摘要:

SummaryPhenylbutazone is an acidic, lipophilic, nonsteroidal anti‐inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphen‐butazone, γ‐hydroxyphenylbutazone and γ hydroxyoxyphenbutazone. account for some 25–30% of administered dose over 24 h. The plasma half‐life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism.Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE2. It appears to act on prostaglalidin‐H synthase and prostacyclin synthase, after conversion by prostaglandin‐H synthase to reactive intermediates. It markedly reduces prostanoid‐dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation.Phenylbutazone is highly bound (≥ 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half‐life of 3–10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half‐life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 μg/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 μg/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules.Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required.Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about ± 25%.Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200‐fold. However, urinary pH has little effect on the plasma half‐life of phenylbutazone, which is determined mainly by hepatic metabolism and possibly by biliary secretion.Phenylbutazone has a narrow therapeutic index in the horse. If the administered dose is greater than recommended by the manufacturer, toxic effects may be produced, especially if high dose administration is maintained for more than a few days. Signs of toxicity include anorexia, depression, oral and GI ulcers, plasma protein losing enteropathy, and death from shock. Other side‐effects include toxic neutropenia, hepatotoxicity and renal papillary necrosis; the latter may occur if access to water is restricted. If phenylbutazone is withdrawn in the early stages of toxicity, the prognosis is good. Late withdrawal is associated with delayed recovery. Death may occur up to 50 days after withdrawal of the drug. This toxicity can be antagonized b

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00008.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

The disposition of phenylbutazone (4.4 mg/kg), administered intravenously to six Welsh Mountain ponies, was described by a two‐compartment open model. Pharmacokinetic parameters were not significantly different after morning dosing in comparison with afternoon dosing. When phenylbutazone (4.4 mg/kg) was administered orally to the same ponies, marked variations in time to peak concentrations were produced with different feeding schedules. When access to hay was permitted before and after dosing, the mean time to peak concentration was 13.2 ± 1.2 h and double peaks in the plasma concentration–time curve were common. Double peaks were also encountered when phenylbutazone was given to ponies deprived of food prior to, and allowed access to hay after, dosing. In this circumstance, mean times to peak concentration were much shorter (3.8 ± 1.3 h after morning dosing and 5.3 ± 1.5 h followed afternoon dosing). Absorption was more regular and double peaks were less apparent when food was withheld both before and after dosing. In order to explain these findings, it is tentatively postulated that, whereas some of the administered dose of phenylbutazone may be absorbed quickly, some may become adsorbed on to the feed and subsequently released by fermentative digestion in the large intestine and/or caecum. The consequences of delayed absorption in fed animals for toxicity and clinical efficacy, and for the use of phenylbutazone in equestrian sports, are considered. Delayed absorption in ponies given access to hay was not accompanied by a significant reduction in total absorption. Bioavailability was estimated to be approximately 69% in fed and 78%, in unfed ponies. Estimates of bioavailability gave similar values for morning (72%) and afternoon (71%)

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00009.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

The reactivity of horse skin to intradermal inoculation of histamine, serotonin and bradykinin was investigated, and the resulting reactions compared with those produced in the same horses by a 1% whole‐body extract ofCnliroides.Both histamine and bradykinin produced large reactions, but there was no significant correlation between the dermal responsiveness to insect allergen and either histamine or bradykinin. Two anti‐hislamine drugs (promethazine hydrochloride and tripelennaniine hydrochloride) were effective in reducing the reaction produced by the insect extr

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00010.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

Albendazole (ABZ) and its sulfoxide (SX) and sulfone (SO) metaliolites inhibit the binding of:3H‐colchicine, a ligancl with high affinity for tubulin to homogenate preparations of the liver flukeFasciola hepatica.The relative potency of these compounds is SX>ABZ>SO. The benzimidazoles (cambendazole, parbendazole, oxibendazole and mebendazole), when tested at a concentration of 10 μM, also inhibited colchicine binding to fluke homogenates. However, a potent new benzimidazole flukacide, triclalbendazole (TCB), was without effect on colchicine binding toF hepaticahomogenates. When intact flukes were exposedin vivoto 10‐5′M SX for as little as 5 min the subsequent binding of3H‐colchicine to fluke homogenates was significantly reduced. However, flukes recovered from sheep either 12 or 24 h after treatment with ABZ did not have a decreased ability to bind colchicine, although the non‐specific binding was higher in flukes from treated sheep, suggesting some interaction of drug with tubulinin vivo.ABZ, SX and SO were effective in preventing embryonation of lluke eggs at doses as low as 0.0 1 μM, but TCB was without effect at concentrations as high as 10 μM. The results suggest that ABZ exerts at least part of its anthelmintic effect by interaction with f

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00011.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

The disposition of sulfatroxazole (STZ) has been studied in goats and pigs after intravenous administration of a single dose. The percentage of protein‐binding decreased with increasing plasma concentration in both species. At 100 μg/ml about 85% was bound to plasma proteins in goats, while the corresponding value was only 55% in pigs. Two metabolites of STZ were isolated from urine and identified as N4‐acetyl‐STZ and 3‐sulfaniIarnido‐4‐methyl‐5‐hydroxy‐methyl‐isoxazole (5′‐OH‐STZ). The goats excreted about 80% of the dose in urine. The majority (64%) was excreted as unchanged STZ, while N4‐acetyl‐STZ and 5′‐OH‐STZ made up 19% and 18%, respectively. The pigs excreted 95% of the dose in urine. Unchanged STZ amounted to 30% and N4‐acetyl‐STZ to 70% of the urinary excretion in pigs, w

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00012.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

Loperamide inhibited the frequency and amplitude of cyclical contractions of the rumen in conscious goats (100 μg/kg, i.v. and sheep (250 μg/kg, i.v.). In goats, the inhibitory effect of loperamide could be prevented by pretreatment with the opiate antagonist naltrexone (≥ 12.5 μg/kg, i.v.), but not by pretreatment with the dopaminergic antagonist domperidone (500 μg/kg, i.v.). Intra‐cerebroventricular administration of 1 μg/kg loperamide in goats significantly depressed ruminal contraction frequency, whereas intravenous administration of 10 μg/kg loperamide did not affect cyclical motility. Administered via the carotid artery, loperamide (4 μg/kg) depressed both frequency and amplitude of cyclical contractions of reticulum and rumen, whereas the same dose was ineffective via the coeliac artery.In vitro, loperamide (10 nM‐100 μM) had no influence on spontaneous activity or tone of the reticular longitudinal muscle strips. It is concluded that loperamide inhibits cyclical ruminal contractions through a central o

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00013.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

Concentrations of oxytetracycline (OTC) in serum and tissue‐cage fluid (TCF) from subcutaneous tissue‐cages were determined after single and repeated intravenous and intramuscular doses of 10 mg/kg to calves. Intravenous administration resulted in higher levels, and greater area under curve (AUC) in TCF, than did intramuscular administration. However, the penetration measured as the ratio of AUC in TCF to AUC in serum was equal, and therefore independent of the route of administration. A linear relationship between AUC in serum and AUC in TCF could be demonstrated. Half‐lives of OTC in serum were 4.9 ± 3.1 h after intravenous, and 6.l ± 2.0 h after intramuscular administration. In TCF the half‐lives were 21.5 ± 4.4 h and 24.5 ± 11.5 h after intravenous and intramuscular administration, respectively. Repeated dosing resulted in accumulation of OTC in TCF. Lesser accumulation in older cages indicated altered characteristics of the cages with the passage of time. In serum, no substantial accumulation was seen after repeated i.v. dosing until the dosing interval was short

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00014.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

The pharmacokinetics of lithium were determined in eight adult dogs. The data were fitted to a two‐compartment model. Single intravenous doses of lithium chloride, and single oral doses of lithium carbonate were used. The mean plasma lithium half‐life(l½)following the single intravenous dose was 21.6 h, and the mean apparent specific volume of distribution of the central compartment (V′c) was 0.189 l/kg. Mean bioavailability was 78.8% following oral administ

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00015.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

Using a monoclonal antibody raised against zeranol, a radioimmunoassay has been validated for the determination of zeranol residues in the faeces of treated steers. The limit of decision defined as the mean apparent concentration of zeranol in the faeces of untreated cattle + 3 SD was 1 ng/g faeces. In a trial in which 27 steers were implanted with zeranol (36 mg) at the base of the ear and six steers were sham implanted, the mean maximum concentration of zeranol in faeces was 5.8 ng/g on Day 15 following implanting, declining to 1.67 ng/g on Day 34 following implanting. During this period there was a marked variation between animals sampled on the same day following implanting. At no time during the trial did the apparent concentration of zeranol in the faeces of untreated animals rise above 0.91 ng/g, which is below the limit of decision for this assay.

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00016.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

Rapid solvent extraction combined with a radioimmunoassay using a nionoclonal antibody raised against a derivative of zeranol has been used to measure the residues of the anabolic agent zeranol in the edible tissues (muscle, liver, kidney and fat) of cattle treated with Ralgro.Calibration curves, both with and without, tissue extracts exhibit good parallelism. Regression analysis for the extraction of‐ zeranol from tissues dosed with standard amounts of zeranol have correlation coefficients of 0.979, 0.99 1, 0.986 and 0.985 for muscle, liver, kidney and fat, respectively.The limits of decision defined as the mean value + 3 SD for the concentrations apparently observed (noise) in tissues from animals not treated with Kalgro were 278, 121, 373 and 110 ng/kg for muscle, fat, liver and kidney, respectively. In the tissues of 4 cows implanted with Ralgro (36 mg), and sampled 70 clays after iniplanting, the highest concentration of zeranol in each tissue was 232 ng/kg (muscle), 391 ng/kg (liver), 287 nglkg (kidney) and 293 nglkg (fat), and residues were detected in all samples of fat (4), 3 kidney samples and I liver sampl

ISSN:0140-7783    

DOI:10.1111/j.1365-2885.1986.tb00017.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY