Influence of anesthetic regimens on the perioperative catecholamine response associated with onychectomy in cats.

Plasma catecholamine concentrations in response to onychectomy were examined in 27 cats receiving different anesthetic regimens. Each cat was anesthetized with a dissociative-tranquilizer combination, and onychectomy was performed on 1 forefoot. One week later, each cat was anesthetized with the same dissociative-tranquilizer combination plus either butorphanol or oxymorphone, and onychectomy was performed on the other forefoot. Four treatment groups were studied: tiletamine-zolazepam and tiletamine-zolazepam-butorphanol combinations were administered to group-1 cats, ketamine-acepromazine and ketamine-acepromazine-butorphanol combinations were administered to group-2 cats, tiletamine-zolazepam and tiletamine-zolazepam-oxymorphone combinations were administered to group-3 cats, and ketamine-acepromazine and ketamine-acepromazine-oxymorphone combinations were administered to group-4 cats. All drug combinations were administered IM. Central venous blood samples were drawn for catecholamine analysis after injection of drug(s), after onychectomy, and 1, 2, and 4 hours after injection. Tiletamine-zolazepam alone or tiletamine-zolazepam-butorphanol prevented epinephrine release for 2 hours after injection of drug(s). Norepinephrine concentration increased significantly (P < 0.05) from baseline after onychectomy for tiletamine-zolazepam-butorphanol and at 4 hours for tiletamine-zolazepam and tiletamine-zolazepam-butorphanol. After onychectomy, there was no difference in epinephrine values between tiletamine-zolazepam and tiletamine-zolazepam-oxymorphone. Ketamine-acepromazine prevented increases in norepinephrine and epinephrine concentrations for up to 2 hours after surgery. Addition of butorphanol to ketamine-acepromazine decreased norepinephrine values immediately after onychectomy. Addition of oxymorphone to ketamine-acepromazine resulted in lower epinephrine values 4 hours after surgery.

DNA adduct dosimetry and DNA repair in rats and pigs given repeated doses of procarbazine under conditions of carcinogenicity and human cancer chemotherapy respectively.

Procarbazine (PCZ), an antineoplastic agent that produces methylated bases in DNA after metabolic activation, has been implicated in the development of secondary cancers in patients treated for a primary neoplasm. The repair of the important promutagenic lesion, O6-methylguanine (O6-meG) by O6-alkylguanine-DNA alkyl transferase (AGT) is believed to be crucial for the stability of O6-meG and for the tumorigenic outcome after exposure to methylating carcinogens. Using two different animal models, we investigated methyl DNA adduct dosimetry and DNA repair in (i) female rats given repeated doses of PCZ for 20 weeks under conditions of carcinogenicity, and (ii) female pigs administered repeated doses of PCZ for 4 weeks according to a regimen comparable to that given to human subjects undergoing cancer chemotherapy. After each successive week, four rats and three pigs were killed and tissues including blood, liver, mammary gland, spleen, thymus and lymph node were taken. The levels of O6-meG, 7-methylguanine (7-meG) in DNA and of AGT were determined in these tissues. In the rat, O6-meG in the liver DNA, and to a lesser degree in the spleen was efficiently removed throughout the 20 week dosing period, as indicated by the O6-meG/7-meG ratio being much less than 0.11. In the target organs, accumulation of O6-meG began in the mammary gland after 9 weeks, and in the lymph node and thymus after 3 weeks of dosing. Interestingly, the accumulation of O6-meG in the mammary gland correlates well with a concomitant decrease in AGT level as from week 10 and may be related to the induction of mammary gland tumors, first detected in two animals at week 10. In pigs, after a total dose of 750-4000 mg of PCZ, the range of 7-meG detected in leukocyte DNA was 21-66 mumol/mol G, which compares well with recent findings in cancer patients treated with PCZ. Similar levels of 7-meG were detected in the pig liver, thymus and lymph node. O6-MeG was only detectable in leukocyte DNA at week 4 with our present method. Compared with control pig tissues, a depressed AGT level was found in the leukocyte, lymph node and brain of the treated animals.

The formation, disposition, and hepatic metabolism of dimethylnitrosamine in the pig.

The disposition, metabolism, and endogenous formation of N-nitrosodimethylamine (NDMA) from nitrosatable precursors was studied in the intact pig and in animals with cannulated hepatic and portal veins and catheterized bile ducts. Rates of disappearance of NDMA from peripheral venous and arterial blood after iv injections were virtually identical and the compound appeared in bile after a lag time of about 1 hr, with a subsequent decline in biliary concentration at about the same rate as in circulating blood. Measurements of NDMA in portal and hepatic vein blood after oral doses of 10, 1.0 and 0.1 mg/kg, respectively, showed progressively greater hepatic extraction with levels in the hepatic vein approaching the limits of detection after the lowest dose. Both halothane and ethanol virtually abolished the hepatic extraction of NDMA, presumably due to their known inhibitory action on its metabolism in the liver. Endogenous formation of NDMA and N-nitrosomorpholine after oral doses of the amines plus nitrite was demonstrated by their detection and measurement in the portal vein blood. Morpholine was nitrosated more effectively than dimethylamine and inhibited the nitrosation of the latter when the two amines were given together. NDMA was found in the portal blood after sequential oral administration of aminopyrine and nitrite, the concentration being considerably greater after fasting for 24 hr than after a 2-hr fast when much food was present in the stomach.

Elimination of salicylic acid in goats and cattle.

Sodium salicylate was administered to cattle and goats IV and PO according to a crossover design. Total urinary excretion of SA and its metabolites was measured for 3 days after dosing. Salicyluric acid (SUA) was the only metabolite detected in urine of either species. Recovery of sodium salicylate and SUA in goats amounted to 67.9 and 34.6% of the dose, respectively, after IV administration. After oral dosing, total recoveries were 30.2% (sodium salicylate) and 71.7% (SUA) of dose. By comparison, cattle excreted significantly (P less than 0.05) less sodium salicylate (54.0%) and more SUA (49.9%) after IV dosing. The same pattern was observed after oral administration, wherein cattle excreted less than 12% as sodium salicylate and more than 99% as SUA. In both species, almost 90% of the drug excreted as sodium salicylate was found in urine within the first 12 hours after an IV dose and within 24 hours after oral dosing. The excretion of SUA was somewhat slower in both species, especially after oral administration. The data suggested that there were only quantitative differences in the metabolism and elimination of sodium salicylate between the 2 species, with cattle excreting a higher proportion of the drug as the glycine conjugate SUA.

Chlortetracycline in swine--bioavailability and pharmacokinetics in fasted and fed pigs.

Chlortetracycline hydrochloride was administered intra-arterially (11 mg/kg) and as an oral drench (33 mg/kg) to ten 21.0-31.5-kg pigs. Five of the pigs were fasted 18 h prior to dosing and five of the pigs were fed ad libitum prior to dosing. The mean volume of distribution determined by area-under-the-curve calculations for the fasted pigs (0.967 +/- 0.210 l/kg) was significantly less (P less than 0.05) than the mean volume of distribution for the fed pigs (1.39 +/- 0.31 l/kg). Mean total body clearance of the drug was also significantly less (P less than 0.05) in the fasted pigs (0.165 +/- 0.055 l/kg/h) as compared to the fed pigs (0.307 +/- 0.053 l/kg/h). The elimination constants (beta) were not found to be statistically different (P less than 0.05): 0.1811 +/- 0.0057 for the fasted pigs; 0.2260 +/- 0.0461 for the fed pigs. The bioavailability for both groups was similar; 19.12 +/- 8.3% for the fasted pigs and 17.88 +/- 5.3% for the fed pigs. In a second experiment three groups of six pigs which weighed 34.5-44.1 kg were fed a corn-soy diet ad libitum. The rations were fortified with chlortetracycline at 100, 400 or 1000 mg chlortetracycline hydrochloride/kg feed. Chlortetracycline concentrations were determined in plasma samples collected over a 6-day period. Plasma chlortetracycline concentrations reach a plateau within 24 h after initial access to the trial diets and were highly correlated with the dose of the drug consumed (r2 = 0.97).

An experimental model for pharmacokinetic analysis in renal failure.

A renal failure model was developed in the dog to evaluate the effect of varying degrees of renal failure on drug pharmacokinetics. A controlled impairment of renal function was induced by electrocoagulating portions of one kidney and excising the contralateral kidney. The magnitude of renal dysfunction, defined by the percentage of normal glomerular filtration rate (% NGFR), was estimated by 125I-iothalamate total body clearance. The model was evaluated by comparing the pharmacokinetics of oxytetracycline (OTC) before and after the induction of renal failure in two experiments: single intravenous dose (11 dogs); single intravenous and oral doses (8 dogs). Renal failure (RF) was studied in three classes according to % NGFR: less than 25%, severe RF; 25-39%, moderate RF; and greater than or equal to 40%, mild RF. Significant reductions were observed over RF class in OTC pharmacokinetic parameters for elimination and distribution but not for oral absorption.

Pharmacokinetics and metabolism of fenbendazole in channel catfish.

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t 1/2 alpha was 0.51 h, t 1/2 beta was 16.8 h, body clearance (C1B) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t 1/2 (abs) was 1.47 h, the t 1/2 beta was 20.1 h, and the tlag was 0.1 h. Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO2) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.

Plasma concentrations of oxytetracycline in swine after administration of the drug intramuscularly and orally in feed.

Four pigs were used in a 2 X 2 crossover study to determine plasma oxytetracycline (OTC) concentration and OTC pharmacokinetic variables after IM administration of 2 OTC preparations--long acting OTC and a 100-mg of OTC/ml solution (OTC-LA and OTC-100, respectively)--at a dosage of 20 mg/kg of body weight. In a second study, 3 additional pigs were given ad libitum access to feed containing pure OTC (0.55 g/kg of feed). The mean (+/- SD) peak plasma OTC concentration after OTC-LA administration was 6.0 +/- 2.2 micrograms/ml at 30 minutes; the mean peak plasma OTC concentration after OTC-100 administration was 6.7 +/- 3.4 micrograms/ml at 90 minutes. Mean plasma OTC concentration after oral OTC administration in feed peaked at 0.4 micrograms/ml 48 hours after access to OTC-medicated feed and decreased to 0.25 micrograms/ml by the end of that study. Mean plasma OTC concentration was maintained at greater than 0.5 micrograms/ml for less than 48 hours after OTC-LA administration and for less than 36 hours after OTC-100 administration. Mean plasma OTC concentration decreased to less than 0.2 micrograms/ml by 72 hours after IM administration of either product. Calculation of area under the plasma OTC concentration-time curve (AUC) did not reveal significant difference between the 2 OTC formulations. There also was not significant difference (between OTC-LA and OTC-100) in the value of the disappearance rate constant after administration of either OTC formulation. The data did not indicate significant pharmacologic advantage of OTC-LA, compared with OTC-100, when either formulation was administered IM at a dosage of 20 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability, pharmacokinetics, and plasma concentration of tetracycline hydrochloride fed to swine.

A 2 X 2 crossover design trial was conducted in gilts to determine the bioavailability and pharmacokinetics of tetracycline hydrochloride. The bioavailability of tetracycline hydrochloride administered orally to fasted gilts was approximately 23%. After intravascular administration, the disposition kinetics of tetracycline in plasma were best described by a triexponential equation. The drug had a rapid distribution phase followed by a relatively slow elimination phase, with half-life of 16 hours. Its large volume of distribution (4.5 +/- 1.06 L/kg) suggested that tetracycline is distributed widely in swine tissues. Total body clearance was 0.185 +/- 0.24 L/kg/h. Other pharmacokinetic variables were estimated. In a second trial, 3 gilts were fed a ration containing 0.55 g of tetracycline hydrochloride/kg of feed. Resulting plasma concentration of tetracycline was determined at selected times during 96 hours after exposure to the medicated feed. Plasma drug concentration peaked (0.6 micrograms/ml) at 72 hours after access to the medicated feed.

Effects of salinomycin on sow weight change during lactation and on sow reproductive performance.

Forty-five gravid cross-bred sows (mean parity 3.3 +/- .3) were randomly allotted to two dietary treatments: corn-soybean mean (CS) or CS plus 60 mg salinomycin per kilogram of diet (CSS). Sows were fed their respective diets through two successive parities with dietary treatment initiated at 100 d postcoitum and continued until weaning of the second successive litter. Therefore, sows fed CSS received salinomycin for 14 d before the first parturition and for approximately 153 d before the second parturition. Daily feed intake was restricted to 2 kg.hd-1.d-1 during gestation and to 3 kg.hd-1.d-1 from weaning to breeding. All sows. had ad libitum access to feed during lactation. Sows were weighed 7 d prior to parturition, at weaning and at breeding. Weaning-to-estrus interval and farrowing interval were recorded for all sows. Litters were weighed at birth and weaning. There were no differences (P greater than .05) between dietary treatments in sow weights before parturition, at weaning or at breeding for either first or second farrowing. The CSS-fed sows lost more weight from weaning to breeding after the first (P less than .03) and second (P less than .05) lactation periods than CS-fed sows. The CSS-fed sows tended to gain more (P = .06) weight during lactation than CS-fed sows. There were no differences (P greater than .05) between treatments in lactation feed intake, weaning-to-estrus interval, farrowing interval, litter size born or weaned, litter weights at birth or at weaning, or in sow culling rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of N-nitrosodimethylamine in swine.

The pharmacokinetics of N-nitrosodimethylamine (NDMA) have been studied in swine. They were studied following i.v. administration of 0.1, 0.5 and 1.0 mg/kg, and following oral doses of 1.0 and 5.0 mg/kg of NDMA. Following a bolus i.v. dose, the concentration of NDMA in blood declined biphasically with a mean distribution half-life of 7 min and a mean elimination half-life of 28 min. The areas under the blood concentration versus time curves (AUC) were roughly proportional to dose indicating that the pharmacokinetics in this dose range were first order. The mean systemic clearance from blood was 65.8 ml/min/kg, the steady-state volume of distribution was 1.4 l/kg, and the mean residence time was 20 min. Following the oral doses, the AUC and peak concentration in blood were not proportional to the dose. It is likely that the pharmacokinetics at the lower dose were first order, but at the higher dose the pharmacokinetics were no longer first order because metabolism was saturated. The bioavailability of the 1.0 mg/kg dose was 67%. Since the clearance was probably due to metabolism and the clearance from blood exceeded hepatic blood flow, the high bioavailability suggests that extrahepatic metabolism plays an important role in the systemic clearance of NDMA in swine.

Disposition of fenbendazole in cattle.

Fenbendazole (FBZ) was administered to cattle IV and orally in a crossover design. Plasma concentration vs time profiles were reported for FBZ and its major metabolites, the sulfoxide (oxfendazole) and the sulfone. The total excretion of FBZ and its metabolites in urine and feces was also measured for 6 days after administration. All known metabolites were identified in urine and feces except for fenbendazole amine. Neither this minor metabolite nor p-hydroxyfenbendazole (FBZ-OH) appeared in plasma. The major excretory product was FBZ-OH. After oral administration, only 44.6% of the dose was eliminated after 6 days, indicating a fairly high degree of sequestration, probably within the gastrointestinal tract.

Surgical procedure for chronic biliary sample collection in pigs.

To collect biliary samples from pigs, catheters were placed in the distal end of the gallbladders in twelve 20- to 30-kg pigs. An occluder cuff was placed around the bile duct proximal to the duodenum. Inflation of the occluder cuff prevented bile flow into the duodenum and allowed total collection of bile from the catheter in the gallbladder. Deflation of the occluder cuff allowed return of bile flow into the duodenum. Two pigs developed gastric ulcers and two pigs had bile duct dilatation. These responses were attributed to occluder cuffs of inadequate size which could have caused partial or complete obstruction of the bile duct.

Effect of organic vehicles on the pharmacokinetics of aminophylline administered intravenously to goats.

Aminophylline dissolved in water, propylene glycol, or dimethyl sulfoxide was administered intravenously to goats in a randomized cross-over experiment. Model-dependent and model-independent pharmacokinetic parameters for theophylline were compared on the basis of the solvent used in the dosage form administered. No difference was found in any pharmacokinetic parameter. Thus, we found no evidence for the possibility that the organic solvents studied would confound pharmacokinetic investigations of theophylline and similar lipophilic drugs.

Acute selenium toxicosis in sheep.

Acute selenium (Se) toxicosis was evaluated in 20 female crossbred sheep, 8 to 14 mo of age. Five groups of 4 sheep each were given 0.4, 0.6, 0.7, 0.8, or 1.0 mg Se/kg body weight IM. The LD50 for sodium selenite was 0.7 mg Se/kg body weight with a standard error of 0.035 over a 192 hr observation period. The most evident clinical signs were dyspnea and depression. At necropsy, the most consistent lesions in animals which received 0.7, 0.8, and 1.0 mg Se/kg body weight were edematous lungs and pale mottled hearts. Highest tissue Se concentrations in declining order were found in the liver, kidney and heart.

Disposition of fenbendazole in the goat.

The disposition of fenbendazole was studied in goats after oral or IV administration. Plasma concentration vs time profiles were determined for fenbendazole and all of its metabolites. The total excretion of the drug and its metabolites in urine and feces was also measured for 6 days. A biliary cannula was inserted in 1 goat to study the excretion of fenbendazole and its metabolites into the bile. Fenbendazole was converted to its sulfoxide (oxfendazole), and the sulfone, primary amine, and p-hydroxylated metabolites. The active metabolite, oxfendazole, appeared in plasma, but only trace amounts were found in feces or urine. The major excretory metabolite was p-hydroxyfenbendazole.

Pharmacokinetics of selenium administered parenterally at toxic doses in sheep.

Pharmacokinetics of Se were evaluated in 24 female crossbred sheep, 8 to 14 months of age, after toxic doses of Se were administered. Five groups of 4 sheep each were given 0.4, 0.6, 0.7, 0.8, or 1 mg of Se/kg of body weight, IM. Nine of these sheep died within 36 hours after Se administration. Blood Se disappearance curves were triphasic for the 11 sheep that lived for at least 36 hours after Se administration and were biphasic for the 9 sheep that died within 36 hours. The lambda 2 rate constants of Se disposition after IM administration indicated a dose dependency. Sheep given 0.4, 0.6, 0.7, or 0.8 mg of Se/kg had lambda 2 rate constants of 0.110, 0.079, 0.046, and 0.034 hour-1, respectively (r2 = 0.97). The respective half-lives of the 2nd distributive phase after IM administration were 6.3, 8.8, 15.1, and 20.4 hours. In the 11 sheep that had triphasic pharmacokinetics, the mean lambda 3 elimination rate was 0.0011 hour-1. Four additional sheep were given 0.7 mg of Se/kg, IV. These sheep survived and had blood Se disappearance curves that were triphasic. In the 4 sheep given Se IV, the mean lambda 3 elimination rate was 0.0020 hour-1, which represented a biological half-life of 354 hours or 14.7 days.

The pig as an animal model for the study of nitrosamine metabolism.

Surgical procedures have been developed that permit the sampling of portal blood, bile and hepatic blood in intact pigs. Animals so prepared have been used to study liver metabolism and biliary excretion of N-nitrosodimethylamine (NDMA) following oral and intravenous dosing.