Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 1978"
TL;DR: The concept of the two compartment and three compartment models for drug disposition are introduced and developed to demonstrate the mathematical models which may be derived to describe the kinetics of drug distribution and elimination.
Abstract: This series of two review articles deals with general aspects of the mechanisms which govern absorption and distribution of drugs within the body, and the kinetics of drug metabolism and excretion. Emphasis is given to the verification of pharmacokinetic principles in domestic animals, and the clinical applications which proceed therefrom. In the first part, the concept of the two compartment and three compartment models for drug disposition are introduced and developed to demonstrate the mathematical models which may be derived to describe the kinetics of drug distribution and elimination. In the second part bioavailability and drug dosage will be considered.
118 citations
TL;DR: Examination of specifics of energy-generating metabolism and putative neurochemical transmitters allows us certain predictions in relating a given drug activity to an individual species and indicates that such diversity exists among helminth metabolic or nervous systems that a broad-spectrum anthelmintic would most likely inhibit at several sensitive points.
Abstract: The primary physiological mode of action of nearly all drugs used to control helminth parasites is not well understood. Examination of the general modes of action in terms of parasite requirements for survival may, however, provide guidelines to continue our present investigations and direct us for future research.
Two general areas of drug activity are (1) interference with energy-generating metabolism, and (2) interference with proper neuromuscular coordination. Few exceptions are found to these areas because the target organisms require little else for survival.
The target of most previously effective and many presently effective anthelmintics is an adult parasite. Adult helminth parasites must maintain an advantageous feeding site and must transport and metabolize substrates (primarily glucose) to generate life-maintaining energy. Adult worms have almost no other short-term requirements for survival because they have little or no metabolic activity in either lipid synthesis or oxidation, nucleic acid synthesis, or protein synthesis (except egg-laying).
Examination of specifics of energy-generating metabolism and putative neurochemical transmitters allows us certain predictions in relating a given drug activity to an individual species. These examinations indicate that such diversity exists among helminth metabolic or nervous systems that a broad-spectrum anthelmintic would most likely inhibit at several sensitive points.
Published information on drug action and differences in data interpretation are discussed. Two novel areas for future anthelmintic investigations may be (1) juvenile hormone or ecdysone analogs, and (2) pheromones. A combined empirical and rational approach to the development of new drugs may be the most efficient avenue of future research.
44 citations
TL;DR: From experiments with oral administration of trimethoprim to cows it is concluded that metabolism in the cow's liver is at least as important as ruminal degradation.
Abstract: Oral administration of sulphadoxine to adult goats (100 mg/kg body weight) resulted in absorption of about two thirds from the gastrointestinal tract. The absorption rate was lowest in newborn kids and increased with increasing age. Following administration of sulphadoxine (40 mg/kg body weight) through a rumen fistula about 80% was absorbed in cows. Also the elimination rate for sulphadoxine was lower in newborn kids than in adult goats and increased with the age. Oral administration of the trimethorpim (TMP) to kids, goats (20 mg/kg body weight) and cows (8 mg/kg body weight) resulted in higher plasma concentrations in newborn kids than in the older age groups and the maximal concentration of TMP in the blood of adult goats and cows was lower than 0.2 μg/ml. In vitro experiments showed that trimethoprim may be degraded by ruminal microorganisms, but from experiments with oral administration of trimethoprim to cows it is concluded that metabolism in the cow's liver is at least as important as ruminal degradation.
31 citations
TL;DR: Tissue distribution and elimination kinetics of oxytetracycline in sixteen organs and body fluids were determined in young pigs following intravenous and oral administration and relationships between plasma and tissue depletion for several major edible organs were found to be statistically significant.
Abstract: Tissue distribution and elimination kinetics of oxytetracycline in sixteen organs and body fluids were determined in young pigs following intravenous and oral administration. Seventeen non-fasted pigs, 8–10 weeks of age, weight range 16.4–34.5 kg were dosed intravenously at a dose rate of 11 mg/kg bodyweight. An additional seventeen weaning pigs, 12–14 weeks of age, weight range 27.2–36.3 kg were dosed orally at a dose rate of 48–65 mg/kg bodyweight. Oxytetracycline was rapidly distributed (half-life, 6.71 ± 1.13 min) in swine. The mean volume of distribution was 1.26 ± 0.18 l/kg and overall body clearance was 3.82 ± 0.59 ml/kg/min. The elimination half-life of oxytetracycline in pigs was 3.87 ± 0.62 h, which is shorter than has been observed in other domestic animal species. Oxytetracycline became rapidly and efficiently involved in enterohepatic cycling, with as much as 70% of a total intravenous dose being available for reabsorption from the gastrointestinal tract within 1 h after administration. This high degree of enterohepatic recycling prolonged the half-life, and the large amount of drug that entered the enteric tract contributed to the high volumes of distribution and high k12/k21 ratios. The excellent tissue penetration of this drug further contributed to the high volume of distribution and high k12/k21 ratios obtained. Relationships between plasma and tissue depletion for several major edible organs were found to be statistically significant. Blood plasma is proposed as a body fluid for monitoring oxytetracycline tissue residues.
31 citations
30 citations
TL;DR: The findings of rapid metabolism following both routes of injection suggests that metabolism plays a major part in the termination of the effects ofketamine in the sheep, and that plasma levels of ketamine are of more importance than CSF levels in the maintenance of anaesthesia.
Abstract: A comparison of the distribution and metabolism of intravenous and intra-cerebroventricular ketamine hydrochloride in sheep showed that following intravenous administration there was a rapid biexponential decline in plasma ketamine, metabolism was rapid and both the demethylation and subsequent oxidation metabolites were detected. In the urine the second metabolite appeared to be the major one together with a third unidentified metabolite. In the CSF both ketamine and the first metabolite appeared to follow the plasma concentrations, but the entry of the second metabolite seemed to show a much slower pattern. Following injection of ketamine into the lateral cerebral ventricles the levels of ketamine in the CSF declined rapidly and the plasma concentration of ketamine showed a similar pattern to that seen following intravenous injection, indicating a rapid transfer to the blood. The levels of the metabolites found in the CSF suggest that their production does not take place in the CSF and that they penetrate back from the plasma. The findings of rapid metabolism following both routes of injection suggests that metabolism plays a major part in the termination of the effects of ketamine in the sheep, and that plasma levels of ketamine are of more importance than CSF levels in the maintenance of anaesthesia.
27 citations
26 citations
TL;DR: It appears that serum or urine would be a good body fluid for monitoring chloramphenicol residues in tissues, whereas stomach content might be used as an indicator for chlorampshenicol treatment for many days after therapy with the drug.
Abstract: Eighteen non-fasted, 12–16 week old pigs weighing between 20 and 40 kg were dosed with chloramphenicol intravenously at a dose rate of 22 mg/kg body weight. The pharmacokinetics of chloramphenicol were determined in blood plasma and sixteen selected organs and body fluids. The elimination half-life in plasma was estimated to be 2.66pL1.06 h and volume of distribution was 1.39pL0.32 I/kg. The body clearance of chloramphenicol was estimated to be 6.64pL1.52 ml/kg/min. The elimination half-life in tissue was found to range from 1.25 h in kidney to 5.89 h in fat. Most major organs ranged from 2.0 to 5.0 h. Significant correlations were found to exist between plasma concentrations and most major organ concentrations. Chloramphenicol concentrations in muscle, spleen, lung, stomach content, and large intestine content were found to exist slightly beyond the time when concentrations were negative in plasma. However, urine levels exceeded tissue levels at the last slaughter interval. It appears that serum or urine would be a good body fluid for monitoring chloramphenicol residues in tissues, whereas stomach content might be used as an indicator for chloramphenicol treatment for many days after therapy with the drug.
23 citations
TL;DR: Criteria for determining three different drug tolerance levels of edible tissues were presented and discussed and a good estimate was obtained for predicting drug withdrawal times for diseased animals treated with beta-lactam antibiotics, oxytetracycline, and aminoglycoside antibiotics.
Abstract: Using a pharmacokinetic model based on drug concentrations in tissue fluids of normal animals, calculated withdrawal times were compared with the observations made in emergency-slaughtered diseased animals. After multiplying the calculated withdrawal times for muscle and kidney cortex tissues by a factor of 2 to 3, and 4 to 5, respectively, a good estimate was obtained for predicting drug withdrawal times for diseased animals treated with beta-lactam antibiotics, oxytetracycline, and aminoglycoside antibiotics. Criteria for determining three different drug tolerance levels of edible tissues were presented and discussed.
22 citations
TL;DR: A total of forty-eight dogs were utilized to titrate and evaluate the activity of a new miticide, amitraz, applied dermally and evaluated for efficacy against experimentally induced Demodex canis and S. scabiei infestations.
Abstract: A total of forty-eight dogs were utilized to titrate and evaluate the activity of a new miticide, amitraz. The treatment was applied dermally and evaluated for efficacy against experimentally induced Demodex canis and Sarcoptes scabiei infestations. Five different concentrations (2000, 1000, 500, 250, 125 p.p.m.) of the active drug, N'—(2, 4-dimethylphenyl)N—{[(2, 4-dimethylphenyl) imino] methyl} -N-methyl-methanimidamide, were tested. The activity of amitraz was compared to a standard treatment, placebo treatment, and no treatment.
A single dermal treatment with amitraz (all concentrations) indicated activity against both D. canis and S. scabiei. The lowest concentration of active drug (125 p.p.m.) was significantly less efficacious than the four higher concentrations (250, 500, 1000, 2000 p.p.m.). At the 250 p.p.m. (or higher) level the effectiveness of this new miticide was comparable to the standard treatment. The data indicate the 250 p.p.m. concentration is the optimal level and the recommended dilution for treatment of mange mites. Drug reactions related to amitraz were not observed.
21 citations
TL;DR: It is demonstrated that flurbiprofen inhibited the febrile reactions during the acute phase of T. vivax infection, but the drug did not prevent or reverse the associated drop in blood serotonin level during this period.
Abstract: Platelet aggregation leading to a decreased number of thrombocytes and reduced blood serotonin levels can be correlated with parasitaemia as has been observed in goats and cattle infected with T. vivax Y58. Flurbiprofen is a potent anti-inflammatory agent with antipyretic activity. In vitro, this agent inhibits platelet aggregation and blocks serotonin release. The results of the present study demonstrated that flurbiprofen inhibited the febrile reactions during the acute phase of T. vivax infection, but the drug did not prevent or reverse the associated drop in blood serotonin level during this period. Moreover, it was apparent that flurbiprofen had a deleterious effect on goats infected with T. vivax Y58. The infection in the untreated animals (sixteen out of seventeen goats) followed a rather mild and prolonged course with peaks of parasitaemia during the febrile episodes, whereas in flurbiprofen-treated goats (five animals), inoculated with the same number of trypanosomes, the parasitaemia was progressive and terminated in early death with disseminated intravascular coagulation at post mortem examination. These observations would seem to confirm the work of previous investigators, suggesting that anti-inflammatory agents have an aggravatory effect on the course of infection in animals inoculated with various strains of trypanosomes. Important differences exist, however, in the relationship between prostaglandin synthesis in the platelets of the goat and in those of other species.
TL;DR: The ability of these drugs to reduce the level of spike activity accompanying disruption of migrating myoelectric complexes and to inhibit the carbachol-induced increased level of spiking may account for the antispasmodic effects observed after the use of anticholinergic drugs in gastrointestinal disorders.
Abstract: The changes induced in the electrical activity of the small intestine by atropine sulphate, diphemanil methylsulphate, hyoscine butylbromide and prifinium bromide were studied in conscious sheep fitted with chronically implanted electrodes. Increased spike potential activity was induced by carbachol. The mean slow-wave frequency of the antrum was 7.35 ± 0.18/min with burst of spike potentials randomly superimposed on about 63% of the slow waves. The occurrence of the spike bursts was inhibited for 18—30 min after an intravenous injection of atropine (0.75 mg/kg) and during its infusion at the rate of 0.05 mg/kg/min. The activity of the proximal part of the small intestine, which is characterized by migrating myoelectric complexes moving down slowly at hourly intervals, was replaced by irregular series consisting of spike bursts of about 3 min duration, at intervals of about 12 min for a total of 110 min. Such an effect, in which the level of spike activity was reduced, was also observed with hyoscine, diphemanil and prifinium during 80, 120 and 180 min periods respectively. The injection of carbachol was followed by continuous spike activity in which the mean spike level was nearly doubled, as occurs at the onset of diarrhoea. An inhibitory effect was observed at both antral and duodeno-jejunal levels with the four drugs used, that of hyoscine being least marked. The effect of prifinium was more pronounced than that of atropine or diphemanil, especially on the jejunum. The results suggest that the ability of these drugs to reduce the level of spike activity accompanying disruption of migrating myoelectric complexes and to inhibit the carbachol-induced increased level of spiking may account for the antispasmodic effects observed after the use of anticholinergic drugs in gastrointestinal disorders. Prifinium had the longest lasting effect at both antral and duodeno-jejunal levels and seemed to be a good atropine substitute to alleviate gastro-intestinal hypermotility.
TL;DR: All the aminoglycoside antibiotics tested were shown to be relatively ineffective, with penicillin G and tetracycline tended to be higher for isolates from non-human primates and ruminants than for other antibiotics tested.
Abstract: Ninety-nine isolates of obligate anaerobic bacteria obtained from clinical material were tested for susceptibility to ten antimicrobial agents. Regardless of the species of animal from which the isolates were obtained 90–95% were inhibited by ≤4 μg of ampicillin/ml, ≤4 μg of chloramphenicol/ml, ≤1 μg clindamycin/ml, ≤2 μg metronidazole/ml, ≤8 μg minocycline/ml, ≤16 μg penicillin Gyml, and ≤16 μg tetracycline/ml. All the aminoglycoside antibiotics tested (gentamicin, kanamycin, neomycin, and streptomycin) were shown to be relatively ineffective requiring ≥128 μg/ml for the inhibition of >50%of the isolates. The minimal inhibitory concentration of penicillin G and tetracycline tended to be higher for isolates from non-human primates (penicillin G) and ruminants (tetracycline).
TL;DR: It is concluded that in adult ruminants, chloramphenicol is metabolised by rumen microfauna more rapidly than it is absorbed, when administered orally.
Abstract: The biotransformation of chloramphenicol in the ruminant forestomachs was studied by incubating the antibiotic with ovine rumen contents in vitro. Differential centrifugation of rumen contents showed that rapid reduction of the aromatic nitro group of chloramphenicol to an arylamine occurred in those fractions containing ciliates, and this activity was not inhibited by penicillin or streptomycin. It is concluded that in adult ruminants, chloramphenicol is metabolised by rumen microfauna more rapidly than it is absorbed, when administered orally.
TL;DR: Toxicological evaluation suggests that the residues found in slaughter pigs do not per se constitute a danger to public health, but the presence of any drug residue in meat or meat products is undesirable, and alternative, non-pharmacological approaches to the problems arising from transportation prior to slaughter should be considered.
Abstract: An investigation was carried out to determine the residues of azaperone in slaughter pigs and pig meat products. The butyrophenone tranquillizer azaperone is frequently administered to pigs by intramuscular injection in order to reduce mortality and loss of meat quality resulting from transportation from the farm to the slaughter house. In the pig, following administration of azaperone as recommended by the manufacturer (0.4 mg/kg i.m.) residue concentrations of about 0.05 μg/g azaperone, and 0.20 μg/g azaperol (the main biotransformation product in the pig) were found in the kidneys; the kidneys proving to be the sampling organs of choice. Pasteurization and other technological procedures did not influence residues measurably. Toxicological evaluation suggests that the residues found do not per se constitute a danger to public health. None the less, the presence of any drug residue in meat or meat products is undesirable, and alternative, non-pharmacological approaches to the problems arising from transportation prior to slaughter should be considered.
TL;DR: Based on the bioavailability and disposition kinetics a dosage regimen consisting of the intramuscular injection of the dose (10 mg/kg) at 6 h intervals is proposed and an intravenous infusion rate of 48 μg/kgymin is predicted to establish a steady state serum concentration of 15 μg/ml, which is a therapeutic level of the antibiotic for susceptible micro-organisms.
Abstract: The pharmacokinetics of kanamycin were studied in beagle dogs. A parenteral preparation of kanamycin sulphate (5% aqueous solution), which was given at a dosage level of 10 mg/kg of body weight, was the drug product used. The disposition curve which resulted from the intravenous administration of a single bolus dose of the drug was completely described by the biexponential equation:
Cp= 50e-0.1977t+ 36.3e-0.0128t where Cp represents concentration of the drug in the serum at time t (in minutes) and the experimental constants are mean values. Pseudo-distribution equilibrium was rapidly attained and the apparent volumes of the central and peripheral compartments of the two-compartment open model were the same (ca 125 ml/kg). Body clearance (mean ± S.D., n= 6) of kanamycin was 3.21 ±0.72 ml/kg/min. The half-life of the drug was short (58.18 ± 18.43 min) and independent of the route of parenteral (intravenous and intramuscular) administration. Absorption of kanamycin from the intramuscular site was rapid, with a half-time of 9.08 ± 1.10 min. A systemic availability of 89.1 ± 15.8% was obtained. Based on the bioavailability and disposition kinetics a dosage regimen consisting of the intramuscular injection of the dose (10 mg/kg) at 6 h intervals is proposed. An intravenous infusion rate of 48 μg/kgymin is predicted to establish a steady state serum concentration of 15 μg/ml, which is a therapeutic level of the antibiotic for susceptible micro-organisms.
TL;DR: It is suggested that rumen function may interfere with the absorbtion of chloramphenicol following oral administration to ruminants, even in relatively young animals.
Abstract: Three experiments were carried out to investigate the mechanisms whereby adequate plasma levels of chloramphenicol may be obtained following oral administration in young calves but not in older animals. In the first experiment, plasma levels of chloramphenicol following an oral dose of 50 mg/kg were followed in six calves, given weekly doses for the first 11 weeks of life. A plasma chloramphenicol level of 5 μg/ml, taken as the minimum therapeutic level, was attained only for a few hours in the 1 week old calves. Thereafter plasma levels decreased very rapidly until the fourth week, and rather more slowly between the fourth and eleventh weeks. At 11 weeks the plasma chloramphenicol level fell to around 0.3 μg/ml, which was the lower limit of sensitivity for the assay technique used. In the second experiment, the same single dose was administered to calves in the twelfth or eighteenth weeks of life which had not previously been exposed to the antibiotic. Plasma levels of 1 μg/ml were barely reached. This suggests that the non-absorbtion of chloramphenicol is unlikely to be related to repeated administration of the antibiotic. In the third experiment, the same single dose was administered orally to two cows. Chloramphenicol could not be detected in the plasma following such administration, and some side-effects were observed in the 48 h following dosing. It is suggested that rumen function may interfere with the absorbtion of chloramphenicol following oral administration to ruminants, even in relatively young animals.
TL;DR: Lithium was administered to young pigs in order to estimate its pharmacokinetic parameters in this species and a suitable dosage for chronic psychopharmacological experiments and a chronic oral administration of 0.5 mEq/kg twice a day provides minimal plasma levels without toxic side effects.
Abstract: Lithium was administered to young pigs in order to estimate its pharmacokinetic parameters in this species and a suitable dosage for chronic psychopharmacological experiments. Distribution time (10 h) and volume (1 l/kg), elimination half-life (10–20 h), toxic plasma levels (about 1.4 mEq/l) are closely similar to those reported in man. A chronic oral administration of 0.5 mEq/kg twice a day provides minimal plasma levels of 0.5 to 1.0 mEq/l, without toxic side effects.
TL;DR: Serum digoxin concentrations were in the therapeutic range 8 h after the second daily dose of digoxin had been administered, and lengthening of the PR interval and a decrease in the heart rate were observed.
Abstract: Healthy dogs were treated once-a-day for 20 days, with a liquid oral dosage form of digoxin (0.022 mg/kg). Serum digoxin concentrations, measured by radio immunoassay technique, were in the therapeutic range 8 h after the second daily dose of digoxin had been administered. Of the ten dogs treated, four had digoxin serum concentrations above those accepted to be moderately toxic. Results of a blood urea nitrogen and a phenolsulfonphthalein test, determined at days 0, 5, 8, 12, 15 and 19 after the beginning of the investigation all were within normal limits. Serum osmolality, calcium, potassium, and sodium, determined daily, evidenced no significant difference from control values. Lengthening of the PR interval and a decrease in the heart rate were observed. Digitalization of dogs can be achieved without the use of a loading dose and within a much shorter time than was previously reported.
TL;DR: The in vitro inactivation of crude endotoxins (lipopolysaccharides) of four Escherichia coli strains by polymyxin B and colistin in mastitic milk was investigated utilizing the Limulus amebocyte lysate test.
Abstract: The in vitro inactivation of crude endotoxins (lipopolysaccharides) of four Escherichia coli strains by polymyxin B and colistin in mastitic milk was investigated utilizing the Limulus amebocyte lysate test Although minor differences were observed among the endotoxins in respect to susceptibility to inactivation, activity of each was markedly reduced by both drugs
TL;DR: The data indicates that blood plasma would be a satisfactory body fluid for estimating this drug in tissue, and the pharmacokinetics of penicillin G were determined in plasma and tissues.
Abstract: Twenty-two young cross-bred swine were treated either intravenously or orally with potassium penicillin G. The pharmacokinetics of penicillin G were determined in plasma and tissues. The plasma half-life of penicillin G in swine was found to be 19.45±1.69 min, and the distribution and elimination kinetics were found to fit a classical two-compartment model. The volume of distribution was found to be 0.53±0.12 1/kg, and the body clearance was found to be 19.06±5.06 ml/min/kg which exceeded the effective renal plasma flow of 16.50±2.73 ml/min/kg, suggesting that the drug was eliminated both by tubular excretion and glomerular filtration. The elimination rate constants (Beta) for the major organs were as follows: muscle, 0.00343 min-1; lung, 0.0310 min-1; fat, 0.0394 min-1; and kidney, 0.0213 min-1, which compared favorably with the elimination rate constant found in plasma (0.0320 min-1). These values were found to be significantly similar at the level of P < 0.005 in muscle, spleen and fat, and at a level of P < 0.025 in lung tissue. The data indicates that blood plasma would be a satisfactory body fluid for estimating this drug in tissue.
TL;DR: Twenty-six experiments were performed on six healthy, non-lactating cows with normal oestrous cycles and Absorption of sodium benzylpenicillin from the uterus in oestrus and on day 12 following Oestrus was compared with intravenous injection.
Abstract: Twenty-six experiments were performed on six healthy, non-lactating cows with normal oestrous cycles. Absorption of sodium benzylpenicillin from the uterus in oestrus and on day 12 following oestrus was compared with intravenous injection. Absorption, as shown in plasma from the uterus of six cows in oestrus, occurred to a greater extent (mean peak 12.80 ± S.E.M. 3.36 i.u./ml) than from the uterus in the luteal phase on nine occasions (mean peak 3.92±0.75 i.u./ml.). Intrauterine infusion of 10% Lugol's iodine solution before the administration of antibiotic did not significantly alter absorption on day 12 in six cases (mean peak 5.07±1.51 i.u./ml).
TL;DR: Findings confirm the neuromuscular blocking activity of certain antibiotic agents, and indicate the potential for this adverse side effect in food-producing animal species.
Abstract: The neuromuscular blocking effects of several antibacterial agents were examined in young pigs and lambs using a sciatic nerve-gastrocnemius muscle preparation. Intravenous administration of streptomycin, neomycin or tetracycline produced a decrease in indirectly stimulated contractions of the gastrocnemius muscle; whereas, chloramphenicol, sulphadiazine and penicillin-G had no discernible neuromuscular blocking effects. Present findings confirm the neuromuscular blocking activity of certain antibiotic agents, and indicate the potential for this adverse side effect in food-producing animal species.
TL;DR: The disposition and excretion of ethanol in horses has been studied after oral administration and the highest concentration in blood and in parotid saliva occurred within 1 h of administration.
Abstract: The disposition and excretion of ethanol in horses has been studied after oral administration. Ethanol was rapidly absorbed from the gastrointestinal tract. The highest concentration of ethanol in blood and in parotid saliva occurred within 1 h of administration. The concentrations were dose dependent. The mean rate of disappearance of ethanol from blood was 6.3 mg/100 ml/h. The ratio of the concentration of ethanol in parotid saliva to that in venous blood was 1.16:1. The mean rate of elimination was 51 mg/kg body weight/h. The proportion of ethanol excreted in the urine was 0.7% of the dose.
TL;DR: Data from this investigation did not suggest the need to routinely alter the dosage of salicylate in the presence of CT induced toxic hepatitis, and it was not possible to correlate laboratory parameters with pharmacokinetic parameters.
Abstract: The effect of carbon tetrachloride (CT) induced toxic hepatitis on the pharmacokinetics of sodium salicylate was studied in beagle dogs. Plasma concentrationtime profiles were determined for sodium salicylate in ten healthy dogs and in the same dogs after CT administration. Laboratory tests for liver disease were performed before and after liver injury in order to examine the feasibility of using commonly employed laboratory tests as a guide for determining dosage regimens of sodium salicylate in the presence of liver dysfunction. The disappearance of sodium salicylate from the plasma of dogs was a first-order process through 8 h in both the normal and liver disease states. After CT, there was an alteration in the kinetic behavior between 8 and 24 h after salicylate administration. This change was linked to the decreased ability of the damaged liver to form glucuronides. The changes observed in the pharmacokinetics of salicylate before and after CT induced liver dysfunction were minimal and not statistically significant. The majority of the dogs, however, demonstrated a slightly decreased half-life after CT administration. This was due to an increase in the urinary excretion of unchanged salicylate. It was not possible to correlate laboratory parameters with pharmacokinetic parameters. Therefore, dosage alterations could not be based upon laboratory data. Data from this investigation, however, did not suggest the need to routinely alter the dosage of salicylate in the presence of CT induced toxic hepatitis.
TL;DR: The averaged data obtained from eight selected tissue sites were consistent with the two-compartment pharmacokinetic model presented and confirmed that residues of sulphathiazole in edible tissue can be predicted from serum and urine concentrations of the drug.
Abstract: Plasma, urine and tissue concentrations of sulphathiazole were determined at various times following intravenous administration to fifteen cattle. The averaged plasma and urine data were consistent with a two-compartment pharmacokinetic model with a half-life of elimination of 1.3 h and a total volume of distribution of 0.41 l/kg body weight. Sulphathiazole was eliminated by excretion of unchanged drug into urine (48%) and by formation of acetylated and polar metabolites. The averaged data obtained from eight selected tissue sites were consistent with the two-compartment pharmacokinetic model presented and confirmed that residues of sulphathiazole in edible tissue can be predicted from serum and urine concentrations of the drug.
TL;DR: A new method for the experimental induction of pig gastroesophageal ulcers, by means of simultaneous injections of betazole and reserpine for 5 days under the nutrient (glucose solution) drinking condition, is proposed and it is considered that this method may be superior to the repository histamine method.
Abstract: The ulcerogenic and secretogenic properties of betazole, (an H2 agonist), and/or reserpine on pig stomachs were studied. (1) Betazole (50 mg/body) and reserpine (0.02 mg/kg) were successively injected (i.m.) for 5–10 days into starved animals. Gastroesophageal ulcers, pathologically similar to naturally occurring ulcers were observed in all pigs (10/10), whether a nutrient solution (5% glucose, 1 litre/day) was supplied or not. In the starved pigs given either betazole or reserpine, only a small ulcer or erosion was observed. (2) In four pigs which were given commercial mash at a rate of 3% of body weight per day and killed on the 6th or 10th day of successive injections of both drugs, the incidence of ulcers was 2/4. (3) The gastric secretogenic effect of betazole and/or reserpine was confirmed in pigs with Heidenhain gastric pouches. (4) From these data, a new method for the experimental induction of pig gastroesophageal ulcers, by means of simultaneous injections of betazole and reserpine for 5 days under the nutrient (glucose solution) drinking condition, is proposed. The authors consider that this method may be superior to the repository histamine method, with respect to the absence of adverse effects, practical convenience and pathological and etiological similarities with naturally occurring ulcers.
TL;DR: The disposition of sulfamerazine in the plasma and urine of cattle was determined following single intravenous and oral doses and the averaged and the individual animal data were described by a two-compartment pharmacokinetic model.
Abstract: The disposition of sulfamerazine in the plasma and urine of cattle was determined following single intravenous and oral doses. The averaged and the individual animal data were described by a two-compartment pharmacokinetic model. The drug was eliminated with a biological half-life of 6.2 h, primarily by renal excretion of unchanged sulfamerazine and metabolism to acetylsulfamerazine. Sulfamerazine (in solution) was absorbed with a half-life 6.7 h and with relative completeness (68%) following oral administration.
TL;DR: A strong correlation would have explained the dog's high resistance and would have strongly indicated lipid peroxidation as the mechanism of CPZ-induced in vitro hemolysis, but no such correlation was found.
Abstract: Chlorpromazine (CPZ) affects the hemolytic process in vitro. Hemolysis rates induced by CPZ at 10-3 M concentration were measured in blood from humans, monkeys, horses, cattle, goats, rats and dogs. Hemolysis data were plotted in the form of Lineweaver-Burke plots and the kinetics considered. The canine red cell was markedly more resistant than the other species as represented by a smaller Vmax. Basal glutathione peroxidase levels of the red cell were assayed in an attempt to correlate the enzyme activity with the haemolysis rates in the species studied. A strong correlation would have explained the dog's high resistance and would have strongly indicated lipid peroxidation as the mechanism of CPZ-induced in vitro hemolysis. No such correlation was found.