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Safety of ceftiofur sodium administered intramuscularly in horses
1992
Mahrt, C.R.
Ceftiofur sodium, a broad-spectrum cephalosporin antibiotic, was evaluated for safe use in horses. Male or female horses were allotted to groups and were given either saline solution (control), or 2.2, 6.6, or 11 mg of an aqueous solution of ceftiofur sodium/kg of body weight/d, IM, for 30 or 31 days. These dosages are expressed in terms of the ceftiofur free acid, and represent 1 to 5 times the proposed therapeutic dosage (2.2 mg/kg/d) administered for 3 times the maximal recommended duration of 10 days. Some of the horses were euthanatized and necropsied on day 31 or 32. The other horses were evaluated for an additional 30 days, and some were euthanatized and necropsied on day 60. The following types of data were collected: clinical observation; physical examination; pelleted food consumption; body weight; hematologic, serum biochemical, and urinalysis findings; organ weight; gross necropsy observations; and histopathologic findings. Ceftiofur sodium was generally well tolerated at the exaggerated doses and treatment durations used in these safety studies. Slight to mild decrease in pelleted food consumption was detected in horses given 6.6 or 11 mg of ceftiofur sodium/kg/d. Decreased food consumption began on day 2 and lasted for approximately 9 to 12 days. Generally, mild skeletal muscle irritation was detected by gross and microscopic examination of the injection sites of horses given ceftiofur sodium. Prevalence and severity of the muscle irritation tended to increase with increasing concentration of the dosing solution. Increases in serum aspartate transaminase and creatine kinase activities were detected in some of the ceftiofur-treated horses, and were attributed to mild skeletal muscle irritation at the injection sites. Slight increases in numbers of circulating neutrophils and plasma concentration of fibrinogen were detected in the blood of some ceftiofur-treated horses, and were attributed to mild inflammation at the injection sites or possibly in the large intestine because of a change in bacterial flora.
Show more [+] Less [-]Systemic toxicosis associated with azathioprine administration in domestic cats
1992
Beale, K.M. | Altman, D. | Clemmons, R.R. | Bolon, B.
Five cats were treated with an azathioprine suspension (2.2 mg/kg of body weight on alternate days) and 2 cats were given vehicle (controls) for 9 weeks. Complete blood and platelet counts and serum biochemistry variables were monitored weekly. Bone marrow aspirates were evaluated every 3 weeks, and core bone marrow biopsy was performed at the end of the study. Profound neutropenia (< 600 cells/microliter) was observed in all treated cats, and 1 cat developed pancytopenia. Treatment was discontinued if the WBC count was < 3,000 cells/microliter. Four weeks after discontinuation of azathioprine, 1 treated cat again was given azathioprine at a lower dosage (1.1 mg of azathioprine/kg on alternate days) and neutropenia recurred within 2 weeks. During treatment, 3 cats developed thrombocytosis, and 2 developed thrombocytopenia. In 4 of 5 cats, neutropenia and thrombocytopenia resolved when azathioprine was discontinued. Bone marrow cytologic examination during treatment revealed reduction of the neutrophil line, with relative increase in monocytes. Core bone marrow biopsy at the completion of the study revealed hypocellular marrow with marked decrease in the myeloid series in cats given azathioprine. One of the cats that was treated with azathioprine had a hyperceullar marrow with increased numbers of mature granulocytes and precursors; however, azathioprine had been discontinued 3 weeks prior to biopsy. Alterations in serum biochemical variables were not associated with azathioprine. Two cats that were treated with azathioprine developed respiratory tract infections, and 1 of them was euthanatized during the study.
Show more [+] Less [-]An experimental model for subclinical edema disease (Escherichia coli enterotoxemia) manifest as vascular necrosis in pigs
1992
Kausche, F.M. | Dean, E.A. | Arp, L.H. | Samuel, J.E. | Moon, H.W.
An experimental model for subclinical edema disease was developed in weanling pigs. In multiple experiments, 3-week-old pigs were weaned, then inoculated intragastrically with 10(10) colony-forming units of an SLT-IIv-positive strain of Escherichia coli originally isolated from a pig with edema disease (principals). Control pigs were inoculated with a nonpathogenic E coli strain. Of 39 principals, 8 developed clinical edema disease within 14 days after inoculation. However, 20 of 21 principals that did not develop clinical signs of edema disease, but were submitted for necropsy examination at 14 days after inoculation, had characteristic vascular lesions of edema disease. Vascular lesions, found principally in ileum and brain, consisted of segmental necrosis of myocytes in the tunica media of small arteries and arterioles. None of the pigs inoculated with a nonpathogenic strain of E coli developed edema disease or vascular lesions. None of the principals necropsied at 2 days after inoculation had vascular lesions. Development of vascular lesions by 14 days after inoculation was used as the end point for detecting subclinical edema disease in the model.
Show more [+] Less [-]Effects of monensin on selenium status and related factors in genetically hypo- and hyperselenemic growing swine
1992
Horvath, C.J. | Stowe, H.D. | Miller, E.R.
Monensin is an ionophoretic antibiotic, which selectively transports alkali metal cations across biological membranes. In growing swine, monensin toxicosis causes acute, degenerative cardiac and skeletal myopathy resembling vitamin E-selenium deficiency. Selenium is an essential trace element incorporated in glutathione peroxidase (GSH-Px), an antioxidant enzyme system that protects subcellular membranes. In our study, we examined the effects of monensin on body weight, Se balance, antioxidant status, and serum concentrations of selected minerals in growing pigs that were genetically hypo- or hyperselenemic (hypo-Se and hyper-Se, respectively). Three groups of eight 8-week-old pigs, each comprised of 4 hypo-Se and 4 hyper-Se pigs (76.4 +/- 3.0 and 106.3 +/- 10.3 ng of Se/ml of serum, respectively), were fed standard diets containing 0.1 mg of supplemental Se/kg of body weight, and either 0, 200, or 400 mg of monensin/kg for a 77-day period, followed by a 28-day monensin withdrawal period. On days 0, 7, 28, 56, 70, and 98, all pigs were weighed and blood was collected for determination of serum GSH-Px, creatine phosphokinase, and aspartate transaminase values, as well as serum concentrations of vitamin E, Se, Ca, Cu, Fe, K, Mg, Na, P, and Zn. Significance of main effects of monensin treatment, genetic Se status, and their interactions was tested by Fisher's variance ratio test, followed by conditional comparison of treatment means with a Bonferroni test. Signs of monensin toxicosis were not observed and monensin consumption had no effect on body weight, or serum creatine phosphokinase, aspartate transaminase, or Se values. However, pigs consuming monensin had consistently higher serum GSH-Px activities, possibly because of increased synthesis of this adaptive antioxidant enzyme. Interactions were not found between monensin and genetic Se status. Hyperselenemic pigs were heavier and had higher serum Se and GSH-Px values than hypo-Se pigs. Furthermore, hypo-Se and hyper-Se pigs were hypo- and hypercupremic, respectively, suggesting genetic regulation of copper status. It is likely that pigs with inadequate antioxidant status (hyposelenemia, hypocupremia) are more susceptible to diseases associated with cellular membrane damage, such as vitamin E-Se deficiency disease and monensin toxicosis.
Show more [+] Less [-]Acute effects of a gamma-glutamylated derivate of S-(1,2-dichlorovinyl)-L-cysteine on renal function and ultrasturcture in pentobarbital-anesthetized dogs: site-specific toxicity involving S1 and S2 cells of the proximal tubule
1992
Ridgewell, R.E. | Krejci, M.E. | Koechel, D.A.
It has been established that L-gamma-glutamylated derivatives of alpha-amino acids are delivered more efficiently to the kidneys than are the parent alpha-amino acids. Therefore, we synthesized L-gamma-glutamyl-S-(1,2-dichlorovinyl)-L-cysteine (L-gamma-glutamyl-L-DCVC), the simplest L-gamma-glutamylated derivative of the nephrotoxic alpha-amino acid S-(1,2-dichlorovinyl)-L-cysteine (L-DCVC), and investigated its effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. Intravenous doses of 23.15 and 92.60 micromoles of L-gamma-glutamyl-L-DCVC/kg of body weight induced significant increases in urinary protein output and significant decreases in the clearance of inulin during the 6-hour post-injection period. Changes were not observed in any of the other 13 renal function variables or in the 11 plasma and blood variables that were monitored throughout the same period. Both doses of L-gamma-glutamyl-L-DCVC induced renal ultrastructural lesions in the S1 and S2 cells of the canine proximal tubule; the remaining 8 cell types downstream and the glomeruli were not damaged. The onset and magnitude of renal function changes and the cell types affected by L-gamma-glutamyl-L-DCVC were virtually identical to those observed previously following IV administration of equivalent doses of L-DCVC to pentobarbital-anesthetized dogs. Rapid removal of the L-gamma-glutamyl group from L-gamma-glutamyl-L-DCVC (ie, deglutamylation) resulting in formation of the parent alpha-amino acid, L-DCVC, can best explain the extreme similarity in the nephrotoxic profiles of these 2 toxicants.
Show more [+] Less [-]Effect of xylazine on the arrhythmogenic dose of epinephrine in thiamylal/halothane-anesthetized horses
1992
Gaynor, J.S. | Bednarski, R.M. | Muir, W.W. III.
The effect of xylazine on the arrhythmogenic dose of epinephrine (ADE) was studied in 9 horses. Anesthesia was induced by administration of guaifenesin (50 mg/kg of body weight, IV) followed by thiamylal (4 to 6 mg/kg, IV) and was maintained at 1 minimal alveolar concentration MAC) of halothane (0.89%). Base apex ECG and facial artery pressure were recorded. Epinephrine was infused in a sequence of arithmetically spaced increasing rates (initial rate 0.25 (Lg/kg/min) for a maximum of 10 minutes. The ADE was defined as the lowest epinephrine infusion rate to the nearest 0.25 microgram/kg/min at which at least 4 premature ventricular depolarizations occurred in a 15-second period. Xylazine (1.1 mg/kg, IV) was administered after the control ADE was determined. Xylazine did not significantly alter the ADE (control, 1.12 +/- 0.38 microgram/kg/min; xylazine, 1.21 +/- 0.46 microgram/kg/min). Blood pressure increased transiently for 8 minutes after xylazine administration. Baseline systolic and diastolic arterial pressures and heart rate were not significantly different from control baseline pressures and heart rate 15 minutes after xylazine administration. Blood pressure and heart rate increased significantly during control and xylazine ADE determinations. Significant differences in pH, PaO2, PaCO2, or base excess were not observed between baseline and ADE in the control or xylazine groups. One horse developed atrial fibrillation, and 2 horses developed ventricular fibrillation during ADE determinations.
Show more [+] Less [-]Acute toxicity of paraherquamide and its potential as an anthelmintic
1992
Shoop, W.L. | Haines, H.W. | Eary, C.H. | Michael, B.F.
Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei and P. charlesii, is a new anthelmintic with potential broad-spectrum use. In initial trials, it had an excellent safety profile in cattle and sheep at doses efficacious against a dozen or more helminths, but recently it produced unexpected and severe toxicosis in dogs at doses far below those that were safe in the ruminants. To provide data on which to build rational safety tests in the future, we tested the acute toxicity of paraherquamide administered PO to male CD-1 mice and compared its profile with the most potent anthelmintic known, ivermectin. The estimated doses lethal to 50% of a group of mice were 14.9 and 29.5 mg/kg of body weight for paraherquamide and ivermectin, respectively. The no-effect doses were 5.6 and 18.0 mg/kg for paraherquamide and ivermectin, respectively. Signs of intoxication in paraherquamide-treated mice, if they developed, emanated within 30 minutes of administration, irrespective of dose, and consisted of either mild depression with complete recovery or a 5- to 10-minute period of breathing difficulty followed by respiratory failure and death by 1 hour after treatment. Gross necropsy findings in paraherquamide-treated mice that died in the high-dose group were normal. Ivermectin-related toxicity was slower and more predictable, taking place over a 3-day period, with dose-dependent signs of intoxication consisting of tremors, ataxia, recumbency, coma, and death. Necropsy of ivermectin-treated mice that died in the high-dose group revealed dehydration, a condition most likely resulting from the coma-induced state. These observations are congruent with clinical data from dog studies and suggest that if broad-spectrum use of ivermectin (expected to be approx 0.2 mg/kg) is unlikely because of idiosyncratic toxic effects in certain dogs, then use of a compound for dogs with an acute safety factor half of ivermectin, such as paraherquamide, would be even more unlikely. These data are also coupled with observations from anthelmintic trials to suggest that ivermectin possesses a substantially greater therapeutic index than does paraherquamide as a broad-spectrum antiparasiticide for ruminants. Although paraherquamide has a lesser therapeutic index, a strategic use for it as an anthelmintic against ruminant parasites that have become resistant to any or all of the other modern broad-spectrum anthelmintics can be suggested.
Show more [+] Less [-]Potential use of simple manganese salts as antioxidant drugs in horses
1992
Singh, R.K. | Kooreman, K.M. | Babbs, C.F. | Fessler, J.F. | Salaris, S.C. | Pharm, J.
The scavenging of superoxide radicals by endogenous and therapeutically administered superoxide dismutases may prevent superoxide-mediated oxidative stress leading to lipid peroxidation, membrane lysis, and cell death in a wide variety of normal and pathologic states. Simple inorganic manganous salts such as MnCl2 also have superoxide dismutase-like activity and are extremely inexpensive, compared with enzymatic superoxide dismutase preparations. In this study, we explored the use of Mn salts as antioxidant drugs. We used the percentage of inhibition of nitroblue tetrazolium reduction by superoxide as a measure of the amount of superoxide dismutase-like activity. We found concentration-related increases in superoxide scavenging activity in simple buffer solutions upon addition of 1.25, 2.5, and 5.0 microM MnSO4. To determine whether Mn salts can inhibit oxidative damage in tissues, we used an in vitro model of lipid peroxidation in ischemic and reoxygenated rat liver slices. Concentrations of 10, 100, and 1000 micromoles MnCl2/L of buffer significantly decreased indicators of lipid peroxidation believed to be initiated by intracellular superoxide. We then determined the effectiveness of MnCl2 as a superoxide scavenger in conscious horses by measuring the superoxide scavenging ability of equine plasma before and during intravenous infusions of 1.0 L volumes of 0.9% saline solution containing 0, 12.5, or 25 mM MnCl2. Plasma Mn concentrations, which were determined by atomic absorption spectrophotometry, increased as a function of time and dose. Intravenously administered MnCl2 concomitantly produced dose-related increases in superoxide scavenging ability of equine plasma at 15, 30, 45, and 60 minutes after the onset of infusion, compared with preinfusion control values. Heart rate and blood pressure of the treated horses, which were monitored to measure toxicity of MnCl2, gradually increased in both treatment groups. Clinical adverse effects of MnCl2 administration included defecation, pawing, hyperexcitability, flank watching, and sweating. The results of this study indicate that simple Mn salts may scavenge superoxide radicals in vivo with minimal adverse reactions and at a trivial cost.
Show more [+] Less [-]Induction of the acute-phase cytokine, hepatocyte-stimulating factor/interleukin 6, in the circulation of horses treated with endotoxin
1992
MacKay, R.J. | Lester, G.D.
Because hepatocyte-stimulating factor/interleukin 6 (IL-6) the principal inducer of acute-phase protein synthesis in the liver, quantification of its activity in blood provides an early and sensitive assessment of the acute-phase response. Circulating IL-6 activity was monitored in 4 adult horses for 72 hours after IV administration of endotoxin. In 4 experiments performed at weekly intervals and in randomized order, each horse was given endotoxin-1,000, 30, 1, and 0 ng/kg of body weight. Plasma IL-6 activity was quantified as the ability to promote growth of the IL-6-dependent B-cell hybridoma, B13.29 clone B9. Interleukin-6 activity (171 +/- 10.2 U/ml) was found in all pretreatment plasma samples and was significantly (P < 0.05) increased above baseline from 2 to 12 hours after 1,000 ng of endotoxin/kg was given and at 3 hours after 30 ng of endotoxin/kg was given. After 1,000- or 30-ng/kg dosage of endotoxin, peak plasma IL-6 activity (10,128 +/- 4,096 and 1,555 +/- 1,326 U/ml, respectively) was observed for 3 hours. The IL-6 response of endotoxin-treated horses began about 1 hour after tumor necrosis factor appeared in the circulation, and its course closely approximated the endotoxin-induced febrile reaction. Significant increase in plasma IL-6 activity was not detected in horses given 1 ng of endotoxin/kg or control buffer.
Show more [+] Less [-]Endotoxin-induced production of interleukin 6 by equine peritoneal macrophages in vitro
1992
Morris, D.D. | Crowe, N. | Moore, J.N. | Moldawer, L.L.
A study was performed to determine whether equine peritoneal macrophages produce interleukin 6 (IL-6) in vitro in response to endotoxin. Peritoneal fluid was collected from 14 clinically normal adult horses and was used as the source of peritoneal macrophages. Macrophages from each horse were isolated and cultured separately in vitro in the absence or presence of various concentrations (0.5, 5, or 500 ng/ml) of endotoxin (lipopolysaccharide from Escherichia coli 055:B5). Culture medium supernatants were collected after 3, 6, 12, and 24 hours' incubation and were frozen at - 70 C until assayed for IL-6 activity. Supernatant IL-6 activity was determined by use of a modified colorimetric assay and the murine hybridoma cell line B13.29 clone B.9, which is dependent on IL-6 for survival. Results indicated that equine peritoneal macrophages produce IL-6 in vitro and that supernatant medium IL-6 activity was significantly (P < 0.05) increased by exposure to endotoxin. Significant (P < 0.05) time and treatment effects on macrophage IL-6 production were apparent. The IL-6 activity peaked at 6 or 12 hours' incubation, then remained high through 24 hours' incubation, regardless of endotoxin exposure. Medium IL-6 activity during 3 and 6 hours' incubation was significantly (P < 0.05) greater in macrophages exposed to 5 or 500 ng of endotoxin/ml than in those exposed to 0.5 ng of endotoxin/ml; however peak IL-6 activity was similar among all endotoxin concentrations. Endotoxin concentration did not have an effect on medium IL-6 activity from macrophages exposed to endotoxin for 12 or 24 hours.
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