Pharmacokinetics of methocarbamol and phenylbutazone in exercised Thoroughbred horses

Methocarbamol (MCBL) is commonly used in performance horses for the treatment of skeletal muscle disorders. Current regulatory recommendations for show horses and racehorses are based on a single oral dose of 5 g, although doses in excess of this are often administered. The goal of the current study was to characterize the disposition of MCBL following higher dose administration and administration in combination with another commonly used drug in performance horses, phenylbutazone (PBZ). Exercised Thoroughbred horses were administered various doses of MCBL as a sole agent and MCBL in combination with PBZ. Blood samples were collected at various times, concentrations of MCBL and PBZ measured using LC‐MS/MS and pharmacokinetic parameters calculated using compartmental analysis. Following administration of 15 g of MCBL, either as part of a single‐ or multiple‐dose regimen, a number of horses exceeded the Association of Racing Commissioners International and the United States Equestrian Federation's recommended regulatory threshold at the recommended withdrawal time. There was not a significant difference between horses that received only MCBL and those that received MCBL and PBZ. Results of the current study support an extended withdrawal guideline when doses in excess of 5 g are administered.     

The effect of phenylbutazone on the plasma disposition of penicillin G in the horse

A pilot study in two ponies showed that the plasma concentrations of intramuscularly administered procaine penicillin were higher if phenylbutazone was administered concurrently. In two other trials, each involving five horses, intravenous sodium penicillin was administered with and without concurrent intravenously injected phenylbutazone, and procaine penicillin was injected intramuscularly with and without oral phenylbutazone. In both cases the plasma concentrations of penicillin were higher when phenylbutazone was given. The pharmacokinetic parameters indicated that the effect was probably due to a lower peripheral distribution because the penetration of penicillin into the tissues was greatly reduced.     

Characterization of a sterile soft-tissue inflammation model in Thoroughbred horses

This paper describes the use of subcutaneously-placed tissue chambers as a sterile soft-tissue inflammation model in Thoroughbred horses. Acute, nonimmune inflammation was initiated by injecting a sterile lambda carrageenan solution into a tissue chamber. This model was used to study the temporal changes in oxygen and carbon dioxide tensions, pH, bicarbonate, protein, albumin, prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) concentrations, cell counts and differential counts in tissue fluid from inflamed tissue chambers and control chambers. Skin temperatures over control and inflamed chambers were also compared. Carrageenan-induced inflammation resulted in significant increases in tissue-fluid carbon dioxide tension, leucocyte count, albumin, and PGE₂ and LTB₄ concentrations. It also resulted in a significant decrease in tissue fluid pH and HCO₃- concentration. Inflammation did not result in significant changes in tissue-fluid protein concentration, differential cell counts or skin temperature over the chambers. The use of this type of tissue chamber is wellsuited for studying the pathophysiology of a self-contained, non-immune inflammatory process. The model described in this paper could prove to be very useful in studies of the distribution of anti-inflammatory drugs and the effects of such drugs on various aspects of the inflammatory process.     

Effects of phenylbutazone on thiamylal disposition and anaesthesia in ponies

Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.     

Effects of phenylbutazone on bone activity and formation in horses

OBJECTIVE: To determine the effects of phenylbutazone (PBZ) on bone activity and bone formation in horses. ANIMALS: 12 healthy 1- to 2-year-old horses. PROCEDURES: Biopsy was performed to obtain unicortical bone specimens from 1 tibia on day 0 and from the contralateral tibia on day 14. Fluorochromic markers were administered IV 2 days prior to and on days 0, 10, 15, and 25 after biopsy was performed. Six horses received PBZ (4.4 mg/kg of body weight, PO, q 12 h) and 6 horses were used as controls. All horses were euthanatized on day 30 and tissues from biopsy sites, with adjacent cortical bone, were collected. Osteonal density and activity, mineral apposition rate (MAR), and percentage of mineralized tissue filling the biopsy-induced defects in cortical bone were assessed. Serum samples from all horses were analyzed for bone-specific alkaline phosphatase activity and concentration of PBZ. RESULTS: MAR was significantly decreased in horses treated with PBZ. Regional acceleratory phenomenon was observed in cortical bone in both groups but was significantly decreased in horses treated with PBZ. Osteonal activity was similar at all time points in all horses. In control horses, percentage of mineralized tissue filling the cortical defects was significantly greater in defects present for 30 days, compared with defects present for 14 days. Differences in percentage of mineralized tissue were not detected in horses treated with PBZ. CONCLUSIONS AND CLINICAL RELEVANCE: PBZ decreased MAR in cortical bone and appeared to decrease healing rate of cortical defects in horses.     

Prevalence of latent alpha-herpesviruses in Thoroughbred racing horses

The objective of this study was to detect and characterize latent equine herpes virus (EHV)-1 and -4 from the submandibular (SMLN) and bronchial lymph (BLN) nodes, as well as from the trigeminal ganglia (TG) of 70 racing Thoroughbred horses submitted for necropsy following sustaining serious musculoskeletal injuries while racing. A combination of nucleic acid precipitation and pre-amplification steps was used to increase analytical sensitivity. Tissues were deemed positive for latent EHV-1 and/or -4 infection when found PCR positive for the corresponding glycoprotein B (gB) gene in the absence of detectable late structural protein gene (gB gene) mRNA. The EHV-1 genotype was also determined using a discriminatory real-time PCR assay targeting the DNA polymerase gene (ORF 30). Eighteen (25.7%) and 58 (82.8%) horses were PCR positive for the gB gene of EHV-1 and -4, respectively, in at least one of the three tissues sampled. Twelve horses were dually infected with EHV-1 and -4, two carried a latent neurotropic strain of EHV-1, six carried a non-neurotropic genotype of EHV-1 and 10 were dually infected with neurotropic and non-neurotropic EHV-1. The distribution of latent EHV-1 and -4 infection varied in the samples, with the TG found to be most commonly infected. Overall, non-neurotropic strains were more frequently detected than neurotropic strains, supporting the general consensus that non-neurotropic strains are more prevalent in horse populations, and hence the uncommon occurrence of equine herpes myeloencephalopathy.     

Biochemical and haematological effects of phenylbutazone in horses

Five matched pairs of horses were used to investigate the effects of phenylbutazone on a range of physiological, biochemical and haematological variables. The drug was given by mouth daily for 15 consecutive days at the manufacturer's recommended dose rates to one group of horses (Group A); the second group (Group B) received equivalent doses of a placebo. For some of the measured parameters, significant changes were recorded in both groups, indicating background instability. Significant decreases in serum total protein, albumin, plasma pH, viscosity and magnesium, and an increase in albumin: globulin ratio occurred in Group A, but not in Group B. These changes were, therefore, attributed to phenylbutazone or its metabolites. Toxicologically, the change in pH is probably unimportant but the decrease in protein concentration may have resulted from a protein losing enteropathy and/or from decreased synthesis in the liver. In one animal which received phenylbutazone, clinical signs of toxicity (lethargy, inappetence, oedema) were observed and evidence of hepatotoxicity and haematological changes were also noted in this horse. It is concluded that recommended dose rates of phenylbutazone should never be exceeded and that the period for which the highest dose (4.4 mg/kg body weight twice daily for four days) is administered should be reduced. In clinical cases, where phenylbutazone toxicity is suspected, measurement of serum or plasma protein concentration might provide an indication of the need to reduce dose levels or stop therapy.     

Inheritance of racing performance of Thoroughbred horses

Horse racing is a contest between horses, usually held for the purpose of betting. Thoroughbred horse racing is the most diffused form of horse racing throughout the world. Thoroughbred is one of the most versatile of horse breeds and has influenced the development of many other breeds. Thoroughbred horses served as a foundation stock for the development of the light horse breeds. The two types of horse racing are flat racing and jumping races/steeplechases. The measures of racing performance are broadly classified into three categories. They are time and its several variations, handicap or similar performance ratings and earnings. One common measure of the performance of racehorses evaluated genetically is racing time or final time. The heritability estimates differed according to method of estimation, age, sex, track and distance. Time measure generally had a heritability in the range of 0.1 to 0.2 with the higher values for shorter races. For handicap and earning measures the heritabilities reported were generally higher in the range of 0.3 to 0.4; hence these may be considered in genetic evaluation of racing performance of Thoroughbred horses. The average generation interval of Thoroughbred horses was 11.2 ± 4.5 and 9.7 ± 3.8 years for males and females respectively, which limits the genetic progress in racing horses. However, the major advantage is that the racing performance may be evaluated in both males and females and repeated observations can be obtained on the same animal in relatively short periods. These factors coupled with the reasonable heritability of some measures of racing performance, suggest that mass selection based on performance tests would be the selection procedure of choice to improve the racing performance of Thoroughbred horses. In general, the inbreeding at the rate that is usually practised in Thoroughbred population does not enable much gene fixing. However, practice of close inbreeding may be avoided, even though it still fascinates breeders at subconscious level.     

Effects of oral cimetidine on plasma concentrations of phenylbutazone in horses

Phenylbutazone was administered to six Thoroughbred horses in a cross-over study in which the horses received cimetidine pretreatment or no cimetidine pretreatment. Blood samples were collected at various times for 48 h after phenylbutazone administration and the plasma was analysed for phenylbutazone. Cimetidine pretreatment elevated phenylbutazone plasma concentrations during the first 8 h after phenylbutazone administration. The absorption rate, maximum phenylbutazone plasma concentrations and AUC were significantly greater with cimetidine pretreatment. The half-life of phenylbutazone did not change with cimetidine pretreatment; however, lower plasma concentrations of the metabolite gamma-hydroxyphenylbutazone were observed with cimetidine pretreatments. Plasma concentrations of the metabolite oxyphenbutazone were unchanged with cimetidine pretreatment compared to control values. Twenty-four-hour plasma concentrations of phenylbutazone were not different from control values with cimetidine pretreatment. This study suggests that concurrent treatment with cimetidine and phenylbutazone 24 h before race time does not result in elevations of plasma phenylbutazone concentrations above control values.     

Effect of growth and training on muscle adaptation in Thoroughbred horses

OBJECTIVE: To determine the effect of growth and training on metabolic properties in muscle fibers of the gluteus medius muscle in adolescent Thoroughbred horses. ANIMALS: Twenty 2-year-old Thoroughbreds. PROCEDURE: Horses were randomly assigned to 2 groups. Horses in the training group were trained for 16 weeks, and control horses were kept on pasture without training. Samples were obtained by use of a needle-biopsy technique from the middle gluteus muscle of each horse before and after the training period. Composition and oxidative enzyme (succinic dehydrogenase [SDHI) activity of each fiber type were determined by use of quantitative histochemical staining procedures. Whole-muscle activity of SDH and glycolytic enzyme (phosphofructokinase) as well as myosin heavy-chain isoforms were analyzed biochemically and electrophoretically, respectively. RESULTS: The SDH activity of type-I and -IIA fibers increased during growth, whereas whole-muscle activity was unchanged. Percentage of type-IIX/B muscle fibers decreased during training, whereas that of myosin heavy-chain IIa increased. The SDH activity of each fiber type as well as whole-muscle SDH activity increased during training. An especially noticeable increase in SDH activity was found in type-IIX/B fibers. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in muscle fibers of adolescent Thoroughbreds are caused by training and not by growth.The most noticeable change was for the SDH activity of type-IIX/B fibers. These changes in the gluteus medius muscle of adolescent Thoroughbreds were considered to be appropriate adaptations to running middle distances at high speeds.     

Thyroid-stimulating hormone: response test in healthy horses, and effect of phenylbutazone on equine thyroid hormones

Adult horses showed a mild diurnal variation in equine plasma thyroxine (T4) concentrations, but not triiodothyronine (T3). Plasma T4 concentrations tended to be higher between 5 PM and 8 PM than at 8 AM. Increases in plasma T4 and T3 were similar in adult healthy horses given 5, 10, or 20 IU of thyroid-stimulating hormone (TSH). The T4 peaked at approximately twice (2.0 +/- 0.4 times) as high as the base line at 6 to 12 hours after the TSH was given. The greatest change from base line T3 occurred at 1 to 3 hours after the TSH was given, but the magnitude of increase was widely variable (4.36 +/- 2.49 times as high as base line). The following method for doing the equine TSH-response test was suggested: (i) prepare plasma or serum sample for determining base line T4 and T3, (ii) inject 5 IU of TSH IM, (iii) prepare plasma or serum samples at 3 and 6 hours after the TSH was injected, and (iv) freeze samples at -20 C until T4 and T3 determination by radioimmunoassay. Treatment of horses with phenylbutazone for 5 days caused a significant decrease in base line T4 and T3 in horses (P less than 0.05). However, phenylbutazone-treated horses responded to the injection of TSH, and the increase in T4 at 6 hours was greater than in the controls (not given phenylbutazone) (P less than 0.02).     

Sudden death in training and racing Thoroughbred horses

We reviewed case records, necropsy reports, and histologic sections from 25 Thoroughbred racehorses that died suddenly at 3 Chicago racetracks. These were young horses ranging in age from 2 to 5 years. There were more females (n = 16) than males (n = 9), and the incidence of death increased slightly in the spring and summer. Twenty-one of the 25 horses died while racing or training. Only 8 of the 25 horses (32%) had lesions sufficient to account for the death. In 6 of those 8 cases, death was caused by massive thoracic or abdominal hemorrhage. The site or nature of the vascular defect in these cases could not be determined. One horse died of severe preexisting pulmonary disease, and one died of encephalitis and cardiac papillary muscle fibrosis. The cause of death was undetermined in 17 horses (68%). Nearly all horses had pulmonary edema, congestion, and/or hemorrhage. We postulate that these unexplained deaths were a result of exercise-induced acute cardiovascular failure.     

Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses

The objective was to compare the gastrointestinal and general toxicity of suxibuzone (SBZ) to that of phenylbutazone (PBZ) when administered orally in horses. Fifteen healthy horses were allocated to three treatment groups. One group received a high dose of PBZ for two weeks; the second group was given an equimolecular dosage of SBZ; and a third group received placebo. Horses were daily monitored, and blood samples were collected before and during the study. On day 18, complete post-mortem examinations were performed.One horse treated with PBZ showed clinical signs of NSAID toxicosis. Small oral ulcers were also detected in other two horses from the PBZ group and in two horses from the SBZ group. There were no statistical differences in the blood parameters among groups. Ulcers in the stomach's glandular mucosa were observed in all horses of the PBZ group, while only two horses of the SBZ group showed ulcerations. PBZ horses had a significant higher ulcerated area, and gastric ulcers were significantly deeper than those in the SBZ and placebo groups. No other lesions were found in any other tissue. In conclusion, SBZ causes significantly lower gastric ulcerogenic effect than PBZ when administered orally at equimolecular doses in horses.