Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 1985"

Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison

Abstract: The efficacy of phenobarbital and primidone against canine epilepsy was compared in a controlled study. Thirty-five dogs showing generalized tonic-clonic seizures (grand mal), treated for a minimum of 6 months, were included in the study; fifteen of these were treated with phenobarbital, the other twenty with primidone. Both drugs were dosed according to the clinical requirement; the daily doses ranged from 5-17 mg/kg phenobarbital and from 17-70 mg/kg primidone. The plasma concentrations of phenobarbital, or of primidone and its metabolites phenobarbital and phenylethylmalondiamide (PEMA), were routinely monitored. Complete control of tonic-clonic seizures for 6 months, at least, was attained in six out of fifteen dogs of the phenobarbital group, and in five out of twenty dogs in the primidone group. A further six dogs on phenobarbital, and seven dogs on primidone, were classified as 'improved', i.e. the rate of seizures was reduced by at least 50%. The rest of the dogs were not improved by the treatment. The difference between the efficacy of phenobarbital and primidone was not significant, but primidone gave rise to signs of liver toxicity in fourteen out of twenty dogs, as indicated by considerable elevations of liver enzyme values (alanine transferase, glutamate dehydrogenase, alkaline phosphatase). Phenobarbital is, therefore, regarded as the drug of first choice for the treatment of canine epilepsy.

Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal or intraruminal administration*

Abstract: Prichard, R.K., Steel, J.W., Lacey, E. & Hennessy, D.R. Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal, or intraruminal administration. J. vet. Pharmacol. Therap. 8, 88–94. The pharmacokinetics of ivermectin in plasma following intravenous, intra-abomasal, and intraruminal administration to sheep was determined. When given intravenously, ivermectin was very slowly eliminated with a terminal half-life of 178 h and a volume of distribution at steady state of 5.3 l/kg indicating sequestration in a temporary depot. Intra-abomasal administration resulted in rapid absorption, a peak plasma concentration of 6O.6 ng/ml at 4.4 h, and 100% bioavailability. However, intraruminal administration produced a much lower peak concentration (17.6 ng/ml at 23.5 h) and bioavailability (25.1%). A subsequent in vitro study indicated that ivermectin may be rapidly metabolized in the rumen. Dr.J. W. Steel, CSIRO Division of Animal Health, McMaster Lahoratory, Private Bag No. 1, P.O., Glebe, NSW 2037, Australia.

Potentiation of the anthelmintic activity of oxfendazole by parbendazole.

Abstract: The ability of parbendazole (PBZ) to potentiate co-administered oxfendazole (OFZ) was investigated. Administration of a range (1.35-36.0 mg/kg) of doses of PBZ with 4.53 mg OFZ/kg demonstrated that significant potentiation occurred at 4.5 mg PBZ/kg. At 4.5 mg PBZ/kg, the area under the plasma OFZ concentration curve was about twice that obtained from oral administration of OFZ alone. When tested against benzimidazole-resistant Haemonchus contortus and Trichostrongylus colubriformis, the mixture of 4.5 mg PBZ + 4.53 mg OFZ/kg was significantly more effective than 4.53 mg OFZ/kg alone, and PBZ alone showed no activity against these resistant nematodes. The demonstration of PBZ-OFZ potentiation has indicated a means of obtaining a more effective use of currently available anthelmintics in the treatment of helminthiasis.

Intramuscular treatment of subclinical staphylococcal mastitis in lactating cows with penicillin G, methicillin and their esters.

Abstract: The relationship between antibiotic milk concentrations and bacteriological efficacy was investigated in groups of lactating cows with subclinical mastitis due to either penicillin G-sensitive or penicillin G-resistant Staphylococcus aureus. Treatments consisted of the intramuscular injection of procaine penicillin G, or its weak base ester penethamate hydriodide, and sodium methicillin, or its weak base ester tamethicillin. Antibiotics were administered once daily for 2 or 4 days at accepted dosages. After four daily, treatments with procaine penicillin G and penethamate hydriodide, infections were eliminated from 56.5% and 68.8%, respectively, of quarters infected with penicillin G-sensitive staphylococci, and from 14.3% and 7.7%, respectively, of quarters infected with penicillin G-resistant staphylococci. After four daily treatments with sodium methicillin and tamethicillin, infections were eliminated from 32.4% and 48.6%, respectively, of quarters infected with penicillin G-resistant staphylococci. The better efficacy of penethamate hydriodide and tamethicillin was considered to be linked to the higher milk drug concentrations obtained with these drugs as opposed to the lower concentrations measured in the milk after treatment with the parent drugs. Cure rates were generally higher after treatment for 4 days than after the 2-day course of therapy. Treatment efficacy decreased progressively with increasing age of the cows. Intramuscular treatment of subclinical staphylococcal mastitis in lactating cows can serve as a useful model for screening existing and new antibacterial agents and drug products intended for the parenteral treatment of clinical staphylococcal mastitis.

Pharmacokinetics of amikacin in the horse following intravenous and intramuscular administration

Abstract: The pharmacokinetics of amikacin sulfate (AK) were studied in the horse after intravenous (i.v.) and intramuscular (i.m.) administration. Serum (Cs), synovial (Csf) and peritoneal (Cpf) fluid concentrations of the drug were measured. Doses of 4.4, 6.6 and 11.0 mg/kg were given. The concentrations at 15 min following i.v. injection were 30.3 +/- 0.3, 61.2 +/- 6.9 and 122.8 +/- 7.4 micrograms/ml, respectively, for the 4.4, 6.6 and 11.0 mg/kg doses. Mean peak Cs values after the intramuscular injections occurred at 1.0 h post-injection and were 13.3 +/- 1.6, 23.0 +/- 0.6 and 29.8 +/- 3.2 micrograms/ml, respectively. The t 1/2 of amikacin was 1.44, 1.57 and 1.14 h for the 4.4, 6.6 and 11.0 mg/kg doses, respectively. In this study, minimum inhibitory concentrations (MIC) of amikacin sulfate were determined for six pathogens. Based on the MIC and the pharmacokinetic parameters, it would appear that the usual therapeutic dose of amikacin would be between 4.4 and 6.6 mg/kg twice daily and, for the more serious life-threatening infections, dosing three times a day.

Pharmacokinetics of anti-epileptic drugs in the dog: a review.

Abstract: Frey, H.-H. & Loscher, W. Pharmacokinetics of anti-epileptic drugs in the dog: a review. J. vet. Pharmacol. Therap. 8, 219–233. Dr H.-H. Frey, Laboratory of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, Koserstrasse 20, D-IOOO Berlin 33, West Germany.

The biology, pathophysiology and control of eicosanoids in inflammation.

Abstract: Higgins, A.J. The biology, pathophysiology and control of eicosanoids in inflammation. J. vet. Pluirmacol. Therap. 8, 1–18. The involvement in inflammatory conditions of those cyclo-oxygenase and lipoxygenase derivatives of arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid), which are known as the eicosanoids, is reviewed iti the light of recent studies. Although it is now generally recognized that cyclo-oxygenase products are fundamental to the inflammatory process as chemical mediators, and that inhibition of the cyclo-oxygenase enzyme pathway explains the mode of action of most non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed in veterinary practice, evidence for the involvement of lipoxygenase products of arachidonate metabolism in inflammation is increasing. The leukotrienes (LTs) are 5-lipoxygenase-derived eicosanoids which have been shown to be leucotactic and involved in anaphylactic and hypersensitivity reactions. Leucocytes, drawn to sites of injury by chemotaxis, themselves liberate pro-inflammatory eicosanoids which perpetuate the response and may aggravate the clinical condition. At therapeutic dose rates, most NSAIDs have no effect on the biosynthesis of LTs, whereas corticosteroids, by inhibiting the release of arachidonic acid, may prevent the formation of both cyclo-oxygenase and lipoxygenase products. However, because of the undesirable side-effects of steroids, the clinical use of these agents in treating inflammatory conditions is sometimes limited. Novel non-steroid inhibitors of cyclo-oxygenase and lipoxygenase enzyme pathways could offer more effective and safer control of inflammation in animals. A.J. Higgins, The Royal Veterinaiy College, North Mymms, Hatfield, Hertfordshire AL9 7TA, England.

Cardiovascular and respiratory effects of acetylpromazine and xylazine on halothaneanesthetized horses

Abstract: Steffey, E.P., Kelly, A.B., Farver, T.B. & Woliner, M.J. Cardiovascular and respiratory effects of acetylpromazine and xylazine on halothane-anesthetized horses. J. vet. Pharmacol. Therap. 8, 290–302. Circulatory and respiratory effects of intravenously administered acetylpromazine (0.033 and 0.067 mg/kg) and xylazine (0.5 and 1.0 mg/kg) were studied in drug cross-over fashion in eight laterally recumbent horses anesthetized only with halothane (1.06%, end-tidal) in O2. Both doses of acetylpromazine caused a significant and sustained elevation in cardiac output via a rise in stroke volume. Xylazine produced an initial significant fall in cardiac output followed by a return to control levels. Halothane anesthesia did not prevent xylazine-related atrioventricular conduction block. All treatments caused a similar significant fall in arterial blood pressure (acetylpromazine, total peripheral resistance-related; xylazine, cardiac output-related). PaCO2 significantly increased after all treatments. PaCC2 decreased significantly only following xylazine treatment. One horse (not included in the tabulation) developed ventricular fibrillation and died 15 min after receiving its first injection (0.5 mg/kg) of xylazine. Dr E. P. Steffey, Department of Surgery, School of Veterinary Medicine, University of California, Davis, CA 95616, U.S.A.

Pharmacological evidence for the involvement of alpha-2 adrenoceptors in the sedative effect of detomidine, a novel sedative-analgesic.

Abstract: Virtanen, R., Ruskoaho, H. & Nyman, L. Pharmacological evidence for the involvement of alpha-2 adrenoceptors in the sedative effect of detomidine, a novel sedative-analgesic. J. vet. Pharmacol. Therap. 8, 30–37. The sedative effect and mechanism of action of a novel imidazole derivative, detomidine, were studied in laboratory animals. Three methods were used to quantify drug-induced sedation: (i) decrease in spontaneous activity of mice; (ii) increase in barbiturate induced anaesthesia lime in mice; (iii) loss of righting reflex in chicks. Clonidine and xylazine were included in the studies for comparison. The sedative potency of detomidine was shown to be approximately equal to that of clonidine and much higher than that of xylazine. In all tests, the sedative effect of detomidine was inhibited by antagonists of alpha-2 adrenoceptors (yohimbine, rauwolscine and idazoxan) but not by alpha-1 antagonists (prazosin, corynanthine). Furthermore, an ex vivo receptor binding study in the rat showed that detomidine-induced decrease in spontaneous activity was significantly correlated to [3Hc]onidine but not to [3H]prazosin displacement in brain membranes. These results show that detomidine has potent sedative effects in mice, rats and chicks, and suggest that this action is mediated through stimulation of alpha-2 adrenoceptors. Raima Virtanen, Fartnos Group Ltd, Research Centre, P.O. Box 425, SF-20101 Turku 10, Finland.

Pharmacokinetics of cefaronide, ceftriaxone and cefoperazone in sheep

Abstract: Guerrini, V.H., Filippich, L.J., Cao, G.R., English, P.B. & Bourne, D.W.A. Pharmacokinetics of cefaronide, ceftriaxone and cefoperazone in sheep. J. vet. Pharmacol. Therap. 8, 120–127. The pharmacokinetics of cefaronide (16gm/kg dose), ceftriaxone and cefoperazone (47gm/kg dose), after intravenous (i.v.) administration were determined in six Merino ewes. The mean values for terminal half life, steady state volume of distribution Vd(ss), renal clearance (ClR) and total body clearance (ClB) for cefaronide were 1.5 h, 0.39l/kg, 0.06l/h/kg and 0.16l/h/kg, for ceftriaxone; 1.7 h, 0.30l/kg, 0.08l/h/kg, and 0.22l/h/kg, and 0.7 h, 0.16l/kg, 0.02l/h/kg and 0.16l/h/kg for cefoperazone, respectively. After 5.5 h, approximately 42% cefaronide, and after 8 h, approximately 37% ceftriaxone and 13% cefoperazone, was excreted in urine. The non-renal elimination of ceftriaxone and cefoperazone appeared to be more rapid in sheep than is reported in man. Cefaronide was excreted largely unchanged in the urine of sheep. Therefore, the elimination of cefaronide in sheep was similar to that found in man. Cefaronide was well distributed in sheep, whereas ceftriaxone and cefoperazone appeared to be distributed to a lesser degree. These Findings underline the different disposition of drugs in different species. Dr V. H. Guerrini, Department of Pharmacy, University of Queensland, St Lucia, QLD 4067, Australia.

The effect of prostaglandin E1 on motility of the equine gut.

Abstract: Hunt, J.M. & Gerring, E.L. The effect of prostaglandin E1 on motility of the equine gut. J. vet. Pharmacol. Therap. 8, 165–173. Prostaglandin E1 was infused intravenously (25, 50 and 75ng/kg/min) in three ponies. Changes in gastrointestinal mechanical and electrical activity were recorded from chronically implanted strain-gauge force transducers and electrodes. Dose-dependent responses were obtained: there were significant decreases in electrical spiking activity in the stomach, left large colon and small colon, with a corresponding decrease of activity in the left dorsal colon mechanogram. The small intestine was also affected, showing a decrease in both contraction rate and amplitude, which was more marked in the proximal jejunum than in the ileum. There was an association between these changes in gastrointestinal activity and the presence of discomfort and diminished gut sounds. Judith M. Hunt, Department of Veterinary Surgery and Obstetrics, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire AL9 7TA, U.K.

Milk fever and calcium metabolism.

Abstract: Allen, W.M. & Sansoni, B.F. Milk lever and calcium metabolism. J. vet. Pharmacol. Therap. 8, 19–29. W.M. Allen, Department of Functional Pathology, AFRC Institute for Research on Animal Diseases, Campion, Newbury, Berkshire RC16 ONN, England.

Central and peripheral serotonergic control of forestomach motility in sheep.

Abstract: Participation of tryptaminergic receptors in the control of forestomach motility was investigated in conscious sheep using strain-gauges and chronically implanted electrodes. Two hours after feeding the sheep, serotonin (5-HT) was infused into the jugular vein (i.v.), or the carotid artery (i.c.), or into the lateral cerebral ventricles (i.c.v.), over a 10-min period. An i.v. dose of 16 micrograms/kg/min abolished the cyclic propagated contractions throughout the forestomach, increased ruminoreticular tone, and induced simultaneous contractions of all the parts of the rumen. A dose of 1.6 micrograms/kg/min i.c. or i.v. 5-HT inhibited phasic contractions. The effects of 5-HT were blocked completely by i.c.v. administration of methysergide (20 micrograms/kg) and imipramine (200 micrograms/kg), and blocked partially by naloxone (25 micrograms/kg), but unaffected by atropine (50 micrograms/kg). The inhibitory effects of i.v. 5-HT were antagonized by methysergide (200 micrograms/kg, i.v.) but unaffected by imipramine (2 mg/kg, i.v.) and atropine (250 micrograms/kg, i.v.). Only the i.v. administration of methysergide blocked the inhibition induced by i.c. infusion (1.6 micrograms/kg/min) of 5-HT. It is suggested that 5-HT exhibits an inhibitory control on forestomach phasic contractions through hypothalamic and bulbar 5-HT receptors, and exerts peripheral excitatory effects on the tone of the rumen wall.

Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH.

Abstract: Houston, T., Chay, S., Woods, W.E., Combs, G., Kamerling, S., Blake, J.W., Edmundson, A.G., Vessiney, R. & Tobin, T. Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH. J. vet. Pharmacol. Therap. 8, 136–149. A survey of plasma and urinary concentrations of phenylbutazone and its metabolites in thoroughbred horses racing in Kentucky was carried out. Poat-race blood samples from more than 200 horses running at Latonia Racetrack and Keeneland in the Spring of 1983 were analysed. The modal plasma concentration of phenylbutazone was between 1 and 2µg/ml, the mean concentration was 3.5µg/ml and the range was up to 15µg/ml. Oxyphenbuta-zone had a modal plasma concentration between 1 and 2µg/ml, a mean concentration of 2.07µg/ml and a range of up to 13µg/ml. γOH-phenylbutazone had a modal plasma concentration of less than 1µg/ml, a mean level of 1.39µg/ml and a range of up to 7.32µg/ml. All plasma concentration frequency distributions were well fitted by log normal distributions. Urinary concentrations of phenylbutazone yielded modal concentrations of less than 1µg/ml, a mean urinary concentration of 2.9µg/ml, with a range of up to 30.5µg/ml. This population fitted a log-normal distribution. For oxyphen-butazone, the modal concentration was less than 3µg/ml, the mean concentration was 15.26µg/ml, with a range to 81.5µg/ml. The frequency distribution of these samples was apparently bimodal. For γOH-phenylbutazone, the modal concentration was less than 4µg/ml, the mean concentration 21.23µg/ml, with a range of up to 122µg/ml. The population frequency distribution for γOH-phenylbutazone was indeterminate. Analysis of the pH of these post-race urine samples showed a bimodal frequency distribution. The pH values observed ranged from 4.9 to 8.7, with peaks at about pH 5.25 and 7.25. This bimodal pattern of urinary pH values is consistent with observations made in England and Japan. Urinary pH influenced the concentrations of phenylbutazone, oxyphenbuta-zone and γOH-phenylbutazone found in the urine samples. The concentration of these metabolites found in alkaline urines were from 32 to 225 times greater than those found in acidic urines. Plasma concentrations of phenylbutazone and its metabolites, however, were unaffected by urinary pH. In interlaboratory experiments, horses running at Hollywood Park were dosed with phenylbutazone at about 2g/1000 lbs 24 and 48 h before racing, and a mean dose of 0.6g/1000 lbs at 72 h prior to racing. Post-race plasma samples from these horses showed phenylbutazone concentrations ranging from 0.44 to 9.97µg/ml, with a mean concentration of 4.09µg/ml. Plasma oxyphenbutazone concentrations in these horses varied from 0.8µg/ml to 11.3µg/ml, with a mean of 5.3µg/ml. Comparison of plasma concentrations of phenylbutazone and oxyphenbutazone in horses racing in Kentucky, with the results of dosing experiments in horses in training, suggests that most horses racing in Kentucky are being dosed with amounts of phenylbutazone broadly equivalent to, or less than, proposed ‘no-race-day medication rule’ dosing schedules. T. Tobin, Kentucky Equine Drug Research and Testing Programs, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546-0076, U.S.A.

Clinical pharmacology of apramycin in calves.

Abstract: The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, were compared with the MIC of dihydrostreptomycin and neomycin for 323 Salmonella, 178 Escherichia coli and twenty-six Pasteurella multocida isolates recovered from newborn calves. Apramycin exhibited better in vitro anti-bacterial activity than dihydrostreptomycin and neomycin; isolates of Salmonella group B and E. coli resistant to the latter were sensitive to apramycin. The two-compartment open model was appropriate for the analysis of serum apramycin concentrations measured after intravenous (i.v.) administration. The distribution half-life (t 1/2 alpha) of the drug was 28 min, the elimination half-life (t 1/2 beta) was 4.4 h, and the apparent volume of distribution (V1) and the distribution volume at steady state (Vdss) were 0.34 and 0.71 l/kg, respectively. The drug was quickly and completely absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered, they were obtained 1-2 h after treatment and the i.m. t 1/2 beta was 5 h. There was no evidence of drug accumulation in the serum after three daily i.m. injections at 20 mg/kg. More than 95% of the i.v. and i.m. doses were recovered in the urine within 96 h post-treatment but the cumulative percentage of drug recovery in the urine after oral treatment was 11%. The durations of free drug concentrations in the tissues after i.v. and i.m. injection were estimated from the serum drug level data, percent of serum protein binding, Vdss, t 1/2 beta, and the MIC. Computations showed that apramycin should be administered i.m. at 20 mg/kg every 24 h in order to maintain in tissues potentially effective drug concentrations sufficient to inhibit 50% of the Salmonella, E. coli, and P. multocida isolates, and at 12-h intervals to inhibit 90% of the isolates.

Low-dose ethanol in the treatment of ethylene glycol poisoning

Abstract: A pharmacokinetic study was conducted to determine the effectiveness of lower doses of ethanol in the treatment of ethylene glycol (EG) poisoning. Four dogs were maintained at serum ethanol concentrations of 0, 35 and 140 mg/dl prior to EG (i.v., 2 ml/kg) administration. The serum EG concentration-time data showed that the 35 mg/dl ethanol level provided as effective an inhibition of EG metabolism as did the 140 mg/dl level. The average urinary excretion rate of oxalic acid post EG administration was reduced to control levels by ethanol. The 35 mg/dl serum ethanol level reduced the total body clearance of EG from 93.9 to 50.0 ml/h/kg and increased the effective half-life from 5.78 to 11.4 h. Clinical testing was accomplished by giving the dogs 12 ml EG/kg body weight orally. One hour later, the dogs were either not treated or treated with a sodium bicarbonate-ethanol solution to obtain a serum ethanol concentration of 50 mg/dl. The clinical test performed in the ethanol-treated dogs showed little change from normal limits. Urine calcium oxalate crystals were seldom found. The dogs given EG (12 ml/kg) but not treated with ethanol were in a coma at 13 h and showed severe metabolic acidosis, dehydration, mild hepatocellular disease and acute renal damage. Urine calcium oxalate crystals were found in high numbers. The rapid death associated with EG poisoning appeared to be due to metabolic acidosis in combination with dehydration.

Cefadroxil in the horse: pharmacokinetics and in vitro antibacterial activity

Abstract: Sodium cefadroxil was administered as a single intravenous dose (25 mg/kg) to six healthy adult mares. Plasma samples were collected over a 24-h period and cefadroxil concentrations were measured by microbiological assay. The pharmacokinetic behavior of the drug was appropriately described in terms of a one-compartment open model. Values for the major pharmacokinetic terms were: extrapolated initial plasma concentration = 59.2 +/- 15.0 micrograms/ml; half-life = 46 +/- 20 min; apparent volume of distribution = 462 +/- 191 ml/kg; and body clearance = 7.0 +/- 0.6 ml/min.kg. In a subsequent study, a suspension of cefadroxil monohydrate was administered intragastrically (25 mg/kg) to the same six horses. Plasma concentrations of the drug peaked at 1-2 h but, in general, absorption was both poor and inconsistent. The data were unsuitable for determination of cefadroxil bioavailability from this oral dosage form. Ninety-nine isolates of eleven bacterial species obtained from clinically ill horses were tested for susceptibility to cefadroxil. All strains of Streptococcus equi, Streptococcus zooepidemicus, coagulase-positive staphylococci, Corynebacterium pseudotuberculosis and five out of six strains of Actinobacillus suis were highly susceptible to the drug (MIC less than 4 micrograms/ml). Escherichia coli, Klebsiella pneumoniae and Salmonella sp. showed intermediate susceptibility (MIC 4-16 micrograms/ml), while all isolates of Corynebacterium (Rhodococcus) equi, Enterobacter cloacae and Pseudomonas aeruginosa proved to be highly resistant to cefadroxil (MIC greater than 128 micrograms/ml).

Disposition of sulfadimidine and its N4‐acetyl and hydroxy metabolites in horse plasma

Abstract: Nouws, J.F.M., Vree, T.B., Baakman, M., Driessens, F., Smulders, A. & Holtkamp, J. Disposition of sulfadimidine and its N4-acetyl and hydroxy metabolites in horse plasma. J. vet. Pharmacol. Therap. 8, 303–311. The plasma disposition of sulfadimidine (SDM) and its metabolites N4-acetylsulfadimidine (N4-SDM), 6-hydroxymethyl-4-methyl-pyrimidine (SCH2OH) and 5-hydroxy-4,6-dimethyl-pyrimidine (SOH), was studied in three horses following intravenous administration of SDM at dose levels of 20 and 200 mg/kg in cross-over trials. The percentages of N4-SDM (0.58-0.90%), SOH (0.83-6.75%) and SCH2OH (0.38-0.71%) in plasma, expressed as a percentage of the total sulfonamide concentration, were small and their plasma concentrations were parallel with SDM from 4 h following administration. At high doses (200 mg/kg), the elimination half-life was slightly longer than at low doses (6.0, 10.5, 11.0 vs 5.0, 9.5, 9.5, respectively). The plasma protein binding was related to the dose; it was for the 20 and 200 mg/kg doses, respectively:SDM:61.5–73.3% and 50.5–52.1%; SOH: 47.1–71.0% and 36.7–39.5%, and for N4-SDM: 45.9–63.2% and 38.3–53.7%. The protein binding for SCH2 OH, measured in samples obtained at the high dose level, ranged from 13.8 to 20.0%. Dr J. F. M. Nouws, RVV-District 6, Wolfskuilseioeg 279, Nijmegen, Tlie Netherlands.

The nephrotoxic potential of gentamicin in the cat: enzymuria and alterations in urine concentrating capability

Abstract: This study investigated the potential for nephrotoxicity of gentamicin in cats by measuring marker enzyme concentrations, [Na], [K], osmolality, and pH of the urine, and blood urea nitrogen (BUN) levels. Gentamicin was administered i.m. at 4.4 mg/kg once daily (s.i.d.) or twice daily (b.i.d.) for 7 days. Concentrations of lactic dehydrogenase (LDH), lysozyme (LZM), alkaline phosphatase (AP), and glutamate dehydrogenase (GD) were measured as total 24-h excretions. The s.i.d. regimen produced only a slight increase in LDH excretion after 5 days, whereas the b.i.d. regimen caused an increase in the excretion of all enzymes. The greatest elevations were observed for LZM and LDH. Of the enzymes studied, these appeared to be the most appropriate to monitor for potential nephrotoxicity, except that urinary concentrations did not correlate well with duration of gentamicin administration. Only slight elevations in BUN were observed for either regimen. Single daily administration increased urine osmolality slightly, but b.i.d. treatment caused a marked and immediate decrease in urine osomolality, [Na], and total Na excretion. Urinary [K] was also depressed, as was total K excretion after 6 days. Urine pH was not substantially affected. This study showed that the recommended daily dose of 4.4 mg/kg produced little if any evidence of nephrotoxicity as indicated by the parameters measured. Twice daily dosing, however, produced elevations in urine enzyme concentrations, and markedly decreased urine osmolality and Na and K excretion. Compared to other species studied, the cat appears particularly sensitive to urine concentrating alterations resulting from repeated gentamicin administration.

Ibuprofen prevents Pasteurella hemolytica endotoxin-induced changes in plasma prostanoids and serotonin, and fever in sheep.

Abstract: Intravenous infusion of Pasteurella hemolytica endotoxin caused marked increases in the plasma levels of thromboxane B2 (TxB2), prostaglandins (PG) and serotonin in sheep. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin before endotoxin infusion averaged 283 +/- 53 (standard error of mean), 281 +/- 14 and 199 +/- 27 pg/ml and 57 +/- 3 ng/ml, respectively. At 50 min during endotoxin infusion, these values were increased to their maximum of 376, 339, 325 and 202% of control, respectively. Body temperature increased from the control value of 39.5 +/- 0.1 degrees C to a maximum of 41.5 +/- 0.1 degrees C at 200-300 min of infusion. In the second part of this study, we have examined the effects of ibuprofen on endotoxin-induced increases in plasma PG, TxB2, and serotonin levels and body temperature. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and temperature prior to ibuprofen and endotoxin infusion averaged 238 +/- 35, 335 +/- 44 and 248 +/- 28 pg/ml, 65 +/- 3 ng/ml and 40.1 +/- 0.2 degrees C, respectively. A loading dose (15 mg/kg) of ibuprofen was followed by infusion of endotoxin (12 micrograms/kg) and ibuprofen (43.3 mg/kg) over 500 min. Plasma levels of 6-keto-PGF1 alpha and serotonin increased only to 131 and 149% of control at 50 min of infusion, and levels of PGF2 alpha and TxB2 decreased to 50 and 80% of control at 100 and 150 min of infusion, respectively. Temperature remained unchanged. Ibuprofen effectively suppressed endotoxin-induced increases in the plasma levels of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin and body temperature. It was concluded from the present study that nonsteroidal anti-inflammatory drugs as an adjunct to antibiotic therapy might have a rational basis in treatment of endotoxin toxicity.

Pharmacokinetic studies of theophylline in horses.

Abstract: Ingvast-Larsson, C, Paalzow, G., Paalzow, L., Ottosson, T., Lindholm, A. & Appelgren, L.E. Pharmacokinetic studies of theophylline in horses. J. vet. Pharmacol. Therap. 8, 76–81. The pharmacokinetics of theophylline were determined in Standardised trotters after single intravenous and oral administration. A bi-exponential equation was fitted to the intravenous data and a tri-exponential equation to the oral data. The biological half-life of theophylline was found to be 14.8 h, the volume of distribution 1.02 l/kg and the total plasma clearance 0.86 ml/kg/min. The oral absorption of the drug was complete (bioavailability 108%) and rapid (absorption half-life 0.4 h). Professor L. E. Appelgren, Department of Pharmacology and Toxicology, Biomedicum. Box 573, S-75J 23 X'ppsala, Sweden.

Treatment of Moraxella bovis infections in calves using a long‐acting oxytetracycline formulation

Abstract: George, L.W. & Smith J.A. Treatment of Moraxella bovis infections in calves using a long-acting oxytetracycline formulation. J. vet. Pharmacol. Therap. 8, 55–61. Studies were undertaken to determine the effectiveness of an oxytetracycline HCl formulation for the prophylaxis and treatment of chronic Moraxella bovis ocular infections in calves. Two separate experiments were performed. For the first, calves were separated into two groups and the eyes were infected with M. bovis. The eyes of these calves were observed and cultured for 37 consecutive days. On the 37th and 40th day, each of the five calves were treated intramuscularly with the drug (20 mg/kg of body weight). The other five calves (second group) remained untreated as controls. The cultures from the five treated calves were negative after the first antibiotic administration and remained so for 14 days. M. bovis was isolated from each eye of the control calves at least once during that time. None of the antibiotic-treated calves was completely resistant when reinfected with M. bovis. For the second experiment, calves were given a prophylactic administration of the formulation and were then infected with M. bovis 48 (n= 4 calves) or 72 (n= 4 calves) h later. These treatments resulted in a lower incidence of keratoconjunctivitis and a decreased duration of bacterial shedding, as compared to controls (n= 8 calves), but did not completely prevent the occurrence of disease or the establishment of ocular infections. Lisle W. George, Department of Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616, U.S.A.

Distribution of oxytetracycline into ocular tissues and tears of calves.

Abstract: George, L., Smith, J. & Kaswan, R. Distribution of oxytetracycline into ocular tissues and tears of calves. J. vet. Pharmacol. Therap. 8, 47–54. A long-acting oxytetracycline formulation was administered (20 mg/kg of body weight) intramuscularly to calves, and the concentrations of the drug in serum, ocular tissues and tears were measured. The drug was distributed selectively to the epithelium of the conjunctiva and to the lacrimal gland ductules, and reached concentrations in each tissue that exceeded those in serum. The drug did not penetrate into the aqueous humour, and produced mean peak lacrimal fluid concentrations 2.0 μg/ml were observed in tears for 72 h. Severe local reactions occurred in all calves that were given the drug subconjunctivally. Lisle W. George, Department of Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616, U.S.A.

Monitoring for antibiotic resistance in enterococci consequent upon feeding growth promoters active against gram-positive bacteria.

Abstract: Linton, A.H., Hinton, M.H. & Al-Challaby, Z.A.M. Monitoring for antibiotic resistance in enterococci consequent upon feeding growth promoters active against Gram-positive bacteria. J. vet. Pharmacol. Therap. 8, 62–70. Commercial chicken and pig farms, using different growth promoters, were monitored for enterococci resistant to a range of antibacterial agents. Due to inconsistent findings attributed to uncontrollable factors, chickens kept under experimental conditions were also studied. A total of 4216 isolates from all the surveys were examined. Resistant isolates were often encountered, even in control groups, suggesting complex population changes not necessarily solely connected with the influence of the growth promoters. It was concluded that comprehensive methods for differentiating strains are necessary to unravel this problem. A. H. Linton, Department of Microbiology, University of Bristol, Bristol, Avon BS8 ITD, England.

Gallbladder motility in sheep: effects of cholecystokinin and related peptides

Abstract: Gallbladder motility was recorded as tonic and small amplitude (rhythmic) contractions in conscious sheep fitted with miniaturized strain-gauge force transducers located in the corpus and fundus. Nichrome wire electrodes were chronically implanted in the gastroduodenal area. Both tonic and superimposed rhythmic gallbladder contractions were increased during feeding. They decreased during the periodic phases of antroduodenal quiescence. The excitatory effects on gallbladder and antroduodenal motility were mimicked by pilocarpine and blocked by atropine. Cholecystokinin (CCK-OP) and caerulein elicited motor responses of the gallbladder in a dose-related manner without antroduodenal stimulation. In contrast, pentagastrin induced gallbladder motor responses with concomitant stimulation of the antroduodenal area. The results suggest that feeding may act to trigger gallbladder motor activity through a mechanism related to the increased antroduodenal activity. Direct effects of CCK-OP and caerulein confirm that gallbladder motor function is also mediated through specific receptor sites.

Some dynamic and toxic effects of theophylline in horses

Abstract: Errecalde, J.O., Button, C. & Mulders, M.S.G, Some dynamic and toxic effects of theophylline in horses. J. vet. Plmrmacol. Therap. 8, 320–327. A single intravenous administration of theophylline as aminophylline at 10 mg/kg to four mares induced a diuresis in which maximal urine production was more than seven times the control volume. The diuretic effect was maximal within the first hour post-administration, and lasted approximately 6 h. Theophylline resulted in dose-related tachycardia, polypnoea and nervous symptoms (tactile, visual and auditory hypersensitivity, muscle tremor, sweating) in normal mares, but had only minor effects on arterial and central venous blood pressures, intrapleural pressure, red blood cell variables and plasma proteins. The upper limit of safe plasma theophylline concentration in horses is approximately 15 μg/ml. Whenever feasible, the oral or intragastric route of administration should be used as it is safer than the intravenous route. Dr C. Button, Regional Veterinary Laboratory, PO Box 388, Benalla, Victoria 3672, Australia.

Pharmacology of the ruminant gastroduodenal junction

Abstract: The following aspects of the pharmacology of the ovine gastroduodenal junction are reviewed: 1 The duodenal brake; 2 Cholinergic stimulation and therapy of gastric stasis; 3 Delayed gastric emptying; 4 Drugs affecting the cyclical activity of the junction.