IMAGING DIAGNOSIS—SPINAL CORD HEMANGIOMA IN TWO DOGS

Intramedullary masses are a dilemma due to the limited access for a nonsurgical biopsy, thus, accurate imaging characterization is crucial. Magnetic resonance imaging findings of two confirmed canine thoracic intramedullary hemangiomas are described. A capillary hemangioma was of mixed intensity but predominantly T2‐hyperintense and mildly T1‐hyperintense to spinal cord with strong contrast enhancement. A cavernous hemangioma had a target‐like appearance in both T1‐weighted (T1w) and T2‐weighted (T2w) images. In T2w images there was a small isointense center surrounded by a relatively large hyperintense area. In T1w images, there was a large isointense centre with a relatively small hyperintense periphery. Such characteristics should prioritize hemangioma as a consideration in a progressive myelopathy due to an intramedullary mass.     

Some reflections on positive results from medication control tests in the USA

This article describes 3 of the drugs responsible for positive tests in American racing in recent years: fentanyl, apomorphine and reserpine. Experimental work is described in which the effect of administration was measured objectively against step counting; other aspects of locomotor stimulation and clinical responses are discussed. The supposed tonic effects of “pangamic acid” are considered and attention is drawn to the view of the US Food and Drug Administration that the substance does not exist.     

Nonsteroidal anti-inflammatory agents and musculoskeletal injuries in Thoroughbred racehorses in Kentucky

Injuries sustained by horses during racing have been considered as an unavoidable part of horse racing. Many factors may be associated with the musculoskeletal injuries of Thoroughbred race horses. This study surveyed the amounts of nonsteroidal anti-inflammatory agents (NSAIDs) in injured horse's biological system (plasma) at Kentucky racetracks from January 1, 1995 through December 31, 1996. During that period, there were 84 catastrophic cases (euthanized horses) and 126 noncatastrophic cases. Plasma concentrations of NSAIDs were determined by High Performance Liquid Chromatography in injured and control horses. The possible role of anti-inflammatory agents in musculoskeletal injuries of Thoroughbred race horses was investigated by comparing the apparent concentrations of NSAIDs in injured horses to concentrations in control horses. The plasma concentrations of phenylbutazone and flunixin were higher in injured horses than in control horses. Most injured and control horses did not have a detectable level of naproxen in their plasma samples. Further studies must be carried out to determine whether horses with higher plasma concentrations of NSAIDs have an altered risk of musculoskeletal injuries compared with other horses.     

The pharmacokinetics, pharmacological responses and behavioral effects of acepromazine in the horse

After intravenous (i.v.) injection, acepromazine was distributed widely in the horse ( V_d = 6.6 litres/kg) and bound extensively (>99%) to plasma proteins. Plasma levels of the drug declined with an α phase half-life of 4.2 min, while the β phase or elimination half-life was 184.8 min. At a dosage level of 0.3 mg/kg acepromazine was detectable in the plasma for 8 h post dosing. The whole blood partitioning of acepromazine was 46% in the plasma phase and 54% in the erythrocyte phase.
Penile prolapse was clearly evident at doses from 0.01 mg/kg to 0.4 mg/kg i.v., and the duration and extent of protrusion were dose related. Hematocrit levels were significantly lowered by administration of 0.002 mg/kg i.v. (about 1 mg to a 500 kg horse) and increasing dosages resulted in greater than 20% lowering of the hematocrit from control levels. Pretreatment of horses with acepromazine also reduced the variable interval (VI 60) responding rate in all horses tested.
These data show that hematocrit changes are the most sensitive pharmacological responses to acepromazine, followed by changes in penile extension, respiratory rate, VI responding and locomotor responses. Acepromazine is difficult to detect in plasma at normal clinical doses. However, because of its large volume of distribution, its urinary elimination is likely prolonged, and further work on its elimination in equine urine is required.     

Population distributions of phenylbutazone and oxyphenbutazone after oral and i.v. dosing in horses

Experiments to determine the residual plasma concentrations of phenylbutazone and its metabolites found in horses racing on a 'no-race day medication' or 24-h rule were carried out. One dosing schedule (oral-i.v.) consisted of 8.8 mg/kg (4 g/1000 lbs) orally for 3 days, followed by 4.4 mg/kg (2 g/1000 lbs) intravenously on day 4. A second schedule consisted of 4.4 mg/kg i.v. for 4 days. The experiments were carried out in Thoroughbred and Standardbred horses at pasture, half-bred horses at pasture, and in Thoroughbred horses in training. After administering the i.v. schedule for 4 days to Thoroughbred and Standardbred horses at pasture, the mean plasma concentrations of phenylbutazone increased from 0.77 microgram/ml on day 2 to 2.5 micrograms/ml on day 5. The shape of the frequency distribution of these populations was log-normal. These data are consistent with one horse in 1,000 yielding a plasma level of 8.07 micrograms/ml on day 5. After administration of the oral-i.v. schedule to Thoroughbred and Standardbred horses at pasture, the mean plasma concentrations of phenylbutazone were 3.4 micrograms/ml on day 2 and 3.5 micrograms/ml on day 5. The range on day 5 was from 1.4 to 8.98 micrograms/ml and the frequency distribution was log-normal. These data are consistent with one horse in 1000 having a plasma level of 15.8 micrograms/ml on day 5. In a final experiment, the oral dosing schedule was administered to 62 Thoroughbred horses in training. Plasma concentrations on day 5 in these horses averaged 5.3 micrograms/ml. The range was from 1.3 to 13.6 micrograms/ml and the frequency distribution was log-normal. Statistical projection of these values suggests that following this oral dosing schedule in racing horses about one horse in 1000 will yield a plasma level of 23.5 micrograms/ml of phenylbutazone 24 h after the last dose.     

Intoxication by tremorgenic mycotoxin (penitrem A) in a dog

A 1-year-old Siberian Husky dog presented with severe muscle tremors after ingestion of a mouldy hamburger bun. Penicillium crustosum and the tremorgenic mycotoxin penitrem A were isolated from the remaining portion of the hamburger bun. When grown in pure culture, the isolate of P. crustosum produced large amounts of penitrem A, along with other penitrem compounds. This is the first reported Australian case of toxicosis by naturally occurring penitrem A.     

Plasma and urinary concentrations of trimetoquinol by LC‐MS‐MS following intravenous and intra‐tracheal administration to horses with heaves

Trimetoquinol (TMQ) is a very potent and fast acting bronchodilator in horses with heaves. This study assessed the plasma and urinary concentrations of TMQ in horses with heaves following administration via the intravenous (IV, 0.2 μg/kg) and intra‐tracheal (IT, 2 μg/kg) routes. TMQ was administered to six horses affected with heaves (RAO – Recurrent Airway Obstruction, used interchangeably) by the above routes and plasma and urine samples collected and stored at ?20 °C until analyzed. Solid Phase Extraction (SPE) of TMQ was followed by highly sensitive ESI(+)‐LC‐MS‐MS (ElectroSpray Ionization, positive mode – Liquid Chromatography – Mass Spectrometry – Mass Spectrometry); with a Limit of Detection (LOD) estimated at 1 pg/mL. Following IV administration, TMQ plasma levels peaked at 1 min at 707 pg/mL, and at 9 min at 306 pg/mL following IT administration. Our results show that TMQ plasma concentrations decline rapidly following IV administration, which is consistent with the fast onset and short duration of TMQ effect that was observed in our previous studies. On the other hand, IT administration showed a very unique plasma concentration pattern. From a regulatory standpoint, the current available TMQ ELISA kit was also used in an attempt to detect TMQ from the plasma and urine samples. We report that the ELISA kit was unable to detect TMQ from any of the samples generated in these studies.     

Synthesis and detection of toltrazuril sulfone and its pharmacokinetics in horses following administration in dimethylsulfoxide

Triazine-based antiprotozoal agents are known for their lipophylic characteristics and may therefore be expected to be well absorbed following oral administration. However, although an increase in lipid solubility generally increases the absorption of chemicals, extremely lipid-soluble chemicals may dissolve poorly in gastrointestinal (GI) fluids, and their corresponding absorption and bioavailability would be low. Also, if the compound is administered in solid form and is relatively insoluble in GI fluids, it is likely to have limited contact with the GI mucosa, and therefore, its rate of absorption will be low. Based on the above considerations, we sought a solvent with low or no toxicity that would maintain triazine agents in solution. As the oral route is most preferred for daily drug therapy, such a solvent would allow an increased rate of absorption following oral administration. In present study, it was demonstrated that dimethylsulfoxide (DMSO) increased the oral bioavailability of toltrazuril sulfone (Ponazuril) threefold, relative to oral administrations of toltrazuril sulfone suspended in water. The cross-over study of toltrazuril sulfone formulated in DMSO indicated that the absolute oral bioavailability of toltrazuril sulfone in DMSO is 71%. The high bioavailability of the DMSO-preparation suggests that its daily oral administration will routinely yield effective plasma and cerebral spinal fluid (CSF) concentrations in all horses treated. Also, this improved formulation would allow clinicians to administer loading doses of toltrazuril sulfone in acute cases of Equine Protozoal Myeloencephalitis. Another option would involve administration of toltrazuril sulfone in DMSO mixed with feed (1.23 kg daily dose) meeting the US Food and Drug Administration (FDA) recommendations for the levels of DMSO permissible in pharmaceutical preparations.     

Phenylbutazone in the horse: a review

Phenylbutazone is an acidic, lipophilic, non-steroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, gamma-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 prostaglandin-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 (greater than 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 microgram/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 microgram/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.(ABSTRACT TRUNCATED AT 400 WORDS)