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1.
Topically applied copper phenylbutazone, phenylbutazone, copper salicylate, salicylate and dimethylsulfoxide glycerol (80:20) were investigated as anti-inflammatory agents in rats and horses. Dimethylsulfoxide and glycerol (80:20) or dimethylsulfoxide, ethanol and glycerol (60:20:20) were used as the drug solvents. Subcutaneously administered carrageenin was used to induce inflammatory oedema, either in the paws of rats or the alar fold of the horse. The severity of the oedema and the anti-inflammatory effect of the drugs were assessed by measuring changes in the paw or alar-fold diameters. Copper salicylate and copper phenylbutazone were effective inhibitors of the inflammatory oedema in both species, but dimethylsulfoxide:glycerol (80:20) was not. In the rat, copper salicylate and copper phenylbutazone were superior anti-inflammatory agents compared to either salicylate or phenylbutazone, respectively. Following the topical application of four times the recommended daily dose of copper phenylbutazone to the horse for 5 days, minor skin irritation occurred and trace concentrations of phenylbutazone (maximum 0.6 microgram/ml) and negligible concentrations of oxyphenbutazone and gamma-hydroxyphenylbutazone were detected in the plasma.  相似文献   

2.
The disposition kinetics and systemic availability of phenylbutazone were studied in healthy dairy cows. The same dose (6mg/kg) of phenylbutazone was administered by the i.v., i.m. and oral routes. The elimination half time after intravenous administration ranged from 32.4 to 60.8h. The result suggested that the distribution of phenylbutazone in cows can be described by a two-compartment open model. Total body clearance of the drug had a mean value of 0.0016 ml/kg-h. The overall tissue to plasma level ratio (k12/k21-β), after distribution equilibrium had been attained was 0.64. Phenylbutazone was shown, by an equilibrium dialysis method, to be highly bound to plasma proteins (93%) at serum levels of 100 μ/ml. The systemic availability of phenylbutazone was 69% and 89% when administered orally and intramuscularly respectively. Animals receiving half the dose of phenylbutazone (3 mg/kg) intravenously did not differ from cows receiving 6 mg/kg in elimination half-life and other distribution and elimination kinetic parameters. Based on the experimental data obtained, a dosage regimen is proposed, consisting of a priming oral dose of 9 mg/kg and maintenance doses of 4.5 mg/kg of phenylbutazone orally administered at 48 h intervals. The relatively long half-life in cattle, however, complicates the use of phenylbutazone because of the drug residue problem.  相似文献   

3.
The clinically recommended dose rate of phenylbutazone (4.4 mg/kg) was administered intravenously as a single dose to five Welsh Mountain ponies. Distribution of phenylbutazone and its active metabolite oxyphenbutazone into body fluids was studied by measuring concentrations in plasma, tissue-cage fluid, peritoneal fluid and acute inflammatory exudate harvested from a polyester sponge model of inflammation. The ready penetration of phenylbutazone into inflammatory exudate was demonstrated by the relatively high mean value for Cmax of 12.4 μg/ml occurring at a time of 4.6 h and a mean AUQ)_24 of 128 μg-h/ml. A high mean exudate: plasma AUCo_24 ratio of 0.83 was recorded. Plasma: exudate concentration ratios for phenylbutazone were initially greater than and subsequently less than one; the slower clearance from exudate was indicated by approximate t½β values of 4.8 and 24 h for plasma and exudate, respectively. These findings may help to explain the relatively long duration of action of phenylbutazone, in spite of a plasma elimination half-life of less than 5 h. Lower values of Cmax and AUC0–24 for phenylbutazone passage into peritoneal fluid (6.3 μg/ml and 45 (μh/ml) were recorded, and a limited number of sampling times indicated a similar degree of penetration as into tissue cage fluid. Mean concentrations of oxyphenbutazone in all fluids were lower than phenylbutazone concentrations at all times, but ready penetration of the metabolite into body fluids, especially into inflammatory exudate, occurred suggesting that oxyphenbutazone may contribute to the anti-inflammatory effect. The hyperaemia of acute inflammation and the high protein levels in inflammatory exudate may both assist passage of phenylbutazone and oxyphenbutazone into exudate. The slower clearance of both compounds from exudate, periton?ceal fluid and tissue cage fluid than from plasma is similar to previous reports for other drugs.  相似文献   

4.
Randomized placebo-controlled crossover studies were carried out in dogs to evaluate how two non-steroidal anti-inflammatory drugs (NSAID) might modulate an acute post-traumatic inflammatory reaction. Two "identical" surgical interventions were performed on the forelimbs of each animal with an interval of 28 days, to enable a paired comparison of the inflammatory signs and the wound/bone healing processes. At one operation 8 dogs received 300 mg phenylbutazone twice daily for 8 days starting on the day before surgery, and at the other operation matching placebo tablets were given. In a similar placebo-controlled trial another group of 8 dogs received 5 mg indomethacin twice daily. With phenylbutazone the post-operative swelling was not significantly reduced compared to placebo, but there was less pain and limping. With indomethacin the swelling was somewhat reduced, but there was no consistent difference to placebo in the pain and limping assessments. None of the drugs appeared to distinctly effect the wound or fracture healing, as evaluated by clinical inspection, comparison of radiographs and comparison of bone sections from the sites of surgery. It proved difficult to select an appropriate dosage of indomethacin due to its high potential to induce GI ulceration and bleeding in dogs. In this experimental surgical model with an acute inflammation, neither phenylbutazone nor indomethacin showed impressive anti-inflammatory or analgesic properties. In the same model paracetamol has proved to significantly and more efficiently, reduce both swelling and pain without any noticeable adverse effects, and appears to be a better alternative than the two presently tested NSAID.  相似文献   

5.
Newer cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as firocoxib, are proposed to reduce inhibition of cyclo-oxygenase-1 (COX-1) and avoid undesirable side effects, while continuing to inhibit inflammation associated with COX-2. However, COX selectivity is typically based on in vitro testing, which may not provide sufficient information critical for treatment selection. This study investigated the pharmacokinetics and ex vivo COX-1 and COX-2 inhibition of phenylbutazone, flunixin meglumine, meloxicam and firocoxib. Horses (n = 3) were administered one of the four drugs, in a randomised cross-over design, with 3-week washout periods. For each drug, three doses were given and sampling performed. Drug plasma concentrations, thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were determined. After one dose, TXB2 and PGE2 levels were significantly higher in horses administered firocoxib compared to flunixin meglumine. Following the third dose, TXB2 levels in horses administered firocoxib and meloxicam were significantly higher compared to flunixin meglumine or phenylbutazone; all drugs reduced PGE2 to a similar degree. The mean plasma half-lives were 5.97 ± 0.47, 4.74 ± 0.14, 8.24 ± 3.74 and 47.42 ± 7.41 h for phenylbutazone, flunixin meglumine, meloxicam and firocoxib, respectively. Firocoxib and meloxicam exhibited significantly less COX-1 inhibition compared to flunixin meglumine and phenylbutazone; all drugs inhibited COX-2. The plasma half-life of firocoxib was longer than the other NSAIDs, including meloxicam. Data from this study have important clinical relevance and should be used to inform practitioners’ drug selection of a COX-1 sparing or traditional NSAID and dose selection and to provide knowledge of the duration for the four NSAIDs studied.  相似文献   

6.
Strøm, H. & Krogsgaard Thomsen, M. Effects of non-steroidal anti-inflammatory drugs on canine neutrophil chemotaxis. J. vet. Pharmacol. Therap. 13, 186–191.
Non-steroidal anti-inflammatory drugs exhibit differences in their ability to suppress polymorphonuclear leucocyte (PMN) functions in different species. The present study investigated the in-vitro and ex-vivo effects of phenylbutazone and flunixin on leukotriene-B4-directed migration of canine PMN. Furthermore, in-vitro comparison was made to indomethacin and the 5-lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA). In vitro , flunixin and NDGA were the most potent inhibitors, with IC 50s of 13 and 7 μmol/l, respectively. Phenylbutazone had an IC 50 of 42 μmol/l whereas indomethacin did not achieve 50% inhibition at concentrations less than 100 μmol/l. Ex vivo , flunixin almost completely abolished the LTB4 response at 1h, and still possessed significant inhibitory activity 24 h after a dosage of 1mg/kg i.v. Phenylbutazone was less active ex vivo but did suppress chemotaxis by 23% (P<0.05) at 1h following an i.v. dose of 20mg/kg. It is suggested that part of the anti-inflammatory action of flunixin in dogs may be attributed to inhibition of PMN recruitment.
M. Krogsgaard Thomsen, Department of Pharmacology, Leo Pharmaceutical Products, DK-2750, Ballerup, Denmark.  相似文献   

7.
Turpentine-induced acute inflammatory responses in chicks were studied experimentally. Foot pad oedema was measured using a plethysmograph. Skin vascular permeability was evaluated using the Evans blue technique. Turpentine injury induced a typical biphasic response when the two parameters of the inflammatory reaction were studied. Some unexpected alterations of the turpentine-induced inflammatory response were seen when chicks received non-steroidal anti-inflammatory drugs. Pretreatment with promethazine, phenylbutazone, methysergide and indomethacin resulted in a decrease in foot oedema. An inhibitory effect upon vascular permeability was found when promethazine, phenylbutazone and indomethacin were used. Methysergide did not inhibit the increase in vascular permeability of the skin. Possible mechanisms are discussed.  相似文献   

8.
Phenylbutazone in the horse: a review   总被引：3，自引：1，他引：2  
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)  相似文献   

9.
The direct effects of four non-steroidal anti-inflammatory drugs (NSAIDs) on equine polymorphonuclear (PMN) and mononuclear (MN) leucocyte movement were investigated using two in vitro assay systems. The Boyden chamber microfilter technique measures both chemokinetic and chemotactic locomotion, and the agarose microdroplet assay measures solely chemokinesis. Zymosan-activated plasma (ZAP) and the synthetic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) were used as standard chemoattractants for PMN and MN leucocytes, respectively. The actions of six concentrations of each NSAID, indomethacin (50 microM-10 mM), phenylbutazone (10 microM-1 mM), oxyphenbutazone (2.5 microM-500 microM) and flunixin (0.1 microM-50 microM), in suppressing cell movement induced by ZAP and FMLP were investigated. All four drugs exerted inhibitory effects on induced movement of both cell types in the Boyden chamber assay, usually in a concentration-dependent manner, although oxyphenbutazone action on PMN cells occurred only at the highest concentration tested. Significant inhibition of PMN and MN cell locomotion was produced by indomethacin, flunixin and oxyphenbutazone, and inhibition of PMN movement by phenylbutazone occurred in the agarose microdroplet assay. Flunixin was the most potent of the four drugs investigated in both assay systems. The findings may be of importance to the use of phenylbutazone and flunixin as NSAIDs in equine medicine, since the concentrations used were similar to concentrations of both drugs and the phenylbutazone metabolite oxyphenbutazone previously reported to occur in equine plasma and inflammatory exudate.  相似文献   

10.
According to a survey, non-steroidal anti-inflammatory agents were the most popular analgesic used in South Africa for management of peri-operative pain, acute post-operative pain and chronic pain. The most popular non-steroidal anti-inflammatory agents are flunixin meglumine and phenylbutazone. The most popular opioid type drug is buprenorphine, followed by morphine. In the peri-operative setting, analgesic agents were not actively administered to 86.3% of cats and 80.7% of dogs. Analgesic premedications were frequently administered, e.g. xylazine or ketamine, but no specific drug was administered for post-operative pain. Veterinarians need to critically review their anaesthetic and analgesic practices in order to achieve balanced anaesthesia.  相似文献   

11.
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.  相似文献   

12.
Moderate to severe ulcerative colitis of the right dorsal colon was diagnosed by necropsy or by exploratory celiotomy and biopsy in 13 horses with a primary clinical complaint of either colic, diarrhea, or weight loss. Clinical signs varied from acute fulminating diarrhea (possibly with fever), colic, dehydration, endotoxic shock and death, to a chronic condition manifested by mild intermittent colic up to several months in duration, and weight loss with or without mild diarrhea. In a large percentage of the horses, those affected had been hypovolemic and received nonsteroidal anti-inflammatory drugs (NSAID) or had received inappropriately high doses of phenylbutazone before the onset of illness. Experimental treatment of two horses with high doses of a phenylbutazone oral paste preparation (6 gm once daily for 5 days) and limitation of their water intake to approximately one half of maintenance requirement (for 5 days) resulted in reproduction of ulcerative colitis involving only the right dorsal colon, which was apparent at necropsy examination 11 and 15 days after initiation of drug use. It was concluded that localized ulcerative lesions in the right dorsal colon may be a previously unreported manifestation of toxicity due to the administration of NSAID.  相似文献   

13.
Carprofen, a non-steroidal anti-inflammatory drug (NSAID), was injected intravenously in six cows after calving, either as a single or a daily dose of 0.7 mg/kg for five days. Carprofen was well tolerated by the cows at this dose rate, the milk production and biochemical variables remaining within the normal ranges. The plasma elimination half-life of carprofen ranged from 44.5 to 64.6 h after repeated daily injections. These values are longer than those reported for other NSAIDs used in veterinary medicine, e.g. flunixin and phenylbutazone. The volume of distribution and the clearance values calculated after a single intravenous injection amounted to 0.09 l/kg and 9.0 ml/min. The concentration of carprofen in milk collected twice daily (morning and evening) was, in general, below the sensitivity limit of the analytical method (25 ng/ml) up to five days after the last carprofen injection; the concentration of carprofen reached about 30 ng/ml in only a few milk samples collected after the fourth or fifth injection. This indicates that carprofen is poorly excreted in the milk.  相似文献   

14.
The potential for interactions between chloramphenicol, phenylbutazone, acepromazine and thiamylal and chloramphenicol, rifampin, and phenylbutazone were evaluated in two groups of experiments. In the first, five horses were given thiamylal intravenously (iv) (6.6 mg/kg) after pretreatment with acepromazine, and the time of recumbency was determined. Administration of chloramphenicol iv (25 mg/kg) 1 h prior to anaesthesia significantly lengthened the recumbency time from 21.8 +/- 4.8 mins to 36.0 +/- 8.3 mins. There was an apparent but not statistically significant decrease in recumbency time when phenylbutazone (4.4 mg/kg) was administered iv daily for 4 days prior to anaesthesia. In the second series of experiments, phenylbutazone (4.4 mg/kg), chloramphenicol (25 mg/kg) and rifampin (10 mg/kg) were administered in various sequences to five different horses. Chloramphenicol pretreatment produced a significant decrease in the elimination rate and rifampin a significant increase in the elimination rate of phenylbutazone. The half-life of elimination of phenylbutazone alone was about 4 h. Following four days pretreatment with rifampin it was approximately 2.7 h, it was approximately 5.6 h and 9.5 h, respectively, when chloramphenicol was administered in one dose 1 h before or two doses 12 h and 1 h before phenylbutazone.  相似文献   

15.
The development of the palatine process in die presence of phenylbutazone and indomethacin was carried out in preparations collected at 13.5 days of gestation, followed by tissue culture in the mouse. It was demonstrated that both agents interfere with the normal development of the palate. The mechanisms which are apparently responsible for this abnormality are discussed.  相似文献   

16.
The pharmacokinetic parameters of phenylbutazone were determined in 18 elephants (Loxodonta africana and Elephas maximus) after single-dose oral administration of 2, 3, and 4 mg/kg phenylbutazone, as well as multiple-dose administrations with a 4-wk washout period between trials. After administration of 2 mg/kg phenylbutazone, mean serum concentrations peaked in approximately 7.5 hr at 4.3 +/- 2.02 microg/ml and 9.7 hr at 7.1 +/- 2.36 microg/ml for African and Asian elephants, respectively, while 3 mg/kg dosages resulted in peak serum concentrations of 7.2 +/- 4.06 microg/ml in 8.4 hr and 12.1 +/- 3.13 microg/ml in 14 hr. The harmonic mean half-life was long, ranging between 13 and 15 hr and 39 and 45 hr for African and Asian elephants, respectively. There was evidence of enterohepatic cycling of phenylbutazone in Asian elephants. Significant differences (P < 0.0001) in pharmacokinetic values occurred between African and Asian elephants for clearance (27.9 and 7.6 ml/hr/kg, respectively), terminal half-life (15.0 and 38.7 hr, respectively), and mean residence time (22.5 and 55.5 hr, respectively) using 2-mg/kg dosages as an example. This suggests that different treatment regimens for Asian and African elephants should be used. There were no apparent gender differences in these parameters for either elephant species.  相似文献   

17.
Tissue irritation after intramuscular injections of 4 nonsteroidal anti-inflammatory agents was studied in 5 lactating cows. Preparations containing phenylbutazone, flunixin, metamizole (dipyrone) and ketoprofen were investigated; physiological saline was used as a control substance. Tissue reactions at the injection sites were examined by palpation and by determining serum creatine kinase. A kinetic method based on creatine kinase released from the injured muscle tissue was used, which allowed estimation of the amount of damaged muscle. The metamizole preparation clearly provoked signs of pain all the cows. After flunixin and phenylbutazone injections slight reactions were observed, and ketoprofen and saline did not cause any clinical signs. Some palpatory findings after injections were found for all the preparations except saline. Based on serum creatine kinase, the 2 most irritating preparations were the ones containing flunixin and phenylbutazone. After injections of these 2 substances, the estimated amount of damaged muscle was about 80 grams. The statistical difference between flunixin and phenylbutazone and the other 2 preparations was significant. Physiological saline had no effect on serum creatine kinase. For preparations containing phenylbutazone and flunixin, intravenous administration is recommended.  相似文献   

18.
The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.  相似文献   

19.
Five ewes were injected with two doses of a nonsteroidal anti-inflammatory drug (NSAI), lysine acetyl salicylate, at birth of their first lamb and one hour later, and five others were injected once only, at birth of their first lamb. A control group of six animals was constituted. The times needed for fetal expulsion and placental release were recorded. The peripheral plasma PgF2 alpha (as PGFM) levels were measured prepartum during the seven last days of gestation, at parturition, then 1 h, 2 h and 12 h after lambing. The results were compared among and within treatment groups. They indicate that the physiological increase in peripheral PGFM levels starts two days before lambing and that the level peaks at lambing. The normal decrease after parturition is emphasized by NSAI injections as detected 1 h and 2 h posttreatment (p < 0.01). The NSAI drug is short-acting as revealed by the lower PGFM levels in twice-treated animals 2 h after birth compared to once treated animals and the similar low levels in all three groups 12 h after birth. The fetal membranes were expelled normally in all treated and nontreated animals, but the time needed for placental expulsion in ewes injected with two doses of NSAI was longer than in controls (p < 0.05). A negative correlation (p < 0.05) was found between plasma PGFM levels measured two hours after lambing and the time needed for fetal membrane expulsion. PgF2 alpha appears to have a role in placental release in the ewe.  相似文献   

20.
Biochemical and haematological effects of phenylbutazone in horses   总被引：1，自引：0，他引：1  
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.  相似文献   

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