Pharmacokinetics of sulfisoxazole compared in humans and two monogastric animal species.

The pharmacokinetic profile of sulfisoxazole was studied and compared in dogs, swine, and humans. The trial was conducted over a 72-hr period after intravenous administration and a 96-hr period after oral administration in dogs and swine. In humans, the trial was conducted over an 8-hr period after oral administration. A two-compartment model system was used to define the pharmacokinetic profile. The mean half-lives for the distribution phase were 4.08, 1.30, and 0.56 hr in dogs, swine, and humans, respectively. For the elimination phase, the mean half-lives were 33.74, 46.39, and 7.40 hr in dogs, swine, and humans, respectively. The mean volume of the central compartment was approximately the same in dogs and swine, 10.6 and 10.5 liters, respectively. Humans had a smaller volume of distribution, 7.7 liters. The steady-state volumes of distribution were 17.2, 30.3, and 16.2 liters in dogs, swine, and humans, respectively. Dogs and swine excreted 42.2 and 30.7%, respectively, of the intravenous dose and 29.4 and 18.3%, respectively, of the oral dose. The bioavailability was 69.8% in dogs and 100.0% in swine. The fraction of drug bound ranged from 30 to 50% in dogs, 40 to 60% in swine, and 25 to 40% in humans.

Comparison of serum bilirubin levels in humans and two monogastric animal species after a single administration of sulfisoxazole.

Administration of sulfonamides during periods of hepatobiliary failure or hepatic immaturity increases the toxic potential of unconjugated or indirect bilirubin. A small but statistically significant increase of indirect, or unconjugated bilirubin was noted in dogs after oral administration of sulfisoxazole (100 mg/kg). A similar increase was not observed in swine after oral or intravenous administration of sulfisoxazole (100 mg/kg) or in humans (approximately 28 mg/kg) after oral administration or in dogs (100 mg/kg) after intravenous administration. Total and conjugated bilirubin showed small but statistically significant increases and were significantly correlated in dogs after oral and intravenous administration of sulfisoxazole (100 mg/kg) and in swine after oral administration of sulfisoxazole (100 mg/kg). There was a significant negative correlation between conjugated and indirect bilirubin, while total bilirubin increased in dogs after oral and intravenous administration of sulfisoxazole. These data illustrate a difference in species and administration route when attempting to assess the potential toxicity of bilirubin.

Subchronic nose-only inhalation study of propylene glycol in Sprague-Dawley rats.

Groups of nineteen Sprague-Dawley rats of each sex were exposed by a nose-only inhalation to 0.0, 0.16, 1.0 or 2.2 mg propylene glycol/litre air, for 6 hr/day, 5 days/wk for 90 days. There were no significant differences in respiratory rates, minute volumes or tidal volumes between any of the groups during aerosol exposure. The uniformity of respiratory parameters between dose groups implied that the delivered doses were proportional to the exposure concentrations. The mean terminal body weights were not significantly different from controls for any group of male animals. The mean body weights of the females exposed to 2.2 mg/litre were significantly less than those of female controls from day 50 onwards. This effect, in female rats, was consistent with a decrease in feed consumption for the high-exposure female rats beginning on study day 43. Statistically significant differences between the treated and control groups in certain haematological parameters, serum enzyme activities, other serum chemistry parameters and organ weights did not show clear dose relationships. There was a significant increase in the number of goblet cells or an increase in the mucin content of the existing goblet cells in the nasal passages of the medium- and high-exposure animals. Exposure to the above concentrations of propylene glycol caused nasal haemorrhage and ocular discharge in a high proportion of animals, possibly as a result of dehydration of the nares and eyes.

Methyl bromide 1-year dietary study in dogs.

Average human exposure resulting from consumption of methyl I bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the loss-, mid- and high-dose groups, respectively, averaged 0.06 ¿ 0.02, 0.13 ¿ 0.03 and 0.28 ¿ 0.08 mg/kg/day in males and 0.07 ¿ 0.03, 0.12 ¿ 0.03 and 0.27 ¿ 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study. the no-observed-effect level (NOEL) for MB was at least 0.28 mg/ kg/day, or approximately 200 times the expected average human dietary exposure.

Methyl bromide: 1-year dietary study in dogs.

Average human exposure resulting from consumption of methyl bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study, in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the low-, mid- and high-dose groups, respectively, averaged 0.06 +/- 0.02, 0.13 +/- 0.03 and 0.28 +/- 0.08 mg/kg/day in males and 0.07 +/- 0.03, 0.12 +/- 0.03 and 0.27 +/- 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study, the no-observed-effect level (NOEL) for MB was at least 0.28 mg/kg/day, or approximately 200 times the expected average human dietary exposure.

Correlation of blood cholinesterase levels with toxicity of sarin in rats.

The dose-mortality response curve for sarin when administered to pregnant rats is extremely steep. The pregnant animal either died during the treatment or survived with no observable fetal toxicity. Animals that died displayed many symptoms characteristic of anticholinesterase toxicity. The present study was conducted to determine whether the maternal deaths, clinical observations, and/or weight loss could be correlated with baseline blood cholinesterase levels in individual animals. Cholinesterase levels (plasma and erythrocyte) were obtained prior to, during, and following treatment of nonpregnant rats by gavage with 380 microg/kg/d sarin for 10 d. After the first dose, there was a drop in the plasma cholinesterase levels, which then remained low throughout the dosing period. There was a statistically significant correlation between body weight loss and plasma cholinesterase levels of the sarin dosed animals. The surviving animals also had lower plasma cholinesterase levels and lower body weights, both of which recovered on the cessation of dosing. The erythrocyte cholinesterase levels were not different between treated and nontreated rats. Neither plasma or erythrocyte baseline cholinesterase levels nor relative or absolute cholinesterase decline values could be used as predictors of mortality from sarin administration in rats.

Blood and ruminal fluid profiles in carbohydrate-foundered cattle.

The relationships of acetylhistamine and histamine to the clinical signs of carbohydrate-induced acidosis were investigated in beef steers. Blood pH and plasma L-lactic acid decreased and serum sodium, serum potassium, ruminal fluid L-lactic acid, ruminal fluid histamine, and ruminal fluid and blood acetylhistamine increased in carbohydrate-engorged steers as compared with the changes in the steers while feeding on pasture (forage-fed steers). Twelve to 14 hours after the steers had become engorged, clinical signs of laminitis ("feedlot founder") were observed in three of six steers. These signs appeared 4 to 6 hours after blood acetylhistamine attained maximal concentration (2.9997 +/- 1.7054 microgram of histamine base/ml of blood) and blood pH decreased to 7.260 +/- 0.026 at 8 hours after engorgement. Blood histamine value reached 0.1298 +/- 0.1095 microgram of histamine base/ml 4 hours after engorgement (8 to 10 hours before the appearance of clinical illness), but had reached maximal concentration 32 hours after engorgement (0.3300 +/- 0.028 microgram of histamine base/ml of blood).

Hepatic glutathione S-transferase activity in mice: effects of Avy/-genotype, obesity, lindane treatment, and sex.

Phenotypically distinct but genetically identical obese mottled yellow Avy/a and lean pseudoagouti Avy/a sibling mice and their congeneic black a/a littermates provide an experimental system for distinguishing phenotypic effects from genotypic effects in the expression of the genotype at the organismic level. Hepatic glutathione S-transferase activity in obese yellow Avy/a (YS X VY) F-1 hybrid female mice was only about 66% of that found in their lean black a/a sisters. This decreased enzyme activity was not a direct effect of the Avy/a genotype but was associated with the obesity of the yellow mice since the enzyme activity in lean pseudoagouti Avy/a female siblings was similar to that found in the black a/a mice. Long-term feeding of 160 ppm lindane in the diet decreased the enzyme activity in all phenotypes but did not eliminate the difference between the obese yellow and lean pseudoagouti and black mice. Interpretation of the available data suggests that no direct relationship exists between the level of hepatic glutathione S-transferase activity and the enhancement of tumor formation in yellow Avy/a mice. Several inbred mouse strains and F-1 hybrids were also screened for this enzyme activity. No strain differences were found but sex differences within different inbred strains were not uniform. In the AE and YS strains and their F-1 hybrid enzyme activity was higher in female than in males. In contrast, BALB/c and VY strain males had higher enzyme activity than the corresponding females.

The effect of three phlebotomy techniques on hematological and clinical chemical evaluation in sprague-dawley rats.

The effects of three phlebotomy techniques - periorbital sinus puncture, tail vein incision and cardiac puncture - were determined on seven hematological parameters and seven clinical chemical parameters in female Sprague-Dawley rats. The mean erythrocyte count, leukocyte count, hemoglobin and hematocrit were reduced with cardiac puncture as compared to the other two techniques. There was a statistically significant increase in the variance of each of these parameters except the leukocyte count. The mean serum lactate dehydrogenase, aspartate animotransferase, alanine aminotransferase, gamma-glutamyl transferase and creatinine were greater in samples collected by cardiac puncture than with the periorbital sinus and tail vein techniques. A statistically significant difference in variance was observed between the orbital sinus puncture and the cardiac puncture for each of these parameters. In all cases except lactate dehydrogenase, the values from the orbital sinus and tail vein techniques were comparable for both hematology and clinical chemistry. A large variance was found by all three techniques for both alkaline phosphatase and lactate dehydrogenase in the rat. Over 60% of the serum samples were hemolyzed from the cardiac puncture technique while approximately 25% of the serum samples from tail vein incision were hemolyzed. In this laboratory the lack of hemolysis and the lower variance make the periorbital sinus venipuncture technique the method of choice for collection of blood samples from rats.

Biochemical, hematological, and histological changes in B6C3F1 mice after intramuscular administration of PROven.

Repeated intramuscular administration of PROven to B6C3F1 mice has a potential cardiotoxic effect, an immunogenic effect, and a hematological effect. A significant decrease in two lactic dehydrogenase isoenzymes of myocardial origin was a result of chronic administration of PROven. The immunological effect was observed as a significant increase in beta- and gamma-globulins. The hematological effect of PROven was to increase the number of circulating neutrophils. Both the immunogenic and hematological effect should be anticipated due to the foreign protein nature of PROven. Following intramuscular injections of PROven, severe inflammatory changes including necrosis of skeletal muscle tissue were seen histologically.

Hematologic and clinical chemistry findings in control BALB/c and C57BL/6 mice.

The normal ranges for a variety of hematologic and clinical chemistry findings in 1,540 control BALB/c and C57BL/6 mice of various ages was determined. The total leukocyte count for both strains was highest at 1-3 months of age, and it usually decreased slightly until the mice were 18 months old. Hemoglobin values decreased with age. In both strains, the values for phosphorous, calcium, alkaline phosphatase, and urea nitrogen decreased after 3 months of age and then increased after 12 months of age. Differences between sexes were present for one or both of the strains for hemoglobin, phosphorus, glucose, cholesterol, aspartate aminotransferase, total protein, albumin, and alkaline phosphatase.

Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats.

Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.

Statistical variation of selected clinical pathological and biochemical measurements in rodents.

The variability in clinical pathological and biochemical measurements among replicates is often greater than the effects under study. To minimize the effects of this variability, it is recommended that replicated concurrent analyses (randomized blocks) of groups of animals be used. That is, some samples from each of the groups of animals to be compared are analyzed at the same time. This process is replicated until a sufficient number of animals are sampled. If replicated concurrent analyses are not conducted and clinical measurements are made at different times for different groups of animals, the biases may be large. Clinical data were examined from several experiments to illustrate that the problems of clinical measurements are not confined to a particular endpoint, species, or sex. In one case, four times as many animals would have been required using nonconcurrent analyses to achieve the same precision as for concurrent analyses. Permutation analyses of two of the data sets indicate that statistical conclusions concerning the comparison of average clinical levels in different groups of animals would have been incorrect, falsely indicating higher or lower levels in a group over one-half of the time with nonconcurrent analyses.

Controlled genetic variation in a subchronic toxicity assay: susceptibility to induction of bladder hyperplasia in mice by 2-acetylaminofluorene.

Five different dose levels of 2-acetylaminofluorene (2-AAF) were fed to weanling mice of 4 different genotypes from three unrelated F1 hybrids for 13 wk to determine differences in susceptibility to induction of bladder hyperplasia. Differences in the prevalence of hyperplasia per se and in the average grade of hyperplasia were interpreted as indicating greater susceptibility. On this basis, males of all genotypes were more susceptible than females. Among the genotypes, (AEX YS)F1 mice (AY) were most susceptible, followed closely by yellow A vy/A(BALB/cXVY)F1 mice (CV). Agouti A/a(BALB/cXVY)F1 mice were less susceptible than their yellow siblings and similar to the (C57BL/6XC3H)F1 mice. Neither body weight gain nor any of the biochemical parameters measured appeared to be affected at any dose level of 2-AAF. However, quantitative differences in several biochemical characteristics were detected among the genotypes. Serum gamma-glutamyl transpeptidase activity was higher in the AY mice than in the other hybrids. Among the CV mice, the yellow animals had lower glutathione S-transferase (GST) activity than their agouti siblings. Hepatic GST activity was lower in CV mice than in either of the other hybrids. Hepatic cytochrome P-450 and bs activities were similar in all hybrids.

Diabetogenic response to streptozotocin varies among obese yellow and among lean agouti (BALB/c x VY)F1 hybrid mice.

To test the hypothesis that the elevated insulin levels in obese neoplasia-susceptible yellow Avy/- mice might be a major factor stimulating tumor formation, it is necessary to use normoinsulinemic yellow mice. Although our attempt to obtain normoinsulinemic, euglycemic mice by streptozotocin treatment was unsuccessful, we did observe significant differences in the responsiveness to this treatment among mice of identical genotype. These differences were observed among female yellow Avy/A and agouti A/a (BALB/c x VY)F1 hybrid mice in the responses of body weight gain, plasma glucose, and plasma insulin levels to a single intraperitoneal injection of either 150 or 200 mg/kg streptozotocin (STZ) at 4 weeks of age followed by a 22-week observation period. Among animals treated with the high streptozotocin dose, 80% of the yellow mice gained almost no weight and became grossly hyperglycemic and hypoinsulinemic; however, only 55% of the agouti mice exhibited such a strong response. In the low dose group, 25% of the yellow mice responded with reduced body weight gain, decreased insulin, and elevated glucose levels whereas none of the agouti mice exhibited such responses. More pancreatic islet tissue mass was present in the untreated yellow control mice than among the comparable agouti mice by the end of the study. In both streptozotocin dose groups and in both genotypes, islet tissue mass was reduced to a much greater extent in the more responsive mice than in the less responsive mice. There appeared to be no correlation between islet tissue mass and insulin level. The phenotypic variation in responsiveness to an exogenous agent among test animals of a single inbred or F1 hybrid genotype reported here is not unique to this F1 hybrid since it is seen in most chronic bioassays when relatively low levels of agent are used.