Biomedical subjects
P Lees
Publications and source records attributed to P Lees.
Pharmacokinetics of phenylbutazone in two age groups of ponies: a preliminary study.
A clinical dose rate (4.4 mg/kg bodyweight) of phenylbutazone was administered intravenously and orally to six Welsh mountain ponies to provide data on the pharmacokinetics and bioavailability of the drug. In three, three-year-old ponies, clearance of the drug from plasma after intravenous administration was almost twice as rapid as in three ponies aged eight to 10 years. After oral administration, plasma phenylbutazone levels were greater in the older ponies, the area under the plasma concentration time curve being almost twice as high. This did not result from more efficient absorption but from slower plasma clearance. The fractional absorption of phenylbutazone was similar in young and older ponies, 0.78 and 0.75, respectively. The 24 hour urinary excretion of phenylbutazone and its hydroxylated metabolites, oxyphenbutazone and gamma-hydroxyphenylbutazone, accounted for approximately 25 per cent of the administered intravenous dose in both young and older ponies. The possible fate(s) of the remaining 75 per cent were considered.
Clinical pharmacology and therapeutic uses of non-steroidal anti-inflammatory drugs in the horse.
Weak organic acids possessing anti-inflammatory, analgesic and antipyretic properties--commonly known as aspirin-like drugs--have been used in equine medicine for almost 100 years. These non-steroidal anti-inflammatory drugs (NSAIDs) may be classified chemically into two groups; the enolic acids such as phenylbutazone and carboxylic acids like flunixin, meclofenamate and naproxen. All NSAIDs have similar and possibly identical modes of action accounting for both their therapeutic and their toxic effects. They block some part of the cyclo-oxygenase enzyme pathway and thereby suppress the synthesis of several chemical mediators of inflammation, collectively known as eicosanoids. The available evidence indicates that some of the newer NSAIDs have a reasonable safety margin but further studies are required. The toxicity of phenylbutazone in the horse has been investigated very thoroughly in recent years and it has been shown to cause renotoxicity and, most significantly, ulceration of the gastrointestinal tract when relatively high doses are administered. Several factors may predispose towards phenylbutazone toxicity in the horse, including breed and age, but high dosage is considered to be particularly important. The absorption into, and fate within, the body of NSAIDs are considered and particular attention is drawn to the ways in which these pharmacokinetic properties relate to the drugs' toxicity and clinical efficacy. In reviewing current knowledge of the clinical pharmacology of this important group of drugs, it is hoped to provide the clinician with a rational, scientific basis for their safe and effective use in equine practice.
Detection of leukotriene B4 in equine inflammatory exudate.
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Arachidonic acid metabolites in carrageenin-induced equine inflammatory exudate.
The presence of cyclooxygenase products of arachidonic acid metabolism in carrageenin-induced inflammatory exudate was investigated in ponies using two models. In the first model, an inflammatory response was stimulated by injecting carrageenin into subcutaneously implanted polypropylene tissue cages and exudates were collected at five predetermined times between 3 and 48 h. In the second model, exudates were harvested at 6, 12 and 24 h from carrageenin-impregnated polyester sponges which had also been inserted beneath the skin. Prostaglandin (PG) E2, thromboxane (TX) B2 and the stable breakdown-product of prostacyclin (PGI2), 6-keto-PGF1 alpha, in exudates were measured by radio-immunoassay (RIA); PGE2-like and PGF2 alpha-like activities were bioassayed following an acid-lipid extraction technique which provided a recovery rate of 78%. Agreement between RIA and bioassay was within acceptable limits. In Model 1, using RIA, mean PGE2 concentration reached 197 ng X ml-1 at 12 h decreasing to less than 12 ng X ml-1 at 24 h. Mean TXB2 and 6-keto-PGF1 alpha levels were highest at 48 h (22.3 and 34.2 ng X ml-1, respectively) after considerable fluctuations and with wide standard errors prior to this time. In the sponge model, however, PGE2 levels were surprisingly low for each group (mean 12.8 ng X ml-1 at 12 h) and TXB2 and 6-keto-PGF1 alpha were similarly lower (means of 3.3 and 8.1 ng X ml-1 respectively at 12 h). Mean total leucocyte counts and total protein concentrations were increased in both models after carrageenin stimulus. PGF2 alpha was not detected in measurable quantities in any exudate.(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of prostaglandin-like activity in equine inflammatory exudate--a preliminary report.
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The acute inflammatory process, arachidonic acid metabolism and the mode of action of anti-inflammatory drugs.
Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, the eicosanoids. It is now recognised that eicosanoid release is fundamental to the inflammatory process. For example, the prostaglandins and other prostanoids, products of the cyclooxygenase enzyme pathway, have potent inflammatory properties and prostaglandin E2 is readily detectable in equine acute inflammatory exudates. The administration of nonsteroidal anti-inflammatory drugs results in inhibition of prostaglandin synthesis and this explains the mode of action of agents such as phenylbutazone and flunixin. Lipoxygenase enzymes metabolise arachidonic acid to a group of noncyclised eicosanoids, the leukotrienes, some of which are also important inflammatory mediators. They are probably of particular importance in leucocyte-mediated aspects of chronic inflammation. Currently available non-steroidal anti-inflammatory drugs, however, do not inhibit lipoxygenase activity. In the light of recent evidence, the inflammatory process is re-examined and the important emerging roles of both cyclo-oxygenase and lipoxygenase derived eicosanoids are explored. The mode of action of current and future anti-inflammatory drugs offered to the equine clinician can be explained by their interference with arachidonic acid metabolism.
Influence of betamethasone on the composition of inflammatory exudate in the horse: a preliminary report.
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Influence of phenylbutazone on eicosanoid levels in equine acute inflammatory exudate.
In a two part cross-over experiment, acute inflammatory exudates were induced in 7 ponies by subcutaneous implantation of 3 sterile carrageenin-soaked polyester sponge strips. Treatment comprised a single therapeutic geenin-soaked polyester sponge strips. Treatment comprised a single therapeutic dose of 4.4 mg/kg phenylbutazone (PBZ) administered intravenously at the time of sponge implantation. Exudates were harvested at 6, 12 and 24 hours and examined for leukocyte and erythrocyte numbers using the improved Neubauer technique; for eicosanoids by radioimmunoassay and by high performance liquid chromatography for concentrations of PBZ and its principal metabolite oxyphenbutazone. Plasma PBZ and oxyphenbutazone levels were measured in treated animals at 6, 12 and 24 hours. The administration of PBZ produced, at 6 hours, highly significant (P less than 0.001) reductions in exudate levels of prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha (the stable breakdown product of prostacyclin, PGI2). Significant (P less than 0.01) reductions in these eicosanoids were maintained in treated animals at 12 and 24 hours. Levels of thromboxane B2 (TXB2), the catabolite of TXA2, were reduced in treated animals at 6 and 12 hours but these changes were not significant. Leukocyte numbers were significantly (P less than 0.001) increased from 6-hour values at 12 and 24 hours in both control and PBZ-treated animals but differences between control and treated ponies were not significant. This is the first report in ponies of eicosanoid inhibition following the administration of a non-steroid anti-inflammatory drug (NSAID). It is proposed that the model of inflammation used in this study might provide a means of assessing the efficacy and duration of action of NSAIDs in the horse.
Tissue-cage model for the collection of inflammatory exudate in ponies.
In a series of experiments to examine equine inflammatory exudates for the presence of metabolites of arachidonic acid, including prostaglandin E2 (PGE2), a model for the induction and collection of exudates in ponies has been developed. Multiperforated polypropylene practice golf balls implanted subcutaneously in the mid-neck region were well tolerated and proved to be the most successful model. One such cage was implanted in the neck of each of seven ponies. Inflammatory exudates were induced by injecting 3.0 or 0.5 ml carrageenin into the cages and aspirates collected between three and 48 hours later. These were examined for PGE2-like activity, total protein concentration and leucocytes. All three variables increased following the injection of both dose levels of carrageenin.
Flunixin inhibits prostaglandin E2 production in equine inflammation.
A model of acute inflammation was used in a cross-over study in Welsh mountain ponies to assess the actions of flunixin meglumine on selected components of a localised inflammatory reaction induced by injecting 0.5 ml of a 2 per cent carrageenin solution into subcutaneously implanted tissue cages. Samples of exudate were harvested at predetermined times between three and 48 hours. Increases in leucocyte numbers and protein concentration were not prevented by flunixin treatment. Prostaglandin E2-like activity was present in exudates from untreated ponies with the highest mean concentration occurring at 12 hours. The production of prostaglandin E2-like activity by the inflamed tissues of treated animals was blocked by flunixin for at least 24 hours.
Paste preparation of phenylbutazone.
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Biochemical and haematological effects of a revised dosage schedule of phenylbutazone in horses.
Five pairs of matched horses were used to study the biochemical and haematological effects of a revised dosage schedule of phenylbutazone. One group of five horses received a phenylbutazone paste formulation daily for 12 days and a second group of five animals received a placebo preparation for a similar time. Some statistically significant differences were recorded from pretreatment levels in both groups of horses. These changes represented instability in baseline levels and could not be ascribed to phenylbutazone administration.
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.
Phenylbutazone in the horse.
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Pharmacokinetics of phenylbutazone and its metabolites in the horse.
Phenylbutazone was given orally to 2 groups of horses and the plasma levels of the drug and its 2 principal metabolites oxyphenbutazone and gamma-hydroxyphenylbutazone measured by high performance liquid chromatography. Animals in Group 1 received single oral doses in a range from 1.1 to 13.2 mg/kg and were sampled over the succeeding 24 h. Considerable individual variation was observed both in timing and magnitude of the plasma drug responses between horses, but 24 h after dosing a clear dose response relation was recorded. Group 2 horses were given the recommended therapeutic dosage regimen and sampled over 24 h periods twice weekly. After 4 days at 8.8 mg/kg in 2 divided doses mean peak plasma levels of phenylbutazone reached 24 micrograms/ml and showed evidence of cumulation. After 4 days at 4.4 micrograms/kg, peak plasma concentrations had fallen to 10 micrograms/ml and mean peak levels just failed to reach 4 micrograms/ml 3 days after reducing dosage to 2.2 mg/kg once daily. Plasma concentrations of oxyphenbutazone did not exceed 25 per cent of the parent drug and the gamma-hydroxy metabolite was only just detectable and never exceeded 1 microgram/ml.
Analysis of phenylbutazone and its metabolites by high performance liquid chromatography.
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