Antirheumatic effect of pirfenidone in a double blind clinical pilot trial in humans.

The antirheumatic effect of pirfenidone was compared with a positive control drug, oxyphenbutazone which is used in patients suffering from rheumatoid arthritis, in a double blind clinical trial in humans. The data collected in this pilot project revealed that pirfenidone was more effective (p < 0.025) than oxyphenbutazone in providing relief from arthritic pain. In addition, a greater number (p < 0.025) of patients reported favorable response to oral pirfenidone than oral oxyphenbutazone. However, there were no significant differences in the number of patients who dropped out from the trial and the number of patients who tolerated the drugs for 21 days of the trial between the pirfenidone and oxyphenbutazone groups. It was concluded from this pilot study that pirfenidone potentially offers a novel therapeutic modality for the management of rheumatoid arthritis with little or no adverse effects unlike steroidal and non-steroidal anti-inflammatory drugs which are frequently used for this chronic debilitating disease.

Evaluation of dosage forms. VI. Studies of commercial oxyphenbutazone tablet dosage forms.

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and Cmax.

Pharmacokinetics of phenylbutazone in camels.

OBJECTIVE: To document disposition variables of phenylbutazone and its metabolite, oxyphenbutazone, in camels (Camelus dromedarius) after single i.v. bolus administration of phenylbutazone, with a view to making recommendation on avoiding violative residues in racing camels. ANIMALS: 6 healthy camels (4 males, 2 females), 5 to 7 years old, and weighing from 350 to 450 kg. PROCEDURE: Blood samples were collected to 0, 5, 10, 15, 45, and 60 minutes and at 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 26, 28, 30, 40, 48, 50, 53, and 60 hours after i.v. administration of 4.5 mg of phenylbutazone per kg of body weight. Urine was obtained in fractions during the entire blood sample collection period. Serum and urine phenylbutazone concentrations were measured by high-performance liquid chromatography; assay sensitivity was 100 ng/ml. Serum oxyphenbutazone concentration was measured by gas chromatography/mass spectrometry; assay sensitivity was 10 ng/ml. RESULTS: Disposition of phenylbutazone was best described by a two-compartment open model. Mean +/- SEM elimination half-life was 13.44 +/- 0.44 hours. Total body clearance was 12.63 +/- 1.64 mg/kg/h. Renal clearance was between 0.3 and 0.4% of total body clearance. The elimination half-life of oxyphenbutazone was 23.9 +/- 2.09 hours. CONCLUSIONS: The elimination half-life and total body clearance of phenylbutazone in camels are intermediate between reported values in horses and cattle. Extrapolation of a dosage regimen from either species to camels is, therefore, not appropriate. Elimination of phenylbutazone in camels is mainly via metabolism. Owing to the long half-life of phenylbutazone and of oxyphenbutazone, and to the zero drug concentration regulation adopted by the racing commissioner in the United Arab Emirates, practicing veterinarians would be advised not to use phenylbutazone in camels for at least 7 days prior to racing.

Pharmacokinetic and pharmacodynamic studies on phenylbutazone and oxyphenbutazone in goats.

Phenylbutazone was administered intravenously and orally to six goats as a single dose of 4.4 mg/kg and its disposition and bioavailability and the disposition of its active metabolite, oxyphenbutazone, in plasma were investigated. The effect of the administration of the drug of oxyphenbutazone on ex vivo serum thromboxane (TX)B2 generation in platelets was also studied. Phenylbutazone was eliminated slowly with mean (se) elimination half-lives (t1/2 beta) of 15.3 (1.15) hours and 22.0 (3.32) hours after intravenous and oral administration, respectively. The bioavailability of phenylbutazone paste administered orally was 61 (7) per cent (corrected by the t1/2 beta) and relatively slow absorption was observed, as indicated by a time of maximum drug concentration (tmax) of 3.47 (0.39) hours and a mean absorption time (MAT) of 10.4 (8.61) hours. The concentration of oxyphenbutazone in plasma was low and the ratio of the areas under the curve (AUC) of oxyphenbutazone to phenylbutazone was approximately 0.02:1 after both intravenous and oral administration. Thromboxane B2 generation in the platelets was significantly inhibited (P < 0.05) from one to 12 hours after intravenous administration and from two to 12 hours after oral administration. The results suggest that phenylbutazone is a potentially useful non-steroidal anti-inflammatory drug for use in goats by either route of administration.

Comparative pharmacokinetics of phenylbutazone and its metabolite oxyphenbutazone in clinically normal horses and donkeys.

OBJECTIVE: To compare plasma disposition of phenylbutazone and its metabolite oxyphenbutazone after i.v. administration of phenylbutazone in horses and donkeys. ANIMALS: 4 clinically normal horses and 6 clinically normal donkeys. PROCEDURE: Blood samples were collected from each animal at time 0 (before) and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after i.v. administration of a bolus dose of phenylbutazone. Serum was analyzed in triplicate by use of high-performance liquid chromatography for determination of phenylbutazone and oxyphenbutazone concentrations. The serum concentration-time curve for each horse and donkey was analyzed separately to estimate model-independent pharmacokinetic variables. RESULTS: Significant differences were found in several pharmacokinetic variables of phenylbutazone and oxyphenbutazone in horses, compared with donkeys. Mean total body clearance of phenylbutazone in horses was fivefold less than that in donkeys (29.3 and 170.3 ml/kg/h, respectively). Mean values for area under the curve and mean residence time in horses (118.3 micrograms/h/ml and 3.6 hours, respectively) were significantly greater than values in donkeys (28.3 micrograms/h/ml and 1.7 hours, respectively). Mean values for apparent volume of distribution at steady state were not significantly different between horses and donkeys. For oxyphenbutazone, mean time to peak concentration in donkeys was significantly less than that in horses (1.6 and 6.4 hours, respectively). CONCLUSION: Phenylbutazone clearance in donkeys was higher than that in horses, and appearance of the metabolite oxyphenbutazone in serum was more rapid in donkeys than in horses, indicating that hepatic metabolism of phenylbutazone is more rapid in donkeys than in horses. CLINICAL RELEVANCE: Because serum concentration of phenylbutazone after single i.v. bolus administration (4.4 mg/kg of body weight) decreases more rapidly in donkeys, compared with horses, phenylbutazone may require more frequent administration in donkeys to achieve therapeutic efficacy.

A new approach to encapsulating nonsteroidal anti-inflammatory drugs. IV. Effect of cellulose derivatives with different functional groups on the bioavailability and gastric ulcerogenic activity of acidic as well as basic nonsteroidal anti-inflammatory drugs.

The bioavailability and gastric ulcerogenic activity of oxyphenbutazone and glafenine (acidic and basic nonsteroidal anti-inflammatory drugs), coated with different cellulose derivatives were assessed in albino rats. The cellulose derivatives chosen have different functional groups, acidic (carboxymethyl cellulose), basic (chitosan) and neutral (hydroxypropylmethyl cellulose). The bioavailability was dependent on the drug and polymers. Generally, all the cellulose derivatives chosen decreased the gastric ulcerogenic activity of the drugs studied.

Plasma and serum concentrations of phenylbutazone and oxyphenbutazone in racing Thoroughbreds 24 hours after treatment with various dosage regimens.

The plasma and serum concentrations of phenylbutazone (PBZ) and oxyphenbutazone were measured in 158 Thoroughbred horses after various doses of PBZ wer given. All horses were competing or training at racetracks in various parts of the country. All horses used in the study had not been given PBZ 24 hours before they were placed on a specific dosage schedule. Samples were collected 24 hours after the last PBZ administration. Four grams of PBZ were given daily by stomach tube, paste, or tablet for 3 days. On day 4, 24 hours before sample collection, an IV dose of 2 g of PBZ was given, regardless of the dose and method of administration. The 24-hour PBZ plasma concentrations were 3.51, 6.13, and 6.40 micrograms/ml, respectively. After 2 g of PBZ was administered IV daily for 4 days, the plasma PBZ concentration was 4.16 g/ml; after a single 2-g IV administration, the serum concentration was 0.87 g/ml. Concentrations of oxyphenbutazone were 3.35 (stomach tube), 4.29 (paste), 3.60 (tablet), 3.65 (4-day IV), and 1.11 g/ml (single IV). A significant relationship was not found between the serum and the urinary concentrations at this 24-hour measurement. Split samples sent to various laboratories confirmed the stability of high-performance liquid chromatography as a method of analysis.

Survey of orthopaedic surgical research in a university center (Linköping).

Since 1969, seven orthopedic dissertations on the following subjects were submitted from the author's hospital. Postoperative use of special elastic bandages and oxyphenbutazone significantly decreased the frequency of thrombosis. Use of a randomized single-blind technique significantly improved chronic cases of lumbago by a new traction treatment called auto-traction. Two control groups were treated by bed rest and analgesics or routine physiotherapy measures. With a new mechanical device for tibial osteotomy, the precision of the angular change was significantly increased. In intracapsular hip fractures treated by Deyerle's technique, only 18% had necrosis of the femoral head after two years. By use of a new radiologic method for determining the stability of tibial fractures it was possible to determine a stability quotient; the quotient established the point at which the fracture could be mobilized without risk of delayed union or pseudarthrosis. In shoulder joint dislocations, three to four weeks of immobilization resulted in a recurrence rate equal to that of ordinary treatment in a sling. In a randomly selected group of people in Sweden, the incidence of shoulder dislocations was 2%. Forty percent of these patients had never seen a doctor. In Colles' fracture, the uptake of radioactive Tc-MDP was significantly increased by treating the fracture with electromagnetic fields. Arthroscopic percutaneous meniscectomies reduced the operation time normally required for an arthrotomy by an average of 30 minutes.

Availability of oxyphenbutazone from different suppository formulations.

The in vitro release of oxyphenbutazone as well as its rectal absorption in rabbits from different suppository formulations were investigated. It was proved that polyethylene glycol base gave higher medicament release than adeps solidus base. Incorporation of nonionic surfactants in Witepsol H 15 increased or decreased oxyphenbutazone release while incorporation of hydrophilic aerosil caused a reduction in the released amount of the medicament. A mixture of Witepsol H 15 or H 12 and Brij 58 (85:5) gave the highest in vitro release and the highest rectal absorption of the medicament. A correlation was found to exist between the in vitro release of oxyphenbutazone and its rectal absorption in rabbits.

[Treatment of typhoid fever with chloramphenicol or ampicillin combined with oxyphenbutazone]. / Tratamiento de las fiebres tíficas con cloranfenicol o ampicilina asociados a oxifenbutazona.

Ninety-four patients with typhoid fever were treated, at random, with three therapeutic regimens: chloramphenicol alone, chloramphenicol plus oxyphenbutazone, and ampicillin plus oxyphenbutazone. The results are evaluated analyzing the body temperature graph and by serial blood had bone marrow cultures taken at intervals until they became negative. Bacteriologic diagnosis was confirmed by blood culture (39.3%) and/or bone marrow culture (77%). The mean duration of fever was 3.3 days for the group treated with chloramphenicol-oxyphenbutazone, 4.3 for those with chloramphenicol alone and 5 days for the group ampicillin-oxyphenbutazone; at the same time, blood cultures became negative at 4.4, 5.5 and 4.4 days respectively. Negativization of bone marrow cultures was not influenced by the addition of oxyphenbutazone. It is concluded that the influence of oxyphenbutazone in shortening the febrile period or in the negativization of blood cultures is not significant. It is considered that oxyphenbutazone is not an important therapeutic tool in this group of diseases.

Tanderil/chloramphenicol eye ointment in the treatment of the "Red Eye" seen in general practice.

An open study is reported in which 35 general practitioners treated 128 patients suffering from 'Red Eye' with a new eye ointment containing 10% Tanderil(oxyphenbutazone) and 1% chloramphenicol. One hundred and seventeen patients completed the seven day treatment period, in which time 99 had completed resolution of the symptoms and were discharged, the remaining 18 patients needed a longer period of treatment. Eleven patients failed to complete the study period, of whom 5 patients were subsequently referred to a specialist and 6 had their treatment changed by the general practitioner. Six patients showed signs of allergy to the ointment, all of whom were being treated for allergic conjunctivitis. Seventeen per cent of patients had some difficulty in applying the eye ointment or complained of subsequent blurring of vision.