Identification and characterization of the enzymes responsible for the metabolism of the non‐steroidal anti‐inflammatory drugs,flunixin meglumine and phenylbutazone,in horses

The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug–drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450‐mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma‐hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5‐OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5‐OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug–drug interactions and identification of reasons for varying pharmacokinetics between horses.     

Genetics of equine bleeding disorders

Genetic bleeding disorders can have a profound impact on a horse's health and athletic career. As such, it is important to understand the mechanisms of these diseases and how they are diagnosed. These diseases include haemophilia A, von Willebrand disease, prekallikrein deficiency, Glanzmann's Thrombasthenia and Atypical Equine Thrombasthenia. Exercise-induced pulmonary haemorrhage also has a proposed genetic component. Genetic mutations have been identified for haemophilia A and Glanzmann's Thrombasthenia in the horse. Mutations are known for von Willebrand disease and prekallikrein deficiency in other species. In the absence of genetic tests, bleeding disorders are typically diagnosed by measuring platelet function, von Willebrand factor, and other coagulation protein levels and activities. For autosomal recessive diseases, genetic testing can prevent the breeding of two carriers.     

Equine pituitary pars intermedia dysfunction: current understanding and recommendations from the Australian and New Zealand Equine Endocrine Group

The purpose of this article is to provide a review of the current knowledge and opinions about the epidemiology, clinical findings (including sequelae), diagnosis, treatment and monitoring of equine pituitary pars intermedia dysfunction, particularly in the Australian context. This information and the recommendations provided will assist practitioners in making informed decisions regarding the diagnosis and management of this disorder.     

Calving rates in a tropical beef herd after treatment with a synthetic progestagen, norgestomet, or a prostaglandin analogue, cloprostenol

Maiden heifers and lactating cows of known ovarian status and of several breeds were treated with a synthetic prostaglandin, cloprostenol, or a synthetic progestagen, norgestomet, at the start of an artificial insemination (AI) program. Animals in the cloprostenol treatment received 2 injections 10 days apart. Over the next 26 days those animals that showed oestrous behaviour were inseminated. Synchronisation rates and calving rates to insemination over the first 7 days were calculated. Those in the norgestomet treatment received an implant of norgestomet plus an injection of norgestomet and oestradiol valerate. The implant was removed 10 days later and the animals were given an injection of pregnant mare serum gonadotrophin (PMSG). They were inseminated at 48 h (maiden heifers) or 56 h (lactating cows) after implant removal. Calving rates to fixed-time insemination were recorded. After completion of the AI program the animals in both treatments were joined with bulls. Overall calving rates (AI plus bulls) were calculated. By day 7 of the program, 82% of the maiden heifers and 76% of the lactating cows in the cloprostenol treatment had been detected in oestrus. By day 21 the respective figures were 99% and 81% Norgestomet treatment had an immediate and a prolonged effect on ovarian activity in those females classified as having inactive ovaries at the start of the AI program. Calving rates of those females to fixed-time AI and overall were similar to those of the females with active ovaries in both treatments. Their calving rates to fixed-time insemination, and overall calving rates for the lactating females, were significantly higher than the corresponding values of their contemporaries treated with cloprostenol and inseminated on observed oestrus over 7 days. For those females classified as having active ovaries at the start of the AI program, calving rates to first insemination and overall were similar for both treatments. Overall calving rates of lactating cows of each breed were, with one exception, higher in the norgestomet treatment than in the cloprostenol treatment. Although norgestomet treatment was more expensive than cloprostenol treatment, the advantage in calf crop resulted in an overall monetary advantage to the norgestomet treatment.     

Effect of oral administration of dantrolene sodium on serum creatine kinase activity after exercise in horses with recurrent exertional rhabdomyolysis

OBJECTIVE: To determine the effect of oral administration of dantrolene sodium on serum creatine kinase (CK) activity after exercise in horses with recurrent exertional rhabdomyolysis (RER). ANIMALS: 2 healthy horses and 5 Thoroughbreds with RER. PROCEDURE: 3 horses received 2 doses of dantrolene (4, 6, or 8 mg/kg, p.o., with and without withdrawal of food) 2 days apart; 90 minutes after dosing, plasma dantrolene concentration was measured spectrofluorometrically. On the basis of these results, 5 Thoroughbreds with RER from which food was withheld received dantrolene (4 mg/kg) or an inert treatment (water [20 mL]) orally 90 minutes before treadmill exercise (30 minutes, 5 d/wk) during two 3-week periods. Serum CK activity was determined 4 hours after exercise. Plasma dantrolene concentration was measured before and 90 minutes after dosing on the first and last days of dantrolene treatment and before dosing on the first day of the inert treatment period, RESULTS: 90 minutes after dosing, mean +/- SEM plasma dantrolene concentration was 0.62 +/- 0.13 and 0 microg/mL in the dantrolene and inert treatment groups, respectively. Serum CK activity was lower in dantrolene-treated horses (264 +/- 13 U/L), compared with activity in water-treated horses (1,088 +/- 264 U/L). Two horses displayed marked muscle stiffness on the inert treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In 5 horses with RER from which food had been withheld, 4 mg of dantrolene/kg administered orally provided measurable, though variable, plasma concentrations and significantly decreased serum CK activity after exercise in 4 of those horses.     

A Comparative Review of Vitamin E and Associated Equine Disorders

Vitamin E is a primary chain‐breaking antioxidant that prevents cyclic propagation of lipid peroxidation. Across species, vitamin E is essential for normal neuromuscular function by acting as a potent antioxidant, as well as by modulating the expression of certain genes, inhibiting platelet aggregation and stabilizing plasma membranes. This review focuses on vitamin E structure, absorption, metabolism, current equine dietary recommendations, the interplay between antioxidants and exercise, a discussion of the necessity of vitamin E supplementation in the horse above the Nutritional Research Council (NRC) 2007 requirements, and a review of equine diseases that are associated with a vitamin E deficiency. Particular emphasis is placed on the proteins involved in vitamin E absorption, transport, and metabolism as potential candidates for vitamin E‐associated diseases across species.