the following day, with event stimuli provided by investigators entering the room at 5 pm and at 7 am the following morning. One minute of ECG data were sampled every 15 min and these means were averaged to generate hourly means for the 24 hour data collection period. Treatment with atropine attenuated RT interval shortening when compared with the vehicle group at both the 5 pm and 7 am stimulus. In contrast, propranolol was not associated with significant effects on RT interval duration at either time point. These results suggest that parasympathetic withdrawal is the primary factor responsible during both awake hours (5 pm) and in the transition from deep sleep to the awake state (7 am) in the facilitation of RT interval shortening following an excitatory stimulus. The attenuation of RT interval shortening following atropine treatment may be a direct effect, or an indirect effect requiring an excited state to become evident. The use of a model that eliminates the need to apply correction factors to repolarization indices helps to clarify the role of the autonomic nervous system on ventricular repolarization.
Descriptors: autonomic nervous system physiology, heart innervation, heart physiology, heart rate physiology, heart ventricles innervation, ventricular function, adrenergic beta antagonists pharmacology, atropine pharmacology, autonomic nervous system drug effects, biological clocks drug effects, biological clocks physiology, bundle of his drug effects, bundle of his physiology, circadian rhythm physiology, dogs, electric stimulation, electrocardiography drug effects, heart rate drug effects, membrane potentials drug effects, membrane potentials physiology, models, animal, muscarinic antagonists pharmacology, pacemaker, artificial, parasympathetic nervous system drug effects, parasympathetic nervous system physiology, propranolol pharmacology, sympathetic nervous system drug effects, sympathetic nervous system physiology, time factors.

O'reilly, J.D., C.J. Charlton, B.H.E. Smith, and E.J. Harper (2000). Mild sedation causes oxidative stress in domestic dogs. FASEB Journal 14(4): A200. ISSN: 0892-6638.
NAL Call Number: QH301.F3
Descriptors: pharmacology, toxicology, lipid peroxidation, mild sedation, oxidative stress, meeting abstract.

Olivry, T., J.S. Paps, P. Bizikova, K.M. Murphy, H.A. Jackson, and J. Zebala (2007). A pilot open trial evaluating the efficacy of low-dose aminopterin in the canine homologue of human atopic dermatitis. British Journal of Dermatology 157(5): 1040-2. ISSN: 0007-0963.
NAL Call Number: RL1.B7
Descriptors: aminopterin therapeutic use, dermatitis, atopic veterinary, dog diseases drug therapy, folic acid antagonists therapeutic use, dermatitis, atopic drug therapy, dogs, models, animal, pilot projects, treatment outcome.

Ollerstam, A., S.A. Visser, G. Duker, T. Forsberg, A.H. Persson, L.B. Nilsson, J.A. Bjorkman, J. Gabrielsson, and A. Al Saffar (2007). Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs. Journal of Pharmacological and Toxicological Methods 56(2): 131-44. ISSN: 1056-8719.
NAL Call Number: QP901.J6
Abstract: INTRODUCTION: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. METHOD: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). RESULTS: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. DISCUSSION: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.
Descriptors: cardiac pacing, artificial, long qt syndrome physiopathology, sinoatrial node physiopathology, telemetry methods, anesthesia, aza compounds administration and dosage, aza compounds pharmacokinetics, aza compounds toxicity, cisapride administration and dosage, cisapride pharmacokinetics, cisapride toxicity, consciousness, dogs, dose response relationship, drug, drug evaluation, preclinical methods, electrocardiography methods, ether a go go potassium channels physiology, half life, heart rate drug effects, infusions, intravenous, long qt syndrome chemically induced, models, animal, phenethylamines administration and dosage, phenethylamines pharmacokinetics, phenethylamines toxicity, quinolines administration and dosage, quinolines pharmacokinetics, quinolines toxicity, sinoatrial node drug effects, sulfonamides administration and dosage, sulfonamides pharmacokinetics, sulfonamides toxicity, terfenadine administration and dosage, terfenadine pharmacokinetics, terfenadine toxicity, time factors.

Olmos Zuniga, J.R., C. Hernandez Jimenez, E. Diaz Martinez, R. Jasso Victoria, A. Sotres Vega, M.O. Gaxiola Gaxiola, J. Villalba Caloca, M. Baltazares Lipp, P. Santillan Doherty, and J.A. Santibanez Salgado (2007). Wound healing modulators in a tracheoplasty canine model. Journal of Investigative Surgery the Official Journal of the Academy of Surgical Research 20(6): 333-8. ISSN: 0894-1939.
Abstract: Postsurgical tracheal stenosis results from fibrosis formation due to ischemia. There are healing modulators, hyaluronic acid (HA) and collagen polyvinylpyrrolidone (CPVP), which reduce collagen fibers formation. Thus we can hypothesize that the topical application of one of these modulators can diminish postsurgical tracheal scarring and stenosis. The aim of this work was to evaluate the macroscopic, microscopic, and biochemical changes of tracheal healing after the application of HA or CPVP in a canine tracheoplasty model. The study design was prospective experimental investigation in a canine model. Eighteen mongrel dogs underwent three cervical tracheal rings resection and end-to-end anastomosis. They were randomized into three groups according to treatment: group I (control group) (n = 6), topical application of saline solution on tracheal anastomosis; group II (n = 6), topical application of 15 microg HA on tracheal anastomosis; and group III (n = 6), topical application of 2.5 mg CPVP on tracheal anastomosis. They were evaluated clinical, radiological and tracheoscopically during 4 weeks. They were euthanized at the end of the study time. Macroscopic, microscopic, and biochemical changes of tracheal anastomosis healing were analyzed. Collagen formation was quantified by the Woessner method. All the animals survived the surgical procedure and study period. Macroscopic, radiologic, and endoscopic studies showed that animals in group I developed tracheal stenosis, inflammation, and firm fibrous tissue formation, and histological studies also showed severe inflammatory reaction and fibrosis formation. Groups II (HA) and III (CPVP) showed well-organized thin collagen fibers with minimal inflammatory response. Biochemical evaluation revealed a higher collagen concentration in group I animals (analysis of variance [ANOVA] p < .05 and Tukey p < .01). Thus, hyaluronic acid or collagen polyvinylpyrrolidone administered after tracheal anastomosis diminished the degree of stenosis and inflammatory reaction. Both modulators improved tracheal healing.
Descriptors: collagen pharmacology, hyaluronic acid pharmacology, povidone pharmacology, trachea surgery, wound healing drug effects, dogs, fibrosis, models, animal, postoperative complications etiology, trachea pathology, tracheal stenosis etiology.

Padda, G.S., C. Kishioka, and B.K. Rubin (2001). Propofol and methohexital have no significant effect on mucus secretion or clearance in the anesthetized dog. Critical Care Med.Icine 29(5): 1045-8. ISSN: 0090-3493.
Abstract: OBJECTIVE: Anecdotal reports suggest that propofol (Diprivan) may stimulate mucus hypersecretion in patients without pulmonary disease. The purpose of this study was to evaluate the effect of methohexital or propofol anesthesia on the physical and transport properties of airway mucus in spontaneously breathing dogs. DESIGN: Randomized, controlled, crossover laboratory study. SETTING: University laboratory. SUBJECTS: Four healthy, purpose-bred female beagle dogs. INTERVENTIONS: Dogs were anesthetized with 5 mg/kg of propofol by intravenous bolus followed by a maintenance infusion at 0.4 mg x kg(-1) x min(-1) or 4 mg/kg of methohexital followed by an infusion at 0.3 mg x kg(-1) x min(-1). Premedication with 0.05 mg/kg of acepromazine was given, and either atropine (0.2 mg) or saline was given by intravenous bolus at the time of induction. Dogs were intubated but spontaneously breathing throughout the experiment. Tracheal secretions were collected after induction and again after 40 mins. MEASUREMENTS AND MAIN RESULTS: The volume of secretions collected on the endotracheal tube during the 1.5-hr experiment and on a bronchoscopy brush over 10 mins during the experiment was measured. Tracheal epithelial potential difference was measured bronchoscopically by saturated agar bridges, and tracheal mucus transport velocity was determined by timing particle transport. The dynamic viscoelasticity of collected mucus was assessed by microrheometry, and secretion mucociliary transportability was measured in vitro. There were no differences in any physical or transport properties of airway secretions that could be attributed to the anesthetic agent. Secretion volume was significantly lower (p < .05) and epithelial potential difference was significantly higher (p = .03) with atropine premedication. Despite this, there were no differences in tracheal mucus transport velocity, viscoelasticity, or secretion mucociliary transportability with either anesthetic agent or with atropine. CONCLUSIONS: This study suggests that neither methohexital nor propofol significantly affects mucus secretion or clearance in healthy dogs.
Descriptors: female, beagle dogs, methohexital nor propofol, anesthesia, mucus secretion.

Qian, M., W. West, J.T. Wu, B. Lu, and D.D. Christ (2003). Development of a dog microdialysis model for determining synovial fluid pharmacokinetics of anti-arthritis compounds exemplified by methotrexate. Pharmaceutical Research 20(4): 605-610. ISSN: 0724-8741.
NAL Call Number: RS1
Abstract: Purpose: The purpose of this study was to develop and validate an animal model of drug disposition in synovial fluid (SF) by comparing microdialysis with arthrocentesis using the anti-arthritic drug methotrexate (MTX). Methods: Microdialysis probes were calibrated in vitro with the no net flux method using dog synovial fluid. The probes were implanted surgically into the stifle joint space of four dogs and were dialyzed overnight using a portable microinfusion pump. The membrane integrity of the probes was monitored by retrodialysis using an internal standard. After an intravenous bolus of 2.5 mg/kg of MTX, unbound concentrations in synovial fluid, as well as total plasma concentrations, were measured by liquid chromatography tandam mass spectrometer (LC/MS/MS) in samples collected from 0 to 48 h postdose. Results: The probe membrane remained intact at least 48 h after implantation. The mean probe recovery and unbound fraction of MTX in SF were 46.8% and 44.8%, respectively. The unbound fraction of MTX was 44% in synovial fluid. MTX penetrated into the joint space rapidly, with maximal concentrations of 6.6 muM reached at approximately 1 h postdose. The unbound MTX area under the curve in SF was approximately 40% of the total area under the curve in plasma. These data agree well with the previous data obtained for MTX using arthrocentesis. Conclusion: In contrast with arthrocentesis, microdialysis enables the collection of multiple serial SF samples from individual animals with minimal trauma and potential blood contamination. This animal model should prove valuable for studying the disposition of new anti-arthritis compounds or biomarkers in SF.
Descriptors: models and simulations, computational biology, pharmacology, skeletal system, movement and support, arthritis, joint disease, liquid chromatography tandem mass spectroscopy, chromatographic techniques, spectrum analysis techniques, no net flux method, retrodialysis, laboratory techniques, dog microdialysis model.

Rees, C.A. and D.M. Boothe (2004). Evaluation of the effect of cephalexin and enrofloxacin on clinical laboratory measurements of urine glucose in dogs. Journal of the American Veterinary Medical Association 224(9): 1455-1458. ISSN: 0003-1488.
NAL Call Number: 41.8 Am3
Abstract: Objective-To determine the effects of cephalexin and enrofloxacin on results of 4 commercially available urine glucose tests in dogs. Animals-6 healthy adult female dogs. Procedure-In a crossover design, cephalexin (22 and 44 mg/kg (10 and 20 mg/lb), PO, q8h) or enrofloxacin (5 and 10 mg/kg (2.3 and 4.5 mg/lb), PO, q 12 h) was administered to dogs for 1 day. Urine samples were tested for glucose at 0, 6, and 24 hours after drug administration. In vitro, dextrose was added to pooled glucose-negative canine urine samples containing either no antimicrobial or known concentrations of either antimicrobial; urine samples were then tested for glucose. Results-In vivo, false-positive results were obtained by use of a tablet test in the presence of both antimicrobials and by use of a strip test in the presence of cephalexin. In vitro, false-positive results were obtained with the tablet test at the highest urine concentration of cephalexin (2,400 mug/mL) and with a strip test at the highest concentration of enrofloxacin (600 mug/mL). Enrofloxacin in urine samples containing dextrose caused the urine glucose tests to underestimate urine glucose concentration. Conclusions and Clinical Relevance-Cephalexin and enrofloxacin at dosages used in clinical practice may result in false-positive or false-negative urine glucose results, and care should be taken when using urine as a basis for identifying or monitoring diabetic animals.
Descriptors: metabolism, pharmacology, veterinary medicine, medical sciences, diabetes, endocrine disease, pancreas, metabolic disease.

Rigaud, M., P. Filip, P. Lirk, A. Fuchs, G. Gemes, and Q. Hogan (2008). Guidance of block needle insertion by electrical nerve stimulation: a pilot study of the resulting distribution of injected solution in dogs. Anesthesiology 109(3): 473-8.
Abstract: BACKGROUND: Little is known regarding the final needle tip location when various intensities of nerve stimulation are used to guide block needle insertion. Therefore, in control and hyperglycemic dogs, the authors examined whether lower-intensity stimulation results in injection closer to the sciatic nerve than higher-threshold stimulation. METHODS: During anesthesia, the sciatic nerve was approached with an insulated nerve block needle emitting either 1 mA (high-current group, n = 9) or 0.5 mA (low-current group, n = 9 in control dogs and n = 6 in hyperglycemic dogs). After positioning to obtain a distal motor response, the lowest current producing a response was identified, and ink (0.5 ml) was injected. Frozen sections of the tissue revealed whether the ink was in contact with the epineurium of the nerve, distant to it, or within it. RESULTS: In control dogs, the patterns of distribution using high-threshold (final current 0.99 +/- 0.03 mA, mean +/- SD) and low-threshold (final current 0.33 +/- 0.08 mA) stimulation equally showed ink that was in contact with the epineurium or distant to it. One needle placement in the high-threshold group resulted in intraneural injection. In hyperglycemic dogs, all needle insertions used a low-threshold technique (n = 6, final threshold 0.35 +/- 0.08 mA), and all resulted in intraneural injections. CONCLUSIONS: In normal dogs, current stimulation levels in the range of 0.33-1.0 mA result in needle placement comparably close to the sciatic nerve but do not correlate with distance from the target nerve. In this experimental design, low-threshold electrical stimulation does not offer satisfactory protection against intraneural injection in the presence of hyperglycemia.
Descriptors: coloring agents administration and dosage, electric stimulation methods, hyperglycemia physiopathology, needles, sciatic nerve physiopathology, coloring agents pharmacokinetics, disease models, animal, dogs, models, animal, peripheral nerves physiology, peripheral nerves physiopathology, pilot projects, random allocation, sciatic nerve physiology.

Riou, L.M., C. Ghezzi, G. Vanzetto, A. Broisat, J.P. Mathieu, R. Bontron, R. Pasqualini, and D. Fagret (2003). Verapamil does not inhibit 99mtcn-noet uptake in situ in normal or ischemic canine myocardium. Journal of Nuclear Medicine 44(6): 981-987. ISSN: 0161-5505.
NAL Call Number: RM845.J78
Abstract: Bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium (V) (99mTc) (99mTcN-NOET) is a new myocardial perfusion imaging agent currently undergoing phase III clinical trials in the United States and in Europe. 99mTcN-NOET cellular uptake has been shown to be inhibited by the calcium channel inhibitor verapamil in cultured newborn rat cardiomyocytes. However, the effect of verapamil on in situ 99mTcN-NOET myocardial uptake remains unknown. Therefore, the aim of this study was to evaluate whether the inhibitory effect of verapamil on the cellular uptake of 99mTcN-NOET shown in vitro could be reproduced in situ in a canine model of normal and ischemic myocardium. Methods: 99mTcN-NOET uptake in normal and ischemic myocardium (70% flow reduction in the left anterior descending coronary artery) was measured in the absence or presence of verapamil (0.015 mg/kg/minX10 min) in anesthetized, open-chest dogs (n=17). Control animals were infused with adenosine (0.2 mg/kg/min) to match the verapamil-induced increase in flow. Results: By verapamil treatment, a clinically relevant plasma concentration of the calcium channel inhibitor was attained (mean+-SEM, 290+-152 ng/mL). In normal myocardium (n=8), regional blood flow at the time of 99mTcN-NOET injection was not statistically different in verapamil- and adenosine-treated dogs (1.69+-0.03 vs. 1.61+-0.04 mL/min/g, respectively). 99mTcN-NOET uptake was slightly higher in the presence of verapamil (0.39+-0.01 vs. 0.38+-0.01 counts per minute (cpm)/(Bq/kg)/g for adenosine; P=0.04). However, no significant difference in 99mTcN-NOET myocardial uptake was observed after normalization of the tracer uptake to regional myocardial blood flow. In ischemic myocardium (n=9), regional blood flow was lower in verapamil-treated than in adenosine-treated animals (0.22+-0.02 vs. 0.29+-0.03 mL/min/g; P<0.05). 99mTcN-NOET uptake in the ischemic area was not inhibited by verapamil (0.09+-0.01 vs. 0.10+-0.01 cpm/(Bq/kg)/g; P=not significant). Conclusion: Verapamil does not inhibit 99mTcN-NOET uptake in situ in normal and ischemic canine myocardium. These results suggest that verapamil should not affect 99mTcN-NOET myocardial uptake in patients referred for myocardial perfusion imaging.
Descriptors: cardiovascular system, transport and circulation, methods and techniques, pharmacology, radiation biology, myocardial ischemia, heart disease, vascular disease.

Rudmann, D.G., M.E. Mcnerney, S.L. Vandereide, J.K. Schemmer, R.R. Eversole, and S.L. Vonderfecht (2004). Epididymal and systemic phospholipidosis in rats and dogs treated with the dopamine d3 selective antagonist pnu-177864. Toxicologic Pathology 32(3): 326-332. ISSN: 0192-6233.
Abstract: Repeat dose oral toxicity studies were conducted in rat and dog to assess the safety for human clinical testing of the potent dopamine D3 receptor antagonist, PNU-177864. Systemic phospholipidosis was the principal treatment-related change with epididymal epithelial cell phospholipidosis being the most prominent finding in rats and dogs. Epididymal epithelial cells had no histologic evidence of degeneration; sperm density and morphology were normal histologically in both species; and sperm concentration, morphology, and motility in the dog were comparable to dogs given vehicle. Other sites with phospholipidosis included lymphoid tissues ( lymph nodes, Peyer's patches, and/or spleen), pulmonary alveolar macrophages, and peripheral blood lymphocytes in rats and dogs and adrenal cortex, liver, pituitary, hair follicles, bone marrow lymphocytes and plasma cells, and skeletal muscle in rats only. The phospholipidosis was resolved after a 6-week recovery period in all tissues but epididymis. There was no evidence of cell injury in tissues that had phospholipid accumulations except in rat skeletal muscle that had multifocal myofiber degeneration and necrosis. For clinical trials, serum AST and CK and peripheral blood lymphocyte vacuolation were considered potential safety biomarkers for skeletal muscle degeneration and phospholipidosis, respectively.
Descriptors: metabolism, pharmacology, reproductive system, male, reproduction, toxicology, epididymal phospholipidosis, metabolic disease, rsystemic phospholipidosis, metabolic disease, repeat dose oral toxicity.

Satoh, Y., A. Sugiyama, A. Takahara, K. Chiba, and K. Hashimoto (2004). Electropharmacological and proarrhythmic effects of a class iii antiarrhythmic drug nifekalant hydrochloride assessed using the in vivo canine models. Journal of Cardiovascular Pharmacology 43(5): 715-723. ISSN: 0160-2446.
Abstract: Cardiovascular effects of Nifekalant were examined using halothane-anesthetized dogs, and its proarrhythmic potential was estimated with chronic complete atrioventricular block dogs. Nifekalant was intravenously administered to the halothane-anesthetized dogs in three doses of 0.03, 0.3, and 3 mg/kg/ 10 minutes with a pause of 20 minutes (n = 6). The low dose hardly affected any of the cardiovascular parameters. The middle dose, a clinically recommended antiarrhythmic dose, decreased the total peripheral resistance, increased the cardiac output, and prolonged the ventricular repolarization phase and effective refractory period. The high dose increased the left ventricular contraction, transiently decreased the mean blood pressure, and enhanced the atrioventricular conduction, besides potentiation of the changes induced by the middle dose. Increment in the repolarization phase by the high dose was greater than that in the refractoriness, leading to increase of ventricular electrical vulnerability. To the atrioventricular block animals, clinically relevant antiarrhythmic dose of 3 mg/kg p.o. of Nifekalant and its 10-times-higher dose were administered. The high dose prolonged QT interval leading to torsades de pointes in all animals (n = 5), which was not detected by the clinical dose (n = 5). These results suggest that antiarrhythmic dose of Nifekalant can be used safely; however, caution should be paid for patients complicating bradycardia and/or a risk of elevated plasma drug concentration.
Descriptors: cardiovascular system, transport and circulation, pharmacology, torsades de pointes, heart disease, atrioventricular conduction, cardiac output, chronic complete atrioventricular block, effective refractory period, left ventricular contraction, mean blood pressure, monophasic action potential, prolonged qt interval, refractoriness, total peripheral resistance, ventricular electrical vulnerability, ventricular repolarization phase.

Satoh, Y., A. Sugiyama, K. Wada, H. Nomura, and K. Hashimoto (2004). In vivo electropharmacological effects of a class iii antiarrhythmic drug dl-sotalol assessed using halothane anesthetized canine model. 77th Annual Meeting of the Japanese Pharmacological Society, Osaka, Japan; March 08-10, 2004,Vol. 94(Supplement 1): 265P,
Descriptors: cardiovascular system, transport and circulation, pharmacology, veterinary medicine, medical sciences, hypotension, vascular disease, blood pressure, left ventricular contraction, ventricular repolarization.

Sattler-J , Hesterberg-R , Lorenz-W , Schmidt-U , Crombach-M , and Stahlknecht-C-D (1985). Inhibition of human and canine diamine oxidase by drugs used in an intensive care unit relevance for clinical side effects. Agents and Actions 16(3-4): 91-94. ISSN: 0065-4299.
Descriptors: enzymology, biochemistry and molecular biophysics, metabolism , pharmacology, toxicology, neuromuscular blocking drugs, cephalosporins, histamine levels.

Scherkl, R., A. Hashem, and H.H. Frey (1996). The tissue cage in dogs - a pharmacological model for plasma- and tissue-kinetics [Die gewebekammer ("tissue cage") beim hund - ein pharmakologisches modell zur darstellung von plasma- und gewebekinetik. Deutsche Tierarztliche Wochenschrift 103(5): 174-177. ISSN: 0341-6593.
NAL Call Number: 41.8 B45
Abstract: The tissue kinetics of naproxen, a drug with a long elimination half life was compared with phenylbutazone and flunixin, which have short elimination half lives in dogs following oral administration. Tissue fluid was obtained using "tissue cages" implanted laterally in the neck. An inflammatory response was produced by injecting 1 to 2 ml of 2% carrageenan into the chamber. Drug concentrations were determined throughout the experiments in both plasma and tissue fluid. Naproxen had an elimination half life of about 72 h and remained in similar concentrations in both tissue fluid and plasma. Phenylbutazone had a longer half life in tissue fluid than in plasma. Flunixin concentrations in plasma and exudate attained equilibrium after 2 to 5 h. Afterwards, flunixin became more concentrated in inflammatory exudate exceeding the concentration in plasma by 2 to 10 times, but then declined with an almost identical half-life in both. The number of leukocytes in exudate (used as a measure of inflammation) was reduced for 2 days after phenylbutazone, for 3 to 4 days after flunixin and for 5 to 7 days after administration of naproxen. It is concluded that phenylbutazone and flunixin, and possibly other non-steroidal anti-inflammatory drugs, could be used at lower concentrations than has been calculated using the dynamics of their plasma concentrations.
Descriptors: blood plasma, leukocytes, dosage, drug therapy, phenylbutazone, pharmacokinetics, flunixin, antiinflammatory agents, dogs.
Language of Text: German, LS=.

Schwarte, L.A., O. Picker, S.R. Bornstein, A. Fournell, and T.W. Scheeren (2005). Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs. Critical Care Medicine. 33(1): 135-42. ISSN: 0090-3493.
Abstract: OBJECTIVE: The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (muHbo(2)) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (Do(2)) and/or oxygen consumption (Vo(2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. DESIGN: Laboratory experiment. SETTING: University animal research laboratory of experimental anesthesiology. SUBJECTS: Chronically instrumented dogs with flow probes for cardiac output measurement. INTERVENTIONS: Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10, followed by four infusion steps: 0.125-1.0, milrinone (5.0, followed by 1.25-10, or dobutamine (2.5-10.0 Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 MEASUREMENTS AND MAIN RESULTS: We measured muHbo(2) (reflectance spectrophotometry), Do(2), Vo(2), and systemic hemodynamics. Levosimendan significantly increased muHbo(2) from baseline (approximately 55% for all groups) to 64 +/- 4% and further to 69 +/- 2% with volume challenge (mean +/- sem). At the systemic level, levosimendan alone only slightly increased Do(2) at a Vo(2). Milrinone elicited similar systemic effects (Do(2), Vo(2), hemodynamics) but failed to increase muHbo(2). Dobutamine, conversely, increased muHbo(2) to a similar extent as levosimendan; however, this was accompanied by marked increases in Do(2) and Vo(2). The gastric mucosa selectivity of these interventions, expressed as slope of the muHbo(2)/Do2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). CONCLUSIONS: Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectively (i.e., at only moderately increased Do(2) and stable Vo(2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.
Descriptors: levosimendan, vasodilator, inodilator, gastric mucosal oxygenation, hemodynamics, pharmacology.

Schwartz, L.M., R.B. Jennings, and K.A. Reimer (1995). Minimum ischemic stress required for myocardial preconditioning in dogs: effect of analgesia, using the opiate agonist-antagonist, butorphanol. FASEB Journal 9(3): A299. ISSN: 0892-6638.
NAL Call Number: QH301.F3
Descriptors: cardiovascular system, transport and circulation, pharmacology, meeting abstract, pentobarbital .

Shibayama, T., T. Hirota, H. Seki, and S. Kuwahara (2003). Disposition of the pivaloyloxymethyl (pom) moiety in cs-834, a novel oral carbapenem, in rats and dogs. 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA; September 14-17, 2003,Vol. 43: 232,
Abstract: Background: CS-834 (CS) is an ester-type prodrug of a carbapenem for oral administration. It is important to investigate the metabolic fate of the ester moiety after dosing from the viewpoint of safety. Methods: The metabolism, excretion and tissue distribution of the POM moiety in CS were examined in rats and dogs after single oral administration of CS labeled on the POM moiety, (pivaloyl-14C)CS, at a dose of 12.65 mg/kg. Results: After oral dosing of (pivaloyl-14C)CS, most of the radioactivity in plasma consisted of pivalic acid (PA) and its conjugates, pivaloylglycine (Pgly), pivaloylglucuronide (Pglu) and pivaloylcarnitine (Pcar), in both rats and dogs. The major radioactivities were PA (32% of total radioactivity), Pgly (21%) and Pglu (15%) in rats and PA (27%) and Pglu (43%) in dogs. Recoveries of the radioactivity in the urine and feces within the first day post-dosing were 93.1% and 2.2%, respectively, in rats and 79.3% and 7.6%, respectively, in dogs. In the urine, the conjugates of PA were mainly detected. Pgly, Pglu, Pcar and PA accounted for 45.6, 42.4, 10.2 and 0.9%, respectively, of the dosed radioactivity in rats and 19.6, 60.6, 17.1 and 0.4%, respectively, of the dosed radioactivity in dogs. In most of the tissue, the levels of radioactivity reached the maximum at 1 hr after oral administration to rats. At this time point, the levels of radioactivity in the liver, kidney, Harderian gland, urinary bladder, stomach and small intestine were 3.19-1.46 times higher than that in the plasma, and those in the other tissues were lower. The levels in most of the tissues decreased in parallel with that in plasma. Conclusions: After oral dosing of (pivaloyl-14C)CS, the PA moiety, which is a part of the POM, was metabolized to its conjugate followed by excretion into the urine. This disposition almost is very similar to those of the POM moiety in cephems such as cefditoren pivoxil and cefetamet pivoxil.
Descriptors: infection, pharmacology, bacterial infections, bacterial disease, drug therapy, antibacterial therapy, clinical techniques, therapeutic and prophylactic techniques, chemotherapy , clinical techniques, drug metabolism studies, drug safety, therapeutics .

Shipe, W.D., J.C. Barrow, Z.Q. Yang, C.W. Lindsley, F.V. Yang, K.A. Schlegel, Y. Shu, K.E. Rittle, M.G. Bock, G.D. Hartman, C. Tang, J.E. Ballard, Y. Kuo, E.D. Adarayan, T. Prueksaritanont, M.M. Zrada, V.N. Uebele, C.E. Nuss, T.M. Connolly, S.M. Doran, S.V. Fox, R.L. Kraus, M.J. Marino, V.K. Graufelds, H.M. Vargas, P.B. Bunting, M. Hasbun Manning, R.M. Evans, K.S. Koblan, and J.J. Renger (2008). Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a T-type Ca2+ channel antagonist. Journal of Medicinal Chemistry 51(13): 3692-5.
NAL Call Number: RS403.A1J6
Abstract: The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.
Descriptors: calcium channel blockers chemical synthesis, calcium channel blockers pharmacology, calcium channels, t type metabolism, drug design, piperidines chemical synthesis, piperidines pharmacology, pyrans chemical synthesis, pyrans pharmacology, blood pressure drug effects, calcium channel blockers chemistry, dogs, dose response relationship, drug, haplorhini, heart rate drug effects, models, animal, molecular structure, piperidines chemistry, pyrans chemistry, rats, structure activity relationship.

Silva, F.C., E. Hatschbach, A.F. Lima, Y.K. Carvalho, and F. Massone (2007). Continuous infusion in adult females dogs submitted to ovariohysterectomy with midazolam-xylazine and/or medetomidine pre-treated with methotrimeprazine and buprenorphine. Acta Cirurgica Brasileira Sociedade Brasileira Para Desenvolvimento Pesquisa Em Cirurgia 22(4): 272-8. ISSN: 0102-8650.
Abstract: PURPOSE: To compare, by continuous infusion of ketamine or medetomidine combined to methotrimeprazine and buprenorphine, ketamine and midazolam, the degree of hypnosis, myorelaxation, anesthetic quality and surgical feasibility through evaluation of possible parametric alterations and recovery quality. METHODS: 20 healthy adult females dogs, aged 3 to 5 years, body weight between 7 and 15 kg, were assigned randomly and homogenously to 2 groups of 10 animals each (n=10), group 1 (G1) and group 2 (G2), respectively. Animals of G1 were subjected to a pre-treatment with intravenous 1.0 mg/kg methotrimeprazine and or 3i/kg. After 15 minutes, a 5.0 mg/kg ketamine and 0.2 mg/kg midazolam were intravenously injected. Immediately after induction, an anesthetic combination of 0.4 mg/kg/h midazolam, 20 mg/kg/h ketamine and 1.0 mg/kg/h xylazine, was continuously and intravenously administered for 30 minutes. The same techniques were used in G2 except for the substitution of xylazine for 30ig/kg/h medetomidine. RESULTS: In G1 there was a 1st and 2nd degree atrioventricular heart block, a longer recovery period and lower quality. In G2 a 1st degree atrioventricular heart block occurred but isolated and ephemeral. CONCLUSIONS: The continuous infusion method, besides reducing drugs utilization, prevented collateral effects allowing a more tranquil recovery with no excitations, both protocols permitted the surgical procedure (ovary-hysterectomy) bringing about a reduction in hypnosis and an accentuated myorelaxation. Xylazine and medetomidine showed a similar pharmacodynamic behavior but with different clinical aspects. The electrocardiographic alterations observed in G2 and in a lower degree in G1 must be well studied. Describers: dogs, ketamine, methotrimeprazine, medetomidine, midazolam and xylazine.
Descriptors: adrenergic alpha agonists administration and dosage, anesthetics, intravenous administration and dosage, hypnotics and sedatives administration and dosage, hysterectomy methods, ovariectomy methods, analgesics, opioid administration and dosage, anesthetics, combined administration and dosage, buprenorphine administration and dosage, dogs, dopamine antagonists administration and dosage, drug evaluation, preclinical, hysterectomy standards, infusion pumps, medetomidine administration and dosage, methotrimeprazine administration and dosage, midazolam administration and dosage, models, animal, ovariectomy standards, random allocation, xylazine administration and dosage.

Siwak, C., H. Callahan, P. Gruet, M. Takagi, and N.W. Milgram (1998). Adrafinil: a novel compound with both behavioral activating and cognitive enhancing effects in aged dogs. Society for Neuroscience Abstracts 24(1-2): 686. ISSN: 0190-5295.
NAL Call Number: QP351.S6
Descriptors: behavior, pharmacology, behavior, learning, meeting abstract, meeting poster

Siwak, C.T., P. Gruet, F. Woehrle, B.A. Muggenburg, H.L. Murphey, and N.W. Milgram (2000). Comparison of the effects of adrafinil, propentofylline, and nicergoline on behavior in aged dogs. American Journal of Veterinary Research 61(11): 1410-1414. ISSN: 0002-9645.
NAL Call Number: 41.8 Am3A
Descriptors: dogs, age differences, animal behavior, efficacy, mental disorders, drug therapy, quality of life, movement, dosage, pharmacodynamics.
Notes: Includes references.

Stambler, B.S., G. Fenelon, R.K. Shepard, H.F. Clemo, and C.M. Guiraudon (2003). Characterization of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. Journal of Cardiovascular Electrophysiology 14(5): 499-507. ISSN: 1045-3873.
Abstract: Atrial Tachycardia in Heart Failure. Introduction: Atrial arrhythmias often complicate congestive heart failure (CHF). We characterized inducible atrial tachyarrhythmias and electrophysiologic alterations in dogs with CHF and atrial enlargement produced by rapid ventricular pacing. Methods and Results: Endocardial pacing leads were implanted in the right ventricle, right atrium, and coronary sinus in 18 dogs. The right ventricular lead was connected to an implanted pacemaker capable of rapid ventricular pacing. The atrial leads were used to perform electrophysiologic studies in conscious animals at baseline in all dogs, during CHF induced by rapid ventricular pacing at 235 beats/min in 15 dogs, and during recovery from CHF in 6 dogs. After 20 +- 7 days of rapid ventricular pacing, inducibility of sustained atrial tachycardia (cycle length 120 +- 12 msec) was enhanced in dogs with CHF. Atrial tachycardia required a critical decrease in atrial burst pacing cycle length (ltoreq 130 msec) for induction and often could be terminated by overdrive pacing. Calcium antagonists (verapamil, flunarizine, ryanodine) terminated atrial tachycardia and suppressed inducibility. Effective refractory periods at 400- and 300-msec cycle lengths in the right atrium and coronary sinus were prolonged in dogs with CHF. Atrial cells from dogs with CHF had prolonged action potential durations and reduced resting potentials and delayed afterdepolarizations (DADs). Mitochondria from atrial tissue from dogs with CHF were enlarged and had internal cristae disorganization. Conclusions: CHF promotes inducibility of sustained atrial tachycardia. Based on the mode of tachycardia induction, responses to pacing and calcium antagonists, and presence of DADs, atrial tachycardia in this CHF model has a mechanism most consistent with DAD-induced triggered activity resulting from intracellular calcium overload.
Descriptors: cardiovascular system, transport and circulation, methods and techniques, pharmacology, arrhythmia, heart disease, atrial tachycardia, congestive heart failure, rapid ventricular pacing.

Stonerook, M., C. Hassler, P. Tosca, J. Merrill, D. Vasconcelos, and A. Smith (2003). Cardiotoxicity study of nsc-638850 (ucn-01) and cytostar (ara-c) given alone or in combination to beagle dogs. Toxicological Sciences 72(S-1): 36 ISSN: 1096-6080.
NAL Call Number: RA1190.F8
Descriptors: pharmacology, toxicology, cardiotoxicity, heart disease, toxicity, drug induced, ecg, electrocardiography, clinical techniques, diagnostic techniques, cardiovascular evaluation, combination chemotherapy, therapeutic and prophylactic techniques, blood pressure, body temperature, heart rate, necrosis, vascular resistance, venodilation .

Stump, D.G., J.F. Holson, L.B. Pearce, V.T. Rentko, and M.S. Gawryl (2003). Finding of developmental toxicity studies of hboc-201 in rodent and canine models. Birth Defects Research 68(3): 250. ISSN: 1542-0752.
NAL Call Number: QL991 .T4
Descriptors: development, pharmacology, toxicology .

Sugiyama, A., Y. Satoh, K. Wada, H. Nomura, Y. Nakamura, and K. Hashimoto (2004). Torsadogenic action of qt-prolonging drugs, astemizole and haloperidol, assessed by the canine chronic atrioventricular block model. Journal of Pharmacological Sciences 94(Supplement 1): 151P. ISSN: 1347-8613.
Descriptors: cardiovascular system, transport and circulation, pharmacology, torsades de pointes, heart disease, toxicity, drug induced, pathology, ventricular fibrillation, holter ecg monitoring, holter electrocardiography monitoring, clinical techniques, intravenous administration, oral administration, clinical techniques, chronic atrioventricular block, effective refractory period, idioventricular automaticity, ventricular repolarization phase

Sumner, D.R., T.M. Turner, R.M. Urban, T. Turek, H. Seeherman, and J.M. Wozney (2004). Locally delivered rhbmp-2 enhances bone ingrowth and gap healing in a canine model. Journal of Orthopaedic Research 22(1): 58-65. ISSN: 0736-0266.
Abstract: The purpose of the present study was to determine if recombinant human bone morphogenetic protein-2 (rhBMP-2) enhances bone ingrowth into porous-coated implants and gap healing around the implants. In the presence of a 3-mm gap between the implant and host bone, porous-coated implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs. In three treatment groups, the test implant was treated with HA/TCP and rhBMP-2 in buffer at a dose of 100 mug/implant (n=5), 400 mug/implant (n=6), or 800 mug/implant (n=5) and placed in the left humerus. In these same animals, an internal control implant was treated only with HA/TCP and buffer and placed in the right humerus. These groups were compared with a previously reported external control group of seven animals in which no growth factor was delivered (J. Orthop. Res. 19 (2001) 85). The BMP treated implants in the two lower dose groups had significantly more bone ingrowth than the external controls with the greatest effect in the 100 g/implant group (a 3.5-fold increase over the external control, p=0.008). All three dose groups had significantly more bone formation in the 3-mm gap surrounding the BMP treated implants than the external controls with the greatest effect in the 800 mug group (2.9-fold increase, p<0.001). Thus, application of rhBMP-2 to a porous-coated implant stimulated local bone ingrowth and gap healing. The enhancement of bone formation within the implant (bone ingrowth) was inversely related to dose.
Descriptors: pharmacology, skeletal system, movement and support, bone ingrowth, gap healing.

Takeda, H., A. Matsuzawa, Y. Igawa, Y. Yamazaki, K. Kaidoh, S. Akahane, M. Kojima, H. Miyata, M. Akahane, and O. Nishizawa (2003). Functional characterization of beta-adrenoceptor subtypes in the canine and rat lower urinary tract. Journal of Urology 170(2 Part 1): 654-658. ISSN: 0022-5347.
NAL Call Number: 448.8 J8234
Abstract: Purpose: We compared the effect of a beta3-adrenoceptor (AR) agonist with that of beta1 and beta2-AR agonists on the urethra and bladder in the dog and rat. Materials and Methods: In an in vitro experiment we studied the relaxant effect of subtype selective beta-AR agonists in canine and rat urethral and bladder smooth muscle using an organ bath method. In addition, in urethane anesthetized rats we measured urethral pressure and bladder pressure simultaneously in the presence of the beta3-agonist CL316243 and the beta2-agonist procaterol in 4 or 5 animals. Results: In the dog the relaxing effects of isoprenaline in the distal urethra were about half those seen in the detrusor and trigone. The rank order of relaxing potency was CL316243 > dobutamine (beta1-agonist) = procaterol in detrusor and trigone but procaterol > dobutamine = CL316243 in the prostatic and distal urethra. In rat urethral smooth muscle in vitro the corresponding order was procaterol > CL316243 > dobutamine and the maximal relaxation to each agonist was about half that seen in the bladder. In the anesthetized rat procaterol clearly decreased urethral pressure but CL316243 produced only a slight decrease at its maximal dose, although each agonists clearly reduced bladder pressure. The beta2-antagonist ICI-118551 counteracted the decrease in urethral and bladder pressure induced by procaterol. Conclusions: In rats and dogs a selective beta3-AR agonist can decrease bladder pressure without affecting urethral pressure.
Descriptors: biochemistry and molecular biophysics, pharmaceuticals, pharmacology, urinary system, chemical coordination and homeostasis.

Takehana, K., G.A. Beller, M. Ruiz, F.D. Petruzella, D.D. Watson, and D.K. Glover (2001). Assessment of residual coronary stenoses using 99mtc-n-noet vasodilator stress imaging to evaluate coronary flow reserve early after coronary reperfusion in a canine model of subendocardial infarction. Journal of Nuclear Medicine 42(9): 1388-1394. ISSN: 0161-5505.
NAL Call Number: RM845.J78
Abstract: Reperfusion is often incomplete after recanalization therapy because of the presence of residual coronary stenoses. Detecting mild to moderate stenoses requires assessing coronary flow reserve with vasodilator stress. 99mTc-(N-ethoxy-N-ethyl-dithiocarbamato)nitrido (N-NOET) is a viability-independent flow tracer and thus may be well suited for assessing coronary flow reserve in the acute phase of reperfusion. Methods: Twelve open-chest dogs underwent 60 min of total left anterior descending artery (LAD) occlusion followed by either full reperfusion (group 1; n = 4) or reperfusion through a residual critical stenosis (group 2; n = 8). 99mTc-N-NOET was given during peak vasodilator stress 165 min after reperfusion, and initial and 60-min delayed images were acquired. Regional blood flow was assessed with radiolabeled microspheres. Results: Infarct size was similar in both groups (9% +- 2% vs. 8% +- 2% of left ventricle). Both initial (0.61 +- 0.02 vs. 0.73 +- 0.01; P < 0.01) and 60-min (0.67 +- 0.02 vs. 0.80 +- 0.01; P < 0.01) defect count ratios (LAD/left circumflex coronary artery (LCx)) differentiated between the 2 groups, reflecting the greater diminution in coronary flow reserve in group 2 dogs (LAD/LCx flow ratios = 0.37 +- 0.04 vs. 0.57 +- 0.09; P < 0.01). Interestingly, coronary flow reserve in the reperfused zone of group 1 was diminished despite the absence of a stenosis. Thus, the difference in 99mTc-N-NOET uptake between the 2 groups was less than expected. Conclusion: In this canine myocardial infarction model with some coronary flow reserve preservation, 99mTc-N-NOET imaging can detect residual coronary stenoses. However, with more prolonged occlusion resulting in more severe endothelial or microvascular dysfunction, it may be difficult to distinguish varying degrees of vessel patency using any coronary flow reserve technique.
Descriptors: cardiovascular system, transport and circulation, pharmaceuticals, pharmacology, radiation biology, subendocardial infarction, heart disease, vascular disease, coronary flow reserve, coronary reperfusion, coronary stenosis, nuclear medicine.

Teo, S.K., D.I. Stirling, S.D. Thomas, M.G. Evans, and V.D. Khetani (2003). A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in beagle dogs. International Journal of Toxicology 22(3): 215-226. ISSN: 1091-5818.
NAL Call Number: RA1190.J61
Abstract: d-Methylphenidate (d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d,l-methylphenidate (d,l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d,l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d,l-MPH in d-MPH content. The 10-mg/kg d-MPH and d,l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d,l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d,l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day.
Descriptors: pharmacology, toxicology, veterinary medicine, medical sciences, attention deficit hyperactivity disorder, ADHD, (Attention Deficit Disorder with Hyperactivity), behavioral and mental disorders, digestive system disease, oral gavage toxicity study, clinical techniques, body weight loss, food consumption.

Thompson, K., R.T. Thompson, J. Sykes, and G. Wisenberg (2003). Long-term magnetic resonance imaging/spectroscopy study of cariporide in a canine cardiac ischemia/reperfusion model. Journal of Cardiovascular Pharmacology 41(4): 536-543. ISSN: 0160-2446.
Abstract: Using both 31P and 1H cardiac magnetic resonance techniques, it is possible to monitor the functional (ejection fraction (EF)) and biochemical (pH) status of the heart following a reperfused ischemic insult. This study assessed the effects of Na+/H+ exchange inhibition with cariporide in a closed-chest canine ischemia/reperfusion model. Dogs received 1-mg/kg cariporide treatments for 3 days after occlusion, but were monitored for 10 days. Baseline intracellular pH (+-SEM) for the control and treated groups were 7.10 +- 0.03 and 7.14 +- 0.04, respectively, and dropped to 6.25 +- 0.08 and 6.38 +- 0.08 during occlusion. There was a significant increase in pH from occlusion to early reperfusion in the control group (P = 0.03) but, during the same time period, this increase was not seen in the cariporide group. There was a significant (P = 0.01) drug interaction in recovery of EF over the 10-day protocol. Individual time-point analysis revealed significant differences at immediate reperfusion through day 3 (73.9% +- 2.5%, 84.5% +- 3.1%; baseline normalized EF controls and cariporide, respectively). Neither pH nor EF measurements were significantly different between the groups at day 10. Despite early functional and metabolic benefits, infarct size, as measured at day 10, was 13.2% +- 2.2% for the controls and 11.8% +- 2.3% for the cariporide group (NS). Thus there were no long-term cariporide functional or biochemical benefits.
Descriptors: cardiovascular system, transport and circulation, methods and techniques, pharmacology, cardiac ischemia reperfusion injury, heart disease, injury, vascular disease, magnetic resonance imaging, imaging and microscopy techniques, laboratory techniques, magnetic resonance spectroscopy, spectrum analysis techniques, ejection fraction, intracellular ph, long term study, sodium ion proton exchange.

Tica, V.I., V. Nestianu, A.A. Tica, M. Beghim, L. Serbanescu, E. Beghim, and S. Bafani (2007). Cercetari experimentale privind utilizarea piritramidei ca analgezic intratecal. [Experimental study of the use of piritramide as intrathecal analgesic]. Chirurgia Bucharest, Romania 1990 102(1): 57-63. ISSN: 1221-9118.
Abstract: Opioids proved their advantages as general and intrathecal (i.t.) analgesics. Piritramide (P), a largely used analgesic opioid today, has not been studied in i.t. administration. Our experimental research aimed in determining the efficiency, security and optimal dose of i.t. P. In 9 adult mongrel dogs equally randomized in 3 groups we injected i.t. P 1.3 mg x kg-l (group 1), P 0.8 mg x kg-l (group 2) and sodium chloride 0,9% (group 3) and we registered the motility, the pain reaction to electrical and mechanical nociceptive stimuli, the respiratory rate and amplitude, electrocardiogram, heart rate, mean arterial blood pressure electroencephalogram and, for 2 subjects from group 1, electromyogram. The P-induced analgesia was strong, dose-dependent, and segmental, with a time of onset of 5-8 min, duration of 1h 45 min-2h 30 min, and prolonged residual analgesic level for 5-6 h. The dogs from the 1st group presented moderate side effects: bradypnea, tachycardia and arterial hypotension at 5 min, reduction in the posterior limbs motility, sleep. We could conclude that i.t. piritramide 0.8 mg x kg-l provides a solid, segmental, long-lasting analgesia, without marked adverse effects.
Descriptors: analgesics, opioid therapeutic use, pain drug therapy, pirinitramide therapeutic use, analgesics, opioid pharmacology, dogs, injections, spinal, models, animal, pirinitramide pharmacology, random allocation, respiration drug effects.
Language of Text: Romanian-Rumanian; Non-.

Tomiyama, Y., M. Murakami, Y. Yamazaki, M. Kojima, and M. Akahane (2003). Comparison between cl-316243- and cgp-12177a-induced relaxations in isolated canine ureter. Pharmacology 68(3): 140-146. ISSN: 0031-7012.
NAL Call Number: RM1.P473
Abstract: We compared the effects of CL-316243, a selective beta3-adrenoceptor agonist, and CGP-12177A, a nonconventional partial beta-adrenoceptor agonist, on the KCl-induced contraction in the isolated canine ureter. CL-316243 concentration dependently relaxed the ureteral contraction, the pD2 value being 7.75 +- 0.11. This relaxation was competitively antagonized by the selective beta3-adrenoceptor antagonist SR58894A and by the nonselective beta-adrenoceptor antagonist bupranolol, their pA2 values being 7.08 +- 0.08 and 6.43 +- 0.09, respectively. CGP-12177A concentration dependently reduced the KCl-induced contraction, the pD2 value being 6.30 +- 0.25. Even at 1 X 10-5 mol/l, CGP-20712A (a selective beta1-adrenoceptor antagonist) did not shift the concentration-response curves for CL-316243 or CGP-12177A. SR58894A did not induce a parallel rightward shift in the concentration-response curve for CGP-12177A, but bupranolol did produce such a shift, pA2 and slope values in the Schild plot being 7.15 +- 0.77 and 0.60 +- 0.15, respectively. Hence, the competition characteristics for SR58894A and bupranolol differed between the CL-316243-induced and CGP-12177A-induced relaxations. Our results suggest that CGP-12177A produces ureteral relaxation in the dog via an atypical beta-adrenoceptor (possibly, an atypical site/state of the beta3-adrenoceptor) as well as via the typical beta3-adrenoceptor.
Descriptors: biochemistry and molecular biophysics, pharmacology, urinary system, chemical coordination and homeostasis, concentration response curves.

Tontodonati, M., N. Fasdelli, E. Moscardo, A. Giarola, and R. Dorigatti (2007). A canine model used to simultaneously assess potential neurobehavioural and cardiovascular effects of candidate drugs. Journal of Pharmacological and Toxicological Methods 56(2): 265-75. ISSN: 1056-8719.
NAL Call Number: QP901.J6
Abstract: INTRODUCTION: Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. A new model using dogs which allows for the integration of these assessments into a single study was established and validated, adopting the most sophisticated technologies for both monitoring behaviour by video recordings and cardiovascular parameters by telemetry. METHODS: Conscious male beagle dogs (n=4) were given single oral doses of vehicle, and D-amphetamine (0.25, 0.75, 1.5 mg/kg) or acepromazine (0.05, 0.3, 2 mg/kg) within two different studies. Blood pressure, heart rate, electrocardiogram (EKG), body temperature, motor activity and behaviour (by video) were monitored continuously for 24 h post-dose. Animals underwent a full neurobehavioural examination the day before dosing, at the time to the maximal plasma concentration (Tmax) and 24 h post-dose. RESULTS: D-Amphetamine: a dose-dependent increase in arterial blood pressure was noted at all doses and was generally associated with an increase in the QA interval, an index of cardiac contractility. Heart rate also increased but only at the 1.5 mg/kg dose. A dose-dependent general excitatory state of the nervous system was observed, characterised mainly by hyper-reactivity, and stereotyped activities. Acepromazine: a decrease in systolic blood pressure was detected at 0.3 and 2 mg/kg generally associated with a decrease in pulse pressure reflecting a negative inotropic effect. A dose-related increase in heart rate accompanied this effect. Dose-dependent general depression of the nervous system was noted; mainly characterised by half-closed eyes, subdued behaviour and impaired posture. In both studies, all dogs completely recovered at approximately 16 h after treatment. DISCUSSION: Cardiovascular and neurobehavioural changes expected from the pharmacology of test substances were accurately detected. No significant fluctuations of the telemetric parameters recorded were noted as a consequence of the handling associated with the direct neurobehavioural examination. These results confirm the validity of this combined model capable of providing a reliable neurobehavioural and cardiovascular assessment of drugs.
Descriptors: behavior, animal drug effects, cardiovascular physiological phenomena drug effects, drugs, investigational pharmacology, models, animal, acepromazine administration and dosage, acepromazine pharmacology, acepromazine toxicity, administration, oral, behavior, animal physiology, blood pressure drug effects, body temperature drug effects, body temperature physiology, dextroamphetamine administration and dosage, dextroamphetamine pharmacology, dextroamphetamine toxicity, dogs, dose response relationship, drug, drugs, investigational administration and dosage, drugs, investigational toxicity, electrocardiography drug effects, electrocardiography methods, heart rate drug effects, hyperkinesis chemically induced, hyperkinesis physiopathology, hypnotics and sedatives administration and dosage, hypnotics and sedatives pharmacology, hypnotics and sedatives toxicity, long qt syndrome chemically induced, long qt syndrome physiopathology, motor activity drug effects, motor activity physiology, reflex, pupillary drug effects, reflex, pupillary physiology, reproducibility of results, sialorrhea chemically induced, sialorrhea physiopathology, telemetry methods.

Trott, D.J., L.J. Filippich, J.C. Bensink, M.T. Downs, S.E. Mckenzie, K.M. Townsend, S.M. Moss, and J.J.C. Chin (2004). Canine model for investigating the impact of oral enrofloxacin on commensal coliforms and colonization with multidrug-resistant escherichia coli. Journal of Medical Microbiology 53(5): 439-443. ISSN: 0022-2615.
NAL Call Number: QR1.J62
Abstract: A model was developed in dogs to determine the impact of oral enrofloxacin administration on the indigenous coliform population in the gastrointestinal tract and subsequent disposition to colonization by a strain of multidrug-resistant Escherichia coli (MDREC). Dogs given a daily oral dose of 5 mg enrofloxacin kg-1 for 21 consecutive days showed a significant decline in faecal coliforms to levels below detectable limits by 72 In of administration. Subsequently, faecal coliforms remained suppressed throughout the period of enrofloxacin dosing. Upon termination of antibiotic administration, the number of excreted faecal coliforms slowly returned over an 8-day period, to levels comparable to those seen prior to antibiotic treatment. Enrofloxacin-treated dogs were more effectively colonized by MDREC, evidenced by a significantly increased count of MDREC in the faeces (7.1 +/- 1.5 log10 g-1) compared with non-antibiotic-treated dogs (5.2 +/- 1.2; P = 0.003). Furthermore, antibiotic treatment also sustained a significantly longer period of MDREC excretion in the faeces (26.8 +/- 10.5 days) compared with animals not treated with enrofloxacin (8.5 +/- 5.4 days; P = 0.0215). These results confirm the importance of sustained delivery of an antimicrobial agent to maintain and expand the colonization potential of drug-resistant bacteria in vivo, achieved in part by reducing the competing commensal coliforms in the gastrointestinal tract to below detectable levels in the faeces. Without in vivo antimicrobial selection pressure, commensal coliforms dominated the gastrointestinal tract at the expense of the MDREC population. Conceivably, the model developed could be used to test the efficacy of novel non-antibiotic strategies aimed at monitoring and controlling gastrointestinal colonization by multidrug-resistant members of the Enterobacteriaceae that cause nosocomial infections.
Descriptors: digestive system, ingestion and assimilation, infection, pharmacology, antibacterial therapy, clinical techniques, therapeutic and prophylactic techniques, oral drug therapy, clinical techniques, therapeutic and prophylactic techniques, bacterial colonization, medical microbiology, methodology, nosocomial infections, sources .

Willigers, H.M., F.W. Prinzen, P.M. Roekaerts, S. De Lange, and M.E. Durieux (2003). Dexmedetomidine decreases perioperative myocardial lactate release in dogs. Anesthesia and Analgesia 96(3): 657-664. ISSN: 0003-2999.
Abstract: The sympatholytic effect of the alpha2-adrenergic agonist dexmedetomidine may decrease emergence-related myocardial ischemic load in patients. However, a direct measure of myocardial ischemia, such as myocardial lactate release, is difficult to obtain in patients. Therefore, we studied mongrel dogs and measured myocardial lactate release, myocardial oxygen supply, hemodynamic variables, and neurohumoral indices of the stress response. After the induction of a standardized degree of borderline myocardial ischemia, either dexmedetomidine (dexmed group, n = 9) or normal saline (control group, n = 9) was infused. Measurements were repeated at the end of the anesthetic period and every 10 min during the 90-min emergence period. In the dexmed group, the cumulative emergence-related lactate release was 46% less than in the control group (95% confidence interval, 20%-80%; P = 0.02). Simultaneously, dexmedetomidine increased the endo-/epicardial blood flow ratio by 35% (control group, 0.4 +- 0.1; dexmed group, 0.6 +- 0.1; P = 0.03). These antiischemic effects of dexmedetomidine were accompanied by reduced plasma concentrations of norepinephrine (126 versus 577 pg/mL) and epinephrine (158 versus 1909 pg/mL) and a slower heart rate (123 +- 6 versus 160 +- 10 bpm, dexmed versus control). The antiischemic effect of dexmedetomidine started before emergence, as evidenced by a decreased prevalence of myocardial lactate release at that time (zero of eight dogs in the dexmed group and four of seven dogs in the control group had lactate release before emergence; P = 0.03).
Descriptors: cardiovascular system, transport and circulation, metabolism, pharmacology, myocardial ischemia, heart disease, vascular disease.

Wilson, J.E., N.V. Chandrasekharan, K.D. Westover, K.B. Eager, and D.L. Simmons (2004). Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs. American Journal of Veterinary Research 65(6): 810-818. ISSN: 0002-9645.
NAL Call Number: 41.8 Am3A
Abstract: Objective-To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). Sample Population-Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. Procedure-11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50% of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. Results-Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. Conclusions and Clinical Relevance-Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.
Descriptors: enzymology, biochemistry and molecular biophysics, pharmacology, cox assay, bioassay techniques, northern blot analysis, genetic techniques, laboratory techniques, western blot analysis, inhibition constant 50, ic 50.

Xu, H.B. and Z.Q. Huang (2007). Vasorelaxant effects of icariin on isolated canine coronary artery. Journal of Cardiovascular Pharmacology 49(4): 207-13. ISSN: 0160-2446.
Abstract: Owing to its cardiovascular therapeutical effects, icariin, a flavonoid isolated from Epimedii herba, is considered to be the major active constituent of Epimedii herba. The aim of this study is to investigate the effect of icariin on precontracted coronary artery isolated from canine. Coronary artery segments were isolated from normal anesthetized Beagle dogs and cut into 5-mm rings. The rings were mounted in an organ chamber and contracted by either 40 mM KCl or 10 microM PGF2alpha, and vasorelaxant tone to icariin was measured. Treatment of icariin could significantly produce a relaxation of precontracted coronary arterial rings with intact endothelium in a concentration-dependent manner. Comparatively, the vasorelaxation disappeared in denuded-endothelium rings. Furthermore, the vasorelaxant effect of icariin was blocked by Nomega-Nitro- L-arginine Methyl Ester (L-NAME), 1H-[1, 2, 4]-oxadiazolo [4, 3-a] quinoxalin-1-one (ODQ) but not by indomethacin and glibenclamide, respectively. Tetraethylammonium (TEA) could partly antagonize the vasorelaxant effect triggered by icariin. There was no significant gene expression difference of the endothelial nitric oxide synthase (eNOS) gene in coronary arterial rings among the different concentrations of icariin by RT-PCR, but the activity of eNOS was increased in a concentration-dependent manner after icariin exposure. These results suggest that icariin produces NO-dependent relaxation in the isolated canine coronary artery, and the possible mechanism is involved in the activation of eNOS protein and NO-cGMP pathway.
Descriptors: coronary vessels drug effects, drugs, chinese herbal pharmacology, flavonoids pharmacology, vasodilation drug effects, analysis of variance, anti arrhythmia agents pharmacology, coronary vessels enzymology, coronary vessels physiopathology, dinoprost pharmacology, dogs, dose response relationship, drug, endothelium, vascular drug effects, endothelium, vascular enzymology, endothelium, vascular physiopathology, enzyme inhibitors pharmacology, glyburide pharmacology, indomethacin pharmacology, models, animal, ng nitroarginine methyl ester pharmacology, nitric oxide synthase type iii drug effects, nitric oxide synthase type iii genetics, nitric oxide synthase type iii metabolism, oxadiazoles pharmacology, oxytocics pharmacology, potassium channel blockers pharmacology, quinoxalines pharmacology, rna, messenger drug effects, rna, messenger metabolism, reverse transcriptase polymerase chain reaction, tetraethylammonium pharmacology, vasodilation genetics.

Yaksh, T.L., N. Tozier, K.A. Horais, S. Malkmus, M. Rathbun, L. Lafranco, and J. Eisenach (2008). Toxicology profile of N-methyl-D-aspartate antagonists delivered by intrathecal infusion in the canine model. Anesthesiology 108(5): 938-49.
Abstract: BACKGROUND: Intrathecal N-methyl-d-aspartate antagonists have antihyperalgesic efficacy. The authors examined toxicity in a canine model of chronic lumbar intrathecal infusion. METHODS: Dogs (10-16 kg) were prepared with lumbar intrathecal catheters connected to vest-mounted pumps (100 microl/h). In phase 1, stepwise incrementations in infusion concentration were performed at 48- to 72-h intervals to determine an infusion dose with minimal but detectable behavioral effects. In phase 2, the dose/concentration defined in phase 1 was infused for 28 days. Behavioral function during infusion and histopathology at sacrifice was assessed. Drugs examined were 2-amino-5-phosphono-valorate (AP5), MK801, memantine, amitriptyline, S-methadone, and saline. RESULTS: In the phase 1 dose ranging, the minimum effect doses for the several agents were as follows: AP5, 1 mg/day; amitriptyline, 1 mg/day; ketamine, 10 mg/day; MK801, 1 mg/day; and memantine, 4 mg/day. In phase 2, infusion of these doses typically resulted in mild hind limb weakness by 3-5 days after initiation of infusion, which progressed over the 28-day infusion interval. In a limited number of animals, a similar effect was observed with S-methadone. Histopathologically, vehicle-infused animals displayed a minor local catheter reaction. With the drug treatments, a gradient of increasing pathology from cervical to lumbar segments was noted. Pathology ranged from local demyelination to necrotizing lesions of spinal parenchyma near the catheter tip. All drugs given at their respective doses produced pathology scores significantly worse than saline controls. CONCLUSIONS: These drugs given for 28 days at acutely tolerable doses lead to spinal pathology. These data suggest a reevaluation of the use of these agents in chronic spinal delivery.
Descriptors: dizocilpine maleate pharmacology, ketamine pharmacology, n methylaspartate antagonists and inhibitors, amitriptyline administration and dosage, amitriptyline pharmacology, dizocilpine maleate administration and dosage, dogs, infusion pumps, implantable, infusions, parenteral, ketamine administration and dosage, memantine administration and dosage, memantine pharmacology, models, animal, sulfamethizole pharmacology.

Yang, X.P. and S. Chiba (2003). Interaction between neuropeptide y y1 receptors and alpha1b-adrenoceptors in the neurovascular junction of canine splenic arteries. European Journal of Pharmacology 466(3): 311-315. ISSN: 0014-2999.
NAL Call Number: QP901.E8
Abstract: Previous study has demonstrated that periarterial electrical nerve stimulation (30-s trains of pulses at a frequency of 1 or 4 Hz) induces a double-peaked vasoconstriction consisting of an initial transient, predominantly P2X-receptor-mediated constriction followed by a prolonged, mainly alpha1-adrenoceptor-mediated response in the isolated canine splenic artery. Treatment with 8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)decane-7,9-dione (BMY 7378, 0.1 mumol/l), a selective alpha1D-adrenoceptor antagonist, produced a slight but significant inhibition of the second peaked responses. A marked inhibition of second peaked responses was obtained by exposure of the tissues to chloroethylclonidine (60 mumol/l), an alpha1B- and alpha1D-adrenoeptor antagonist. Neither BMY 7378 nor chloroethylclonidine affected the first peaked vasoconstrictor responses. (Leu31,Pro34)Neuropeptide Y (10-30 nmol/l), a selective neuropeptide Y Y1 receptor agonist, enhanced the second peaked responses in the presence of BMY 7378 but failed to enhance the responses in the presence of chloroethylclonidine. The results indicate that the postjunctional alpha1B-adrenoceptor subtype is likely coupled to neuropeptide Y Y1 receptors responsible for the cooperation of the sympathetic adrenergic and neuropeptide Yergic transmission in the canine splenic artery.
Descriptors: cardiovascular system, transport and circulation, nervous system, neural coordination, pharmacology .

Yu, S., Y. Ma, T. Xia, and S. Ma (1995). Studies of action of rhodobrun roseum limpr on changes of red cell aggregation and yield-shear stress in dogs with acute experimental coronary occlusion. Zhongguo Zhongyao Zazhi 20(7): 429-431, 449. ISSN: 1001-5302.
Abstract: Following acute occlusion of the left anterior descending coronary artery in dogs, significant increases were observed in the red cell aggregation index, yield-shear stress and red cell electrophoretic time in blood drained from ischemic area. When transfusion was performed with Rhodobrum roseum solution from the right femoral vein, significant rises of the above-said items were observed.
Descriptors: biochemistry and molecular biophysics, blood and lymphatics, transport and circulation, cardiovascular system, transport and circulation, cell biology, pharmacognosy, pharmacology, blood viscosity, myocardial ischemia.
Language of Text: Chinese.

Zaucha, J.M., C. Yu, G. Mathioudakis, K. Seidel, G. Georges, G. Sale, M.T. Little, B. Torok Storb, and R. Storb (2001). Hematopoietic responses to stress conditions in young dogs compared with elderly dogs. Blood 98(2): 322-327. ISSN: 0006-4971.
NAL Call Number: RB145.A1B57
Abstract: Clinical observations show that older patients do not tolerate high-dose chemoradiotherapy as well as younger patients. It is unclear whether this is due to age-related differences in their responses to hematopoietic injury or to differential toxicities to other organs. In the present study, 6 young (0.5 years) and 6 elderly (8 years) dogs were challenged with 7 repeated nonlethal doses of 50 or 100 cGy total body irradiation (TBI) each (total 550 cGy), and 21 days of recombinant canine granulocyte-colony stimulating factor (rcG-CSF) after the last TBI dose. Recoveries of absolute neutrophil, platelet, and lymphocyte counts after each TBI dose, responses to rcG-CSF treatment, and telomere lengths in neutrophils were compared before and after the study. No differences were found in recoveries of neutrophils, platelets, or in responses to rcG-CSF among young and old dogs. In contrast, recoveries were suggestively worse in younger dogs. After rcG-CSF, platelet recoveries were poor in both groups compared with previous platelet recoveries (P<.01). Consequently, 2 old and 3 young dogs were euthanized because of persistent thrombocytopenia and bleeding. At the study's completion, marrow cellularities and peripheral blood counts of the remaining young and elderly dogs were equivalent. The telomere lengths in both groups were significantly reduced after the study versus beforehand (P=.03), but the median attritions of telomeres were not different. It was concluded that aging does not appear to affect hematopoietic cell recoveries after repeated low-dose TBI, suggesting that poor tolerance of radiochemotherapy regimens in older patients may be due to nonhematopoietic organ toxicities rather than age-related changes in hematopoietic stem cells reserves.
Descriptors: aging, pharmacology, radiation biology, blood and lymphatics, transport and circulation, thrombocytopenia, blood and lymphatic disease, radiochemotherapy, radiologic method, therapeutic method, bleeding, hematopoietic responses, stress conditions, total body irradiation.

Zhang, J., Z. Chen, F.R. Cobb, and J.S. Stamler (2004). Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels - an intact canine model. Circulation 110(6): 750-755. ISSN: 0009-7322.
NAL Call Number: RC681.A1 C8
Abstract: Background-It has recently been shown that mitochondrial aldehyde dehydrogenase 2 (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin (glyceryl trinitrate (GTN)) within mitochondria, leading to production of cGMP and vasorelaxation. However, whether this mechanism operates in the systemic and coronary beds that subserve the antianginal action of GTN is not known. In this study, we address this question in an intact canine model. Methods and Results-Fourteen healthy mongrel dogs (weight, 20 to 25 kg) were studied. Coronary blood flow and hemodynamics were continuously monitored by a pulse Doppler flow probe implanted around the left circumflex coronary artery and with catheters in left ventricle and aorta, respectively. Each dog was given a 1-mL bolus injection of GTN, sodium nitroprusside (SNP), or adenosine through a catheter in the left atrium before and 30 minutes after infusion of cyanamide (17 mg/kg), an inhibitor of mtALDH. Cyanamide significantly inhibited both the classic dehydrogenase and GTN reductase activities of mtALDH in situ and attenuated the coronary blood flow increase and declines in blood pressure and left ventricular end-diastolic pressure produced by GTN in vivo. In contrast, mtALDH inhibition had no effect on the coronary and systemic effects of SNP and adenosine. Conclusions-Our data suggest that mtALDH contributes to GTN biotransformation in vivo and thus at least partly underlies the antianginal mechanism of drug action. Our findings also highlight the differences in biometabolism of clinically relevant nitrosovasodilators.
Descriptors: cardiovascular system, transport and circulation, pharmacology .

Zhu, B.M., S. Miyamoto, Y. Nagasawa, T. Wajima, and K. Hashimoto (2003). Effect of the sarcolemmal katp channel blocker hmr1098 on arrhythmias induced by programmed electrical stimulation in canine old myocardial infarction model: comparison with glibenclamide. Journal of Pharmacological Sciences 93(1): 106-113. ISSN: 1347-8613.
Abstract: The blockade of myocardial KATP channels may be antiarrhythmic for ischemic arrhythmias. A new sulfonylthiourea, HMR1098 (1-(15-(2-(5-chloro-o-anisamido)ethyl)-2-methoxyphenylsulfonyl)-3-methylthiourea, sodium salt), was demonstrated to be a cardioselective KATP-channel antagonist and to suppress arrhythmias during acute ischemia. We investigated effects of HMR1098 on the arrhythmias induced by programmed electrical stimulation (PES) in a canine old myocardial infarction model. HMR1098 (3 mg/kg, i.v.) significantly improved the scores of PES-induced ventricular arrhythmias, without changing the blood glucose concentrations. A classical sulfonylurea, glibenclamide (1 mg/kg, i.v.), had no significant effects on these arrhythmias, but reduced the blood glucose and increased the plasma insulin concentrations.
Descriptors: cardiovascular system, transport and circulation, pharmacology, ischemic arrhythmia, heart disease, vascular disease, old myocardial infarction, heart disease, programmed electrical stimulation induced ventricular arrhythmia, heart disease.

Zuperku, E.J., I.F. Brandes, A.G. Stucke, A. Sanchez, F.A. Hopp, and E.A. Stuth (2008). Major components of endogenous neurotransmission underlying the discharge activity of hypoglossal motoneurons in vivo. Advances in Experimental Medicine and Biology 605: 279-84. ISSN: 0065-2598.
NAL Call Number: QP901 .A33
Abstract: Multibarrel micropipettes were used to simultaneously record unit activity and apply antagonists on individual inspiratory hypoglossal motoneurons (IHMNs) to determine the endogenous activation levels of NMDA, non-NMDA, GABA(A) and serotonin receptors responsible for the IHMN spontaneous discharge patterns in decerebrate dogs. IHMN activity is highly dependent on glutamatergic phasic and tonic drives, which are differentially mediated by the receptor subtypes. Endogenous serotonin significantly amplifies IHMN activity, while GABAergic gain modulation acts to attenuate activity. Thus, alterations in the neurotransmission of any of these systems could markedly alter neuronal output to target muscles.
Descriptors: hypoglossal nerve physiology, motor neurons physiology, synaptic transmission physiology, 2 amino 5 phosphonovalerate pharmacology, bicuculline pharmacology, decerebrate state, dogs, excitatory amino acid antagonists pharmacology, ketanserin pharmacology, models, animal, models, neurological, quinoxalines pharmacology, tongue innervation.

Back to Top  
<< Table of Contents << Previous |  Next >>
Last Modified: Jan 23, 2014  
AWIC Home | NAL Home | USDA | AgNIC | ARS | Web Policies and Important Links | RSS Feeds | Site Map
FOIA | Accessibility Statement | Privacy Policy | Non-Discrimination Statement | Information Quality | | White House