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You are here: Home / Publications / Bibliographies and Resource Guides / Canine Models in Biomedical Research, 1990-2009  / Toxicology  Printer Friendly Page
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Canine Models in Biomedical Research,  1990-2009
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Toxicology

Cai, Y., Q. Ma, L. Zhang, J. Zhao, M. Zhu, W. Hu, P. Jiang, and W. Yuan (2004). [Therapeutic effects of rhEPO, rhG-CSF on sulfur mustard induced toxicity in dogs]. Wei Sheng Yan Jiu; Journal of Hygiene Research 33(6): 649-51. ISSN: 1000-8020.
Abstract: OBJECTIVE: To evaluate the therapeutic effects of recombinant human erythropoietin (rhEPO) and recombinant human granulocyte colony stimulating factor (rhG-CSF) on sulfur mustard (SM) induced toxicity in dogs. METHODS: Ten dogs were used as the animal model. Control group had four dogs while treatment group had six. Half an hour after subcutaneously injected with 12 mg/kg (body weight) of SM, the dogs of the treatment group were treated by rhEPO, rhG-CSF and other medicines. General examinations of blood were measured before injecting SM and were continually watched for a week after poisoning. RESULTS: Three dogs in control group died in three days after poisoning, dogs in treatment group all survived. WBC of the control group decreased significantly 3 days after poisoning. RBC of the control group had a slight increase at first, then came down. While WBC and RBC of treatment group remained constant. LYM of both groups descended notably right after poisoning, especially in control group. Two days after poisoning, RC in treatment group began to rise and remained at high level for about a week. No obvious changes of RC in control group were found. CONCLUSION: The use of rhEPO and rhG-CSF after SM exposure can stimulate the growth of the erythrocyte, reticulocyte and leucocyte in dogs. Therefore, rhEPO and rhG-CSF may be significant assistant drugs in future experiment of SM.
Descriptors: toxicity, induced, sulfur mustard, poisoning, recombinant human erythropoietin (rhEPO), recombinant human granulocyte colony stimulating factor (rhG-CSF), blood examination, therapeutic effects .
Language of Text: Chinese; Non-.
Notes: Library: National-Library-of-Medicine.

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.

Fekri, A., N. Semir, S. El Atrous, L. Besbes, B. Riadh, B. Mohamed, M. Soudani, J. Eurin, C. Barthelemy, M. El Ayeb, D. Koussay, and A. Carayon (2003). A canine study of immunotherapy in scorpion envenomation. Intensive Care Medicine. 29(12): 2266-2276. ISSN: 0342-4642.
Abstract: Objective: To evaluate the effects of scorpion venom and antivenom in experimental envenomation. Design: Prospective, controlled animal study. Setting: University research laboratory Subjects: Twenty-nine anesthetized and ventilated dogs. Interventions: The first group of animals had venom alone (0.05 mg/kg). Animals from the second group had simultaneous administration of 10 ml of scorpion antivenom (SAV). In the third and fourth groups, 10 ml and 40 ml SAV, respectively, were injected 10 min following venom. Measurements and results: Hemodynamic parameters using right heart catheter were recorded and dosage of catecholamines, neuropeptide Y (NPY), endothelin-1, and atrial natriuretic peptide (ANP) were performed at baseline and during 60 min following envenomation. In the control group, at 5 min, there was a sharp increase in pulmonary artery occluded pressure (PAOP, from 2 mmHg to 23 mmHg), mean arterial pressure (MAP, from 125 mmHg to 212 mmHg) and systemic vascular resistance (SVR, from 2,450 dyn sec-1 m5 to 5,775 dyn sec-1 m5, P<0.05 for all). Heart rate, cardiac output, and stroke volume decreased. There was a 40-fold increase in epinephrine and norepinephrine plasma concentrations. Circulating NPY and ANP dosages increased too. PAOP and MAP decreased thereafter to reach baseline levels. Simultaneous administration of SAV with venom totally offset the hallmarks of scorpion envenomation. Delayed administration of SAV at any dosage failed to alter the features of scorpion envenomation. Conclusion: While simultaneous administration of SAV and scorpion venom is effective in preventing scorpion envenomation-related manifestations, delayed administration of SAV, either at standard or elevated dosages, failed to alter any of the scorpion envenomation features.
Descriptors: animal models, antivenoms, cardiac output, catecholamines, envenomation, epinephrine, haemodynamics, heart rate, laboratory animals, neuropeptides, norepinephrine, dogs, Scorpiones.

Foster, J.R. (2005). Spontaneous and drug-induced hepatic pathology of the laboratory beagle dog, the cynomolgus macaque and the marmoset. Toxicologic Pathology 33(1): 63-74. ISSN: 0192-6233.
Abstract: This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.
Descriptors: callithrix physiology, liver diseases pathology, liver neoplasms, experimental chemically induced, liver neoplasms, experimental pathology, macaca fascicularis physiology, callithrix metabolism, metabolism, drug evaluation, preclinical, liver diseases genetics, liver neoplasms, experimental genetics, macaca fascicularis metabolism, models, animal, species specificity

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 .

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.

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.

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.

Javerliat, I., O. Goeau Brissonniere, P. Bruneval, and M. Coggia (2007). Experimental study of a new vascular graft prebonded with antibiotic: healing, toxicity, and antibiotic retention. Annals of Vascular Surgery 21(5): 603-10. ISSN: 0890-5096.
Abstract: Despite refinements in surgical techniques, routine antibioprophylaxis, and anesthesiology, vascular prosthetic infections remain a serious complication of reconstructive vascular surgery. The purpose of this study was to evaluate the healing, the toxicity, and the antibiotic delivery of a new vascular graft, preloaded with rifampin and tobramycin. Sixteen dogs underwent infrarenal aortic bypass. They were divided into three groups. In test group 1 (n = 8), dogs received grafts loaded with a standard concentration of antibiotics. In test group 2 (n = 4), dogs received grafts loaded with twice the standard concentration of antibiotics. A control group (n = 4) received a commercial gelatin-sealed graft. Grafts were harvested after different periods of time and submitted to histological evaluation and antibiotic dose determination. Liver and kidney toxicities were evaluated from dosages performed on serum samples taken at different time periods between graft implantation and harvesting. The healing of antibiotic-loaded grafts was similar to that of commercial grafts, without any signs of toxicity. These results suggest resistance to infection of these prebonded grafts in an animal model.
Descriptors: anti bacterial agents administration and dosage, blood vessel prosthesis, prosthesis design, anti bacterial agents blood, anti bacterial agents chemistry, anti bacterial agents toxicity, aorta, abdominal pathology, aorta, abdominal surgery, biocompatible materials chemistry, dogs, gelatin chemistry, giant cells pathology, kidney drug effects, liver drug effects, models, animal, polyesters chemistry, prosthesis related infections prevention and control, rifampin administration and dosage, rifampin blood, rifampin chemistry, rifampin toxicity, surface properties, thrombosis pathology, time factors, tobramycin administration and dosage, tobramycin blood, tobramycin chemistry, tobramycin toxicity, tunica intima pathology, wound healing drug effects.

Kaluzienski, M. (2000). Partial paralysis and altered behavior in dogs treated with melaleuca oil. Journal of Toxicology Clinical Toxicology 38(5): 518-519. ISSN: 0731-3810.
NAL Call Number: RA1190.C5
Descriptors: biochemistry and molecular biophysics, veterinary medicine, medical sciences, toxicology, altered behavior, partial paralysis, meeting abstract

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.

Kling, D.E. and J.J. Schnitzer (2007). Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH). American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 145c(2): 139-57. ISSN: 1552-4868.
Abstract: Congenital diaphragmatic hernia (CDH) is a congenital malformation that occurs with a frequency of 0.08 to 0.45 per 1,000 births. Children with CDH are born with the abdominal contents herniated through the diaphragm and exhibit an associated pulmonary hypoplasia which is frequently accompanied by severe morbidity and mortality. Although the etiology of CDH is largely unknown, considerable progress has been made in understanding its molecular mechanisms through the usage of genetic, teratogenic, and surgical models. The following review focuses on the teratogenic and surgical models of CDH and the possible molecular mechanisms of nitrofen (a diphenyl ether, formerly used as an herbicide) in both induction of CDH and pulmonary hypoplasia. In addition, the mechanisms of other compounds including several anti-inflammatory agents that have been linked to CDH will be discussed. Furthermore, this review will also explore the importance of vitamin A in lung and diaphragm development and the possible mechanisms of teratogen interference in vitamin A homeostasis. Continued exploration of these models will bring forth a clearer understanding of CDH and its molecular underpinnings, which will ultimately facilitate development of therapeutic strategies. (c) 2007 Wiley-Liss, Inc.
Descriptors: diaphragm embryology, hernia, diaphragmatic embryology, lung embryology, vitamin a physiology, vitamin a deficiency complications, disease models, animal, dogs, hernia, diaphragmatic chemically induced, hernia, diaphragmatic genetics, models, animal, phenyl ethers pharmacology, rabbits, rats, sheep, signal transduction, species specificity, teratogens pharmacology, tretinoin metabolism, vitamin a metabolism.

Mehta, A., A.C. Jain, and M.C. Mehta (2003). Electrocardiographic effects of intravenous cocaine: an experimental study in a canine model. Journal of Cardiovascular Pharmacology 41(1): 25-30. ISSN: 0160-2446.
Abstract: Cocaine abuse causes cardiac dysfunction. Acute intravenous administration of cocaine may lead to development of severe arrhythmias, conduction abnormalities, ST-T changes, and sudden death. Understanding arrhythmogenesis due to cocaine may provide a therapeutic approach to reduce morbidity and mortality. We studied the arrhythmogenic activity and other electrocardiographic abnormalities resulting from an intravenous bolus of cocaine. Baseline and postanesthetic electrocardiographic findings were compared with those after administration of intravenous bolus of various doses of cocaine hydrochloride in 20 dogs. The study was done in three phases (phase I: low dose of cocaine (1 mg/kg, 15 experiments); phase II: medium dose (2 mg/kg, 30 experiments); and phase III: high dose (5-7 mg/kg, 10 experiments)). Plasma levels of cocaine were estimated. The low dose induced sinus bradycardia, sinus arrhythmia, atrial ectopic, wandering pacemaker, unifocal ventricular premature contractions, and ventricular couplets. The medium dose generated moderately severe arrhythmias that were of supraventricular origin. Atrial flutter and atrial fibrillation were observed in two experiments each. Ventricular arrhythmias were manifested as unifocal, multifocal, interpolated ventricular premature contractions as well as bigeminy, trigeminy, couplets, and salvos. The high dose of 5-7 mg/kg increased electrocardiographic intervals and caused ST-segment elevation as well as serious life-threatening arrhythmias. Three of the dogs developed sustained ventricular tachycardia followed by ventricular flutter-fibrillation and death.
Descriptors: behavior, cardiovascular system, transport and circulation, toxicology, atrial ectopic, heart disease, atrial fibrillation, heart disease, atrial flutter, heart disease, cardiac arrhythmia, drug abuse, behavioral and mental disorders, sinus arrhythmia, sinus bradycardia, ventricular tachycardia, st changes, unifocal ventricular premature contractions, ventricular couplets, wandering pacemaker.

Mirsalis, J.C., J. Schindler Horvat, J.R. Hill, C.E. Green, C. Mitoma, J.E. Tomaszewski, C.A. Tyson, and S.J. Donohue (2003). Toxicity of a quinocarmycin analog, dx-52-1, in rats and dogs in relation to clinical outcome. Cancer Chemotherapy and Pharmacology 51(3): 193-201. ISSN: 0344-5704.
NAL Call Number: RC271.C5C28
Abstract: Purpose: Quinocarmycin analog DX-52-1 is a cyanated derivative of quinocarmycin, a compound isolated from cultures of Streptomyces melanovinaceus. DX-52-1 was selected for preclinical development because it showed efficacy against melanoma cell lines in the NCI human tumor cell screen and melanoma xenografts in mice. This report describes studies in rats and dogs to determine the maximum tolerated dose (MTD) and identify dose-limiting toxicities (DLT) in each species in different regimens to establish a safe starting dose and potential target organs of DX-52-1 for phase I clinical trials. Methods: DX-52-1 was administered to Fischer 344 rats using repeated intravenous (i.v.) slow bolus injections following q3hX3 and q3hX3,q7dX3 regimens, and to beagle dogs using a single injection, 6-h continuous i.v. infusion (c.i.v.) and weekly 6-h c.i.v. for 3 weeks. Endpoints evaluated included clinical observations, body weights, hematology, serum clinical chemistry, and microscopic pathology of tissues. Results: The MTD of DX-52-1 was a total dose of 18 mg/m2 body surface area for q3hX3 administration in rats and 30 mg/m2 for a single c.i.v. administration in dogs. The total dose MTD for rats on a weekly (q3hX3,q7dX3) regimen was 54 mg/m2, and for dogs on the weekly X3 (6-h c.i.v.) infusion was 60 mg/m2. In rats, significant elevations in blood urea nitrogen and creatinine were observed together with acute renal tubular necrosis histologically. Modest increases in liver enzymes were also observed, as were decreases in reticulocytes that were unaccompanied by histologic changes in liver and bone marrow. In dogs, adverse signs included vomiting/retching, diarrhea, and transient hypothermia; also red blood cells, hemoglobin, hematocrit, and lymphocytes were decreased. Histologic evaluation of tissues from dogs revealed necrosis and cellular depletion of the bone marrow, and extensive damage to the entire gastrointestinal tract, including marked cellular necrosis of the mucosa and lymphoid necrosis of the gastrointestinal associated lymphoid tissue. Destruction of the mucosal lining of the intestinal tract was likely responsible for dehydration, toxemia, septicemia, and shock seen in moribund dogs. Conclusions: The MTD values were comparable between rats and dogs given roughly similar dose regimens (single dose or weekly) and both species tolerated a higher total dose with weekly administration. However, the principal target organ responsible for DLT in rats was the kidney, whereas in dogs, the most severe effects were on the gastrointestinal tract and bone marrow. Both renal and gastrointestinal toxicities were reported in patients after 6-h c.i.v. infusions in a limited phase I clinical trial, indicating that neither animal model alone was predictive of DX-52-1-induced toxicity in humans, and that both species were required to define human toxicity.
Descriptors: animal models, rats, dogs, human, cancer therapy, melanoma, toxicity studies, preclinical development, Quinocarmycin analog DX-52-1, efficacy pharmacology, toxicology, bone marrow toxicity, blood and lymphatic disease, gastrointestinal toxicity, digestive system disease, renal toxicity, toxicity, urologic disease, histopathology, histology and cytology techniques, laboratory techniques, body weight, species differences.

Mueller, T., B. Van-De-Sluis, A. Zhernakova, E. Van-Binsbergen, A.-R. Janecke, A. Bavdekar, A. Pandit, H. Weirich-Schwaiger, H. Witt, H. Ellemunter, J. Deutsch, H. Denk, W. Mueller, I. Sternlieb, M.-S. Tanner, and C. Wijmenga (2003). The canine copper toxicosis gene murr1 does not cause non-wilsonian hepatic copper toxicosis. Journal of Hepatology 38(2): 164-168. ISSN: 0168-8278.
NAL Call Number: RC845
Abstract: Background: Non-Wilsonian hepatic copper toxicosis includes Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and the non-Indian disease known as idiopathic copper toxicosis (ICT). These entities resemble the hepatic copper overload observed in livers of Bedlington terriers with respect to their clinical presentation and biochemical and histological findings. We recently cloned the gene causing copper toxicosis in Bedlington terriers, MURR1, as well as the orthologous human gene on chromosome 2p13-p16. Aim: To study the human orthologue of the canine copper toxicosis gene as a candidate gene for ICC, ETIC, and ICT. Methods: We sequenced the exons and the intron-exon boundaries of the human MURR1 gene in 12 patients with classical ICC, one patient with ETIC, and 10 patients with ICT to see whether these patients display any mutations in the human orthologue of the canine copper toxicosis gene. Results: No mutations in the MURR1 gene, including the intron-exon boundaries, were identified in a total of 23 patients with non-Wilsonian hepatic copper toxicosis. Conclusions: Our results demonstrate that copper toxicosis in Bedlington terriers is not an animal model for the non-Wilsonian hepatic copper toxicosis described in this study.
Descriptors: gastroenterology, human medicine, medical sciences, molecular genetics, biochemistry and molecular biophysics, toxicology, Indian childhood cirrhosis, digestive system disease, etiology, endemic Tyrolean infantile cirrhosis, idiopathic copper toxicosis, metabolic disease, toxicity, etiology, non Wilsonian hepatic copper toxicosis, metabolic disease, toxicity, pathology, clinical presentation.

Nair, B. and A.R. Elmore (2003). Final report on the safety assessment of sodium sulfite, potassium sulfite, ammonium sulfite, sodium bisulfite, ammonium bisulfite, sodium metabisulfite and potassium metabisulfite. International Journal of Toxicology 22(Supplement 2): 63-88. ISSN: 1091-5818.
NAL Call Number: RA1190.J61
Abstract: Sodium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Potassium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are inorganic salts that function as reducing agents in cosmetic formulations. All except Sodium Metabisulfite also function as hair-waving/straightening agents. In addition, Sodium Sulfite, Potassium Sulfite, Sodium Bisulfite, and Sodium Metabisulfite function as antioxidants. Although Ammonium Sulfite is not in current use, the others are widely used in hair care products. Sulfites that enter mammals via ingestion, inhalation, or injection are metabolized by sulfite oxidase to sulfate. In oral-dose animal toxicity studies, hyperplastic changes in the gastric mucosa were the most common findings at high doses. Ammonium Sulfite aerosol had an acute LC50 of >400 mg/m3 in guinea pigs. A single exposure to low concentrations of a Sodium Sulfite fine aerosol produced dose-related changes in the lung capacity parameters of guinea pigs. A 3-day exposure of rats to a Sodium Sulfite fine aerosol produced mild pulmonary edema and irritation of the tracheal epithelium. Severe epithelial changes were observed in dogs exposed for 290 days to 1 mg/m3 of a Sodium Metabisulfite fine aerosol. These fine aerosols contained fine respirable particle sizes that are not found in cosmetic aerosols or pump sprays. None of the cosmetic product types, however, in which these ingredients are used are aerosolized. Sodium Bisulfite (tested at 38%) and Sodium Metabisulfite (undiluted) were not irritants to rabbits following occlusive exposures. Sodium Metabisulfite (tested at 50%) was irritating to guinea pigs following repeated exposure. In rats, Sodium Sulfite heptahydrate at large doses (up to 3.3 g/kg) produced fetal toxicity but not teratogenicity. Sodium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite were not teratogenic for mice, rats, hamsters, or rabbits at doses up to 160 mg/kg. Generally, Sodium Sulfite, Sodium Metabisulfite, and Potassium Metabisulfite were negative in mutagenicity studies. Sodium Bisulfite produced both positive and negative results. Clinical oral and ocular-exposure studies reported no adverse effects. Sodium Sulfite was not irritating or sensitizing in clinical tests. These ingredients, however, may produce positive reactions in dermatologic patients under patch test. In evaluating the positive genotoxicity data found with Sodium Bisulfite, the equilibrium chemistry of sulfurous acid, sulfur dioxide, bisulfite, sulfite, and metabisulfite was considered. This information, however, suggests that some bisulfite may have been present in genotoxicity tests involving the other ingredients and vice versa. On that basis, the genotoxicity data did not give a clear, consistent picture. In cosmetics, however, the bisulfite form is used at very low concentrations (0.03% to 0.7%) in most products except wave sets. In wave sets, the pH ranges from 8 to 9 where the sulfite form would predominate. Skin penetration would be low due to the highly charged nature of these particles and any sulfite that did penetrate would be converted to sulfate by the enzyme sulfate oxidase. As used in cosmetics, therefore, these ingredients would not present a genotoxicity risk. The Cosmetic Ingredient Review Expert Panel concluded that Sodium Sulfite, Potassium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are safe as used in cosmetic formulations.
Descriptors: cosmetics, toxicology, pulmonary edema, respiratory system disease, oral dose animal toxicity test, laboratory techniques, genotoxicity data, lung capacity parameters, pH, skin penetration.

Quimby, F.W., A.C. Casey, and M.F. Arquette (2005). From dogs to frogs: how pets, laboratory animals, and wildlife aided in elucidating harmful effects arising from a hazardous dumpsite. ILAR Journal 46(4): 364-9. ISSN: 1084-2020.
NAL Call Number: QL55.A1I43
Abstract: The medical literature contains many examples of cases in which serendipitous observations have led to important findings. In the example described in this article, laboratory and field observations conducted at the Mohawk Nation Community of Akwesasne led to the important and unexpected finding that frogs once plentiful in the area were no longer observed. Laboratory tests comparing river sediments from Akwesasne to pristine sediment from Ithaca, NewYork, indicated multiple adverse health effects on developing frogs. Some of the behavioral changes observed in the laboratory were similar to those described by residents of Akwesasne before the onset of amphibian decline. The magnitude of changes paralleled frog body burden of polychlorinated biphenyls acquired from the Akwesasne sediment. The impact of these findings on the identification of a hazardous waste site and global amphibian decline are discussed.
Descriptors: environmental exposure adverse effects, hazardous waste adverse effects, polychlorinated biphenyls blood, water pollutants, chemical blood, amphibia, animals, domestic, animals, laboratory, animals, wild, birds, dogs, indians, north american, new york, rats, rivers

Ridgway, P., T.E. Nixon, and J.P. Leach (2003). Occupational exposure to organic solvents and long-term nervous system damage detectable by brain imaging, neurophysiology or histopathology. Food and Chemical Toxicology 41(2): 153-187. ISSN: 0278-6915.
NAL Call Number: 391.8 F73
Abstract: The purpose of the present review is to assess the evidence published in scientific literature that industrial organic solvents as a generic group have the ability to induce long-term nervous system damage in workers that can be detected by techniques other than neuropsychological testing. The main body of evidence considered in this review was 40 studies involving the use of brain imaging, neurophysiological testing, gross autopsy or histopathology in groups of workers with long-term solvent exposure. Case reports involving both solvent abuse and occupational exposure, and experimental animal data have also been reviewed as supporting data. A number of the studies in groups of workers provide evidence of the presence of marginal atrophic abnormalities in the brain or deficits in nerve conduction velocity in solvent-exposed workers. However, there are limitations in the design of many of these studies, the strength of association between exposure and effect is not consistently strong, no dose-response relationship can be detected, the reported changes lack specificity and there is no coherence between the human and experimental animal data. Overall, it is not possible to draw reliable conclusions with respect to the presence or absence of nervous system damage related to the common properties of organic solvents.
Descriptors: nervous system, neural coordination, toxicology, organic solvent abuse, brain imaging, imaging, microscopy techniques, laboratory techniques, gross autopsy, histopathology, cytology techniques .

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.

Schaefer, G.J., D.T. Kirkpatrick, J.F. Holson, C.P. Chengelis, K.S. Regan, and V.J. Piccirillo (2003). A six-week inhalation neurotoxicity study of methyl bromide in dogs. Toxicological Sciences 72(S-1): 304 ISSN: 1096-6080.
NAL Call Number: RA1190.F8
Descriptors: nervous system, neural coordination, toxicology, locomotor activity.

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 .

Sztajnkrycer, M.D., G.R. Bond, S.B. Johnson, and A.L. Weaver (2004). Use of vasopressin in a canine model of severe verapamil poisoning: a preliminary descriptive study. Academic Emergency Medicine 11(12): 1253-61. ISSN: 1069-6563.
Abstract: OBJECTIVES: The purpose of this preliminary study was to evaluate the effect of arginine vasopressin (AVP) administration in a model of shock induced by calcium channel antagonist overdose and to determine endogenous serum AVP concentrations in calcium channel antagonist-induced shock. METHODS: This was a controlled, randomized laboratory investigation based on a previously described canine model of verapamil toxicity. After induction of verapamil toxicity, animals in both the control and the experimental groups (n = 6 each) received a continuous infusion of verapamil. Experimental animals received an escalating dose of AVP, while control animals received an equal volume of 0.9% saline infusion. The hemodynamic end point was return of mean arterial pressure (MAP) to within 20% of baseline. Surviving animals were killed after 60 minutes. RESULTS: In the treatment group, administration of low-dose AVP (4 mU/kg/min) resulted in further declines in cardiac index and heart rate. No significant change was noted in MAP with low-dose AVP. A slight increase in MAP was noted with both escalating doses of AVP and equivalent volumes of normal saline. By the end of the 60-minute antidote/saline phase, the MAPs of the saline control group and the AVP experimental group were similar. The primary hemodynamic end point was not achieved in either the AVP or the saline control arm. Mean baseline serum AVP concentration in control animals was 5.8 pg/mL, increasing to 225 pg/mL during the toxicity phase. CONCLUSIONS: In an animal model of verapamil-induced shock, endogenous AVP levels increased nearly 40-fold compared with baseline levels. Escalating doses of exogenous AVP worsened cardiac index and failed to return MAP to within 20% of baseline.
Descriptors: animal model, induced shock, calcium channel antagonist overdose. toxicity, cadiac index.

Tarasiuk, A., T. Ahmad, and S. Sofer (2002). Volume resuscitation does not alleviate peripheral organ ischemia in dogs injected with scorpion venom. Critical Care Medicine. 30(7): 1581-1588. ISSN: 0090-3493.
Abstract: Objectives: To examine the effect of fluid resuscitation on the haemodynamic changes in dogs injected with scorpion venom and to explore the effects of the venom on the determinants of venous return (i.e., circulatory compliance, time constant, and resistance to venous return). Design: A prospective, controlled animal study. Setting: University animal research laboratory. Subjects: Mixed-breed dogs. Interventions: The effect of volume resuscitation (20 ml/kg of the synthetic colloid polygeline) 1 hr after venom injection (a time previously found to be related to severe decrease in cardiac output) was tested in two series of experiments. In the first series, 12 dogs were given venom and fluid, eight dogs were given venom alone, and four dogs served as the time-controlled group. In the second series, eight dogs were given venom and ten dogs served as controls. Scorpion venom (Leiurus quinquestriatus) at 0.1 mg/kg in the first series and 0.05 mg/kg in the second series was given intravenously. Measurements and Main Results: In the first series of experiments, the venom decreased cardiac output from 5.0+or-1.1 to 2.9+or-0.7 litres/min at 60 mins (p<.001). Arterial pH decreased from 7.39+or-0.05 to 7.16+or-0.1 (p<.001). Blood lactate increased from 0.9+or-0.8 to 3.2+or-1.9 mM (p<.05). Gastric pH decreased from 7.28+or-0.2 to 6.7+or-0.18 (p<.001). Arterial acidosis was secondary to gastrointestinal ischaemia because the gradient between mucosal and arterial PCO2 increased from 17.5+or-7.7 to 98.6+or-75 (p<.01) 60 mins after venom injection. In the second series of experiments, circulatory compliance and time constant increased by 150% and 128%, respectively (p<.05), in dogs injected with venom compared with control dogs. Resistance to venous return increased after venom injection but did not change after fluid infusion. In both series of experiments, volume administration improved cardiac output but had no effect on oxygen delivery, arterial pH, HC03-, lactate, and gastric mucosal pH. Conclusions: Metabolic acidosis and cardiovascular abnormalities seen after scorpion venom injection in dogs are closely related to gastrointestinal hypoperfusion. Fluid resuscitation increased cardiac output but had no effect on gastrointestinal perfusion and acidosis induced by the venom.
Descriptors: scorpion venom , Leiurus quinquestriatus, blood pressure, hemodynamics, heart rate, ischemia, fluid resuscitation, metabolic acidosis, cardiovascular abnormalities.

Tarasiuk, A., S. Khvatskin, and S. Sofer (1998). Effects of antivenom serotherapy on hemodynamic pathophysiology in dogs injected with L. quinquestriatus scorpion venom. Toxicon 36(7): 963-971. ISSN: 0041-0101.
NAL Call Number: 391.8 T66
Abstract: In dogs, scorpion venom causes an immediate increase in cardiac output that declines below baseline values within 1 h. The hypotheses that antivenom given before venom injection may prevent changes in cardiac output, while antivenom given after the inotropic stage of envenomation cannot reverse cardiac output decline were tested. 25 anaesthetized, mechanically ventilated dogs were given 0.1 mg/kg IV venom of the scorpion Leiurus quinquestriatus. The dogs were randomized into 4 groups: 5 dogs were given venom alone (control group) and 6 dogs were given 6 ml of antivenom 1 minute before venom injection while 8 and 6 dogs were given 6 ml of antivenom 20 and 60 min after venom injection, respectively. Parameters reflecting respiratory and circulatory functions were measured for 180 min after venom injection. Scorpion venom caused a gradual decrease in heart rate, an initial elevation of systemic and pulmonary blood pressure and cardiac output followed by a decline in these parameters. PO2, pH and HCO3- gradually decreased, while PCO2 gradually increased from baseline. Antivenom given before venom injection prevented all the effects induced by the venom. Antivenom given at 20 and 60 min after venom injection had no effect on cardiac output and HCO3- decline, but caused an increase in heart rate, PO2 and pH and a decrease in PCO2. It is assumed that antivenom clears free toxins from the circulation, and since cardiac output and HCO3- did not improve after this clearance, it is concluded that following intravenous venom injection, heart and circulation are rapidly affected by the toxins or by other substances released by the venom which do not respond to antivenom. Improvements in respiration and heart rate with antivenom given after venom injection may be secondary to reversion of cholinergic effects of the venom. Improvement in respiration may be also explained by reversion of the toxic effects on Ca2+ activated K+ channels of bronchial smooth muscle. All these effects may be secondary to clearance of toxins by the antivenom.
Descriptors: physiopathology, venoms, heart, antivenoms, laboratory animals, laboratory mammals, blood pressure, envenomation, toxins, pH, blood analysis, smooth muscle, calcium ions, dogs, Leiurus quinquestriatus, Arachnida.

Tarasiuk, A., S. Menascu, and S. Sofer (2003). Antivenom serotherapy and volume resuscitation partially improve peripheral organ ischemia in dogs injected with scorpion venom. Toxicon 42(1): 73-77. ISSN: 0041-0101.
NAL Call Number: 391.8 T66
Abstract: We tested the hypothesis that fluid resuscitation combined with antivenom serotherapy given after injection of scorpion venom may increase cardiac output (CO) and blood pressure (BP) and prevent the decline in bicarbonate, pH and gastric perfusion. Seventeen anesthetized, mechanically ventilated dogs were given 0.1 mg/kg IV venom of the scorpion Leiurus quinquestriatus. The dogs were randomized into three groups: six dogs were given venom alone; three dogs were given 6 ml of antivenom 1 minute before venom injection; eight dogs were given 6 ml of antivenom and 20 ml/kg of synthetic colloid solution, 20 min after venom injection. Parameters reflecting respiratory and circulatory functions were determined at baseline and 120 min after venom injection. Scorpion venom caused a decrease in CO, BP, pH and HCO3-. Gastric mucosal perfusion was severely affected as assessed by mucosal pH (pHi) and the gradient between mucosal and arterial pCO2 ( Delta pCO2). Antivenom given before venom injection prevented all the effects induced by the venom. Antivenom and fluid given 20 min after venom injection caused a marked increase in CO and BP, but had no effect on pH and HCO3- decline (compared with venom alone). Gastric perfusion slightly improved as the increase in Delta pCO2 was attenuated. The combination therapy of antivenom and fluid in this dog model is superior to the therapy of each of them alone. The marked and long-standing improvement of CO is promising and may suggest improvement in HCO3- and pH with time.
Descriptors: animal models, antivenoms, blood flow, blood pressure, cardiac output, drug therapy, envenomation, fluid therapy, ischaemia, laboratory animals, stomach mucosa, venoms, dogs, Leiurus quinquestriatus.

Tarasiuk, A., A. Taya, and S. Sofer (2002). Volume resuscitation does not alleviate peripheral organ ischemia in dogs injected with scorpion venom. Critical Care Medicine. 30(7): 1581-8. ISSN: 0090-3493.
Abstract: OBJECTIVES: To examine the effect of fluid resuscitation on the hemodynamic changes in dogs injected with scorpion venom and to explore the effects of the venom on the determinants of venous return (i.e., circulatory compliance, time constant, and resistance to venous return). DESIGN: A prospective, controlled animal study. SETTING: University animal research laboratory. SUBJECTS: Mixed-breed dogs. INTERVENTIONS: The effect of volume resuscitation (20 mL/kg of the synthetic colloid polygeline) 1 hr after venom injection (a time previously found to be related to severe decrease in cardiac output) was tested in two series of experiments. In the first series, 12 dogs were given venom and fluid, eight dogs were given venom alone, and four dogs served as the time-controlled group. In the second series, eight dogs were given venom and ten dogs served as controls. Scorpion venom (Leiurus quinquestriatus) at 0.1 mg/kg in the first series and 0.05 mg/kg in the second series was given intravenously. MEASUREMENTS AND MAIN RESULTS: In the first series of experiments, the venom decreased cardiac output from 5.0 +/- 1.1 to 2.9 +/- 0.7 L/min at 60 mins (p <.001). Arterial pH decreased from 7.39 +/- 0.05 to 7.16 +/- 0.1 (p <.001). Blood lactate increased from 0.9 +/- 0.8 to 3.2 +/- 1.9 mM (p <.05). Gastric pH decreased from 7.28 +/- 0.2 to 6.7 +/- 0.18 (p <.001). Arterial acidosis was secondary to gastrointestinal ischemia because the gradient between mucosal and arterial Pco2 increased from 17.5 +/- 7.7 to 98.6 +/- 75 (p <.01) 60 mins after venom injection. In the second series of experiments, circulatory compliance and time constant increased by 150% and 128%, respectively (p <.05), in dogs injected with venom compared with control dogs. Resistance to venous return increased after venom injection but did not change after fluid infusion. In both series of experiments, volume administration improved cardiac output but had no effect on oxygen delivery, arterial pH, HCO3-, lactate, and gastric mucosal pH. CONCLUSIONS: Metabolic acidosis and cardiovascular abnormalities seen after scorpion venom injection in dogs are closely related to gastrointestinal hypoperfusion. Fluid resuscitation increased cardiac output but had no effect on gastrointestinal perfusion and acidosis induced by the venom.
Descriptors: scorpion venom, toxicity, fluid resuscitation, hemodynamic changes, metabolic acidosis, gastrointestinal hypoperfusion.

Tegzes, J.H., S.D. Smarick, and B. Puschner (2002). Coma and apnea in a dog with hydroxyzine toxicosis. Veterinary and Human Toxicology 44(1): 24-6. ISSN: 0145-6296.
NAL Call Number: SF601.A47
Abstract: Hydroxyzine is a commonly prescribed H1-receptor antagonist in small animal practice. The most common adverse effect reported after therapeutic dosing is mild sedation; severe reactions resulting in coma have occasionally been reported in children. We present a case of large po hydroxyzine exposure causing in coma and apnea in a dog. Exposure was confirmed with gas chromatography/mass spectrometry analysis of urine. Extensive therapeutic measures to enhance drug elimination and assist ventilation were required for 11 d. The positive outcome justifies critical care of similarly exposed animals. Veterinarians should be aware of the potential for coma and apnea secondary to hydroxyzine exposure.
Descriptors: hydroxyzine, H1-receptor antagonist, poisoning, toxicology, sedation, coma.

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.

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.

Trepanier, L.A. (2004). Idiosyncratic toxicity associated with potentiated sulfonamides in the dog. Journal of Veterinary Pharmacology and Therapeutics 27(3): 129-138. ISSN: 0140-7783.
NAL Call Number: SF915.J63
Abstract: Idiosyncratic toxicity to potentiated sulfonamides occurs in both humans and dogs, with considerable clinical similarities. The syndrome in dogs can consist of fever, arthropathy, blood dyscrasias (neutropenia, thrombocytopenia, or hemolytic anemia), hepatopathy consisting of cholestasis or necrosis, skin eruptions, uveitis, or keratoconjunctivitis sicca. Other manifestations seen less commonly include protein-losing nephropathy, meningitis, pancreatitis, pneumonitis, or facial nerve palsy. The pathogenesis of these reactions is not completely understood, but may be due to a T-cell-mediated response to proteins haptenated by oxidative sulfonamide metabolites. Our laboratory is working on tests to characterize dogs with possible idiosyncratic sulfonamide reactions, to include ELISA for anti-drug antibodies, immunoblotting for antibodies directed against liver proteins, flow cytometry for drug-dependent anti-platelet antibodies, and in vitro cytotoxicity assays. The management of idiosyncratic sulfonamide toxicity involves client education to identify clinical signs early and allow rapid drug discontinuation, supportive care to include possibly ascorbate and glutathione precursors, and avoidance of subsequent re-exposure. It is important to realize that only antimicrobial sulfonamides, such as sulfamethoxazole, sulfadiazine, and sulfadimethoxine, share this clinical syndrome. There is no evidence for cross-reactivity with drugs that have different underlying structures but share a sulfonamide moiety, such as acetazolamide, furosemide, glipizide, or hydrochlorothiazide.
Descriptors: adverse effects, antibodies, clinical aspects, dosage effects, drug allergies, drug toxicity, pathogenesis, reviews, sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfonamides, T lymphocytes, treatment, pharmacology, elisa, immunologic techniques, laboratory techniques, cytotoxicity assay, bioassay techniques, flow cytometry.

Weekley, L.B., P. Guittin, and G. Chamberland (2002). The international symposium on regulatory testing and animal welfare: recommendations on best scientific practices for safety evaluation using nonrodent species. ILAR Journal 43 Suppl: S118-22. ISSN: 1084-2020.
NAL Call Number: QL55.A1I43
Descriptors: toxicity testing, toxicological studies, safety evaluation, data collection, dose selection, repeat dose exposure, blood collection, euthanasia, dog, monkey, minature swine.

Wight, S. (2004). Benefits of 24-hour food access for dogs on toxicology studies. Animal Technology and Welfare 3(2): 131-132. ISSN: 0264-4754.
NAL Call Number: QL55.I5
Descriptors: body weight, dog feeding, experiments, feeding behavior, food intake, growth rate, social interaction, toxicology, unrestricted feeding, dogs.

Wilson, L.D. and C. Shelat (2003). Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication. Journal of Toxicology Clinical Toxicology 41(6): 777-788. ISSN: 0731-3810.
NAL Call Number: RA1190.C5
Abstract: Objective. Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade. Because of cocaine's ability to block cardiac sodium channels, sodium bicarbonate (NaHCO3) has been proposed as an antidote. The hypothesis of this study was that NaHCO3 would correct cocaine-induced conduction abnormalities and resultant hemodynamic compromise in an animal model simulating severe cocaine intoxication. Methods. Design: Prospective, controlled, experimental study in which 15 anesthetized dogs were given three successive boluses of cocaine (7 mg/kg) and then randomized to receive NaHCO3, 2 mEq/kg (n = 8) or placebo (n = 7). Measurements: Arterial, left ventricular, and pulmonary artery pressures; cardiac output (CO); electrocardiogram (ECG); blood gases; and serum concentrations of cocaine were measured at baseline, at fixed time intervals after each bolus of cocaine, and then after administration of NaHCO3 or placebo. Statistical significance was determined by analysis of variance (ANOVA) for repeated measures. Results. Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block; 2 of these dogs expired prior to receiving NaHCO3 and were excluded. Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group. This effect was associated with a brief 30% decrease in MAP (p = NS). After NaHCO3, CO increased 78% and remained increased for 5 min (p < 0.007). One dog converted from complete heart block to sinus rhythm shortly after NaHCO3 administration. Conclusions. NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function.
Descriptors: cardiovascular system, transport and circulation, pharmacology, toxicology, cardiac dysrhythmia, heart disease, drug therapy, drug induced, heart block, heart disease, cardiac output, hemodynamics.

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