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Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.

Drug-induced parotitis is a relatively uncommon adverse drug reaction. Most of the data on drug-induced parotitis consist of isolated case reports with few attempts at rechallenge to confirm the aetiology. Phenylbutazone and oxyphenbutazone have a significant number of reports suggesting that these drugs may be implicated in causing parotitis. Antipsychotics, particularly thioridazine, have been associated with parotitis. Most of these reports relate the anticholinergic oral drying as a predisposing factor in the development of a parotid gland infection. There is inadequate literature on the histamine (H2) receptor blockers, interferon-alpha, doxycycline, trimipramine, nifedipine, methyldopa, nitrofurantoin, nicardipine, isoproterenol or ritodrine to link them as aetiological agents in the development of parotitis.

Non steroidal anti-inflammatory drugs (NSAID's) are one of the most commonly used agents in clinical practice today. All these drugs are known to produce gastro-intestinal lesions. In the present study we found that aspirin, indomethacin and phenylbutazone caused gastric mucosal damage in 90.9%, 100%, respectively while ibuprofen and paracetamol caused gastric mucosal damage in 33.3% and 37.5% respectively. Thus latter two drugs were safer NSAID's. Further more we have demonstrated that endoscopic monitoring of the patients on NSAID's is a sensitive method of early detection of gastric mucosal damage. This monitoring may be particularly valuable in high risk subjects on NSAID's.

A systemic availability study comparing an investigational buffered tablet formulation of oxyphenbutazone and a commercially available product, the efficacy of which has been well established by usage, is reported. The experiment was designed to dissociate formulation factors from all other sources of variation including differences between subjects, sexes, sequences of administration, experimental periods, as well as sex by sequence, sex by period, and sex by formulation interactions. Systemic availability was assessed by conventional pharmacokinetic techniques. Results show that buffering of a tablet formulation consistently increased the rate and degree of absorption. Although the relative magnitude of bioavailability indicators is slightly different according to the method of calculation, the estimates are always higher with the buffered formulation. No statistical difference was observed for plasma concentration-time profiles between sexes. The wide range of observed concentrations over the time interval of this study confirms other reports of individual variations in handling oxyphenbutazone. The differences noted between the two formulations may be attributed to faster dissolution rate characteristics and better dispersion of oxyphenbutazone. Some aspects of the clinical relevance of this situation are discussed briefly.

In a double-blind between-patient study of 69 patients with sports injuries of the knee, diclophenac sodium (Voltaren) was significantly superior to oxyphenbutazone (Tanderil) and placebo in improving the degree of swelling and the condition of the injured knee. Both drugs were superior to placebo with regard to analgesia by the second day of treatment. In addition, diclophenac sodium significantly improved the condition of the injured knee by the end of the trial. Three patients dropped out of the trial for reasons not related to the drug. Two patients in the diclophenac sodium group failed to complete the trial due to rapid recovery and 1 each in the diclophenac sodium and oxyphenbutazone groups because of poor tolerability. Nine patients who completed the trial reported mild to moderate side-effects, consisting mainly of drowsiness and nausea.

Thirty-one patients who suffered from various cancers in the pelvic region were treated in a double-blind clinical long-term study either with placebo, N-(2-methyl-3-chlorophenyl)-anthranilic acid (tolfenamic acid, Clotam) or oxyphenbutazone in order to diminish the local reactions after telecobalt therapy. The results were difficult to judge and no clear differences were seen between the groups. The side-effects were slight and unspecific, except gastrointestinal distresses, which occurred with both tolfenamic acid and oxyphenbutazone, but were more severe with the latter. No significant changes were seen in the blood counts, liver or kidney function tests with tolfenamic acid. In the oxyphenbutazone group S-ALAT, S-AFOS and direct bilirubin were slightly elevated. Blood in feces was more frequent in the drug-treated than in the placebo group. In the light of the present and earlier studies tolfenamic acid appears to cause less side-effects than oxyphenbutazone in prolonged treatment.

The histories of 269 patients whose death certificates did not mention a drug as the cause of aplastic anaemia or agranulocytosis were investigated. Eighty-three deaths were probably caused by drugs, the most common cause of aplastic anaemia being treatment with phenylbutazone (28 deaths) and oxyphenbutazone (11 deaths). Thirteen out of 17 deaths from agranulocytosis were attributed to co-trimoxazole treatment. A separate survey of general practitioners' prescriptions enabled the mortality to be estimated. With the addition of one death due to oxyphenbutazone and four deaths due to phenylbutazone that were reported independently to the committee, the mortality from oxyphenbutazone was 3-8 per 100 000 and from phenylbutazone 2-2 per 100 000. With phenylbutazone the rates varied from under 1 death per 100 000 for men aged under 65 years to 6 per 100 000 for women aged 65 and over. Small numbers precluded estimates for oxyphenbutazone in these subgroups, although a similar trend was suggested. No particular indication for treatment seems to carry a higher risk, the main concern being the use of these two drugs in elderly patients.

In 257 patients with primary or secondary infertility, tubal occlusion or impeded tubal patency was found. The patients received Bactrim or Tandearil and the tubal patency was retested. In a control group of 74 cases, 2 tubal patency tests were done without treatment. Following treatment with Bactrim, 40,4% of the previously occluded fallopian tubes were patent. Following treatment with Tandearil, 34% of the previously occluded tubes were patient. In the non-treated group, 25% of the cases showed tubal patency at the second patency test. The results were more striking for the cases with impeded tubal patency. The success rate was 73,3% following treatment with Bactrim, 50% following treatment with Tandearil and 26,7% in the untreated control group.

Fifty-nine patients on long-term treatment with phenylbutazone or oxyphenbutazone for chronic rheumatic conditions were switched to treatment with naproxen and followed-up for 6 months in a compliance study. All patients were started on 500 mg naproxen twice daily but adjustment of the dosage was permitted. During the 6 months of the study only 3 patients returned to treatment with phenylbutazone. Of the remaining 56 patients, 45 were still taking naproxen after 6 months, 9 were changed to other non-steroidal, anti-inflammatory drugs and 2 were lost to follow-up. The study demonstrates that in routine general practice, phenylbutazone and oxyphenbutazone can be successfully replaced by less toxic drugs.

A combined cholestatic-hepatocellular injury and noncaseating granulomas occurred in two patients 1 and 4 weeks after phenylbutazone therapy. Both patients were jaundiced, one had a macular rash, and both had peripheral blood eosinophilia. Symptoms and signs subsided, and abnormal findings from tests of hepatic function rapidly returned to normal following withdrawal of the drug. Sections of liver biopsy specimens 6 months later showed no granulomas or other pathologic changes. Previously reported cases are reviewed.

Fixed drug eruptions exclusively involving the genitalia of 60 male patients were investigated. Forty-two of the 60 patients completed tests designed to identify the causative drug. Tetracycline, aspirin, metamizole, and trimethoprim-sulfamethoxazole were found to be common etiologic agents. The sites affected were the glans penis, coronal sulcus, and preputial skin. Superficial ulceration or pigmented areas surrounded by an erythematous halo were the main clinical findings at the time of presentation.

A double-blind trial wa carried out in 30 in-patients, mainly with rheumatoid disorders, to compare the efficacy and tolerance of protacine with those of oxyphenbutazone. Patients were given oral doses either of 150 mg protacine or 200 mg oxyphenbutazone 3-times daily for 21 days. Clinical symptoms were assessed by semiquantitative scoring at 5-days' intervals. The same was done for side-effects. Protacine globally reduced the symptom scores by 55% and oxyphenbutazone by 34% (p < 0.001). Frequency and severity of side-effects were significantly less and less severe during protacine than during oxyphenbutazone treatment (p < 0.01). Physiological parameters did not vary during either treatment. Good efficacy, good tolerance and a convenient dose schedule suggest that protacine may well be suited also for long-term treatment.

A series of double-blind randomized trials was carried out in patients suffering from moderate to severe pain after meniscectomy to assess the analgesic effectiveness of diflunisal. In a single-dose study, 150 patients received either diflunisal (125 mg, 250 mg or 500 mg), aspirin (600 mg), or placebo, and hourly assessments were made of pain severity over an 8-hour period. The results showed that 500 mg diflunisal produced comparable relief to aspirin within 3 to 4 hours, but the analgesic effect continued for longer and was still very marked after 8 hours. A multi-dose study in 120 patients receiving doses of diflunisal (375 mg or 500 mg) or placebo confirmed the overall effectiveness of twice daily treatment with diflunisal. In a comparative study against oxyphenbutazone (200 mg t.i.d.), hourly pain scores made on the first post-operative day showed that a single dose of 500 mg diflunisal produced comparable relief over a 12-hour period to that with 2 doses of 200 mg oxyphenbutazone. Overall response to multiple doses was assessed as excellent or good by all the patients receiving diflunisal. Preliminary results are reported on the use of diflunisal in other painful conditions.

Animal experiments have shown that weekly intraarticular injections of various antiphlogistic/antirheumatic drugs into the knee joint induce progressive degenerative alterations in joint cartilage. The observed degenerations and destructions are most similar to the pathophysiology of osteoarthrosis in humans. By X-ray and macroscopic techniques the degenerative processes can be studied qualitatively and quantitatively. A decrease of joint space is a sensitive and early indicator of osteoarthrosis and showed that 10 weeks after intraarticular application of Ibuprofen, Phenylbutazone, Oxyphenbutazone, Flufenamic acid, Niflumic acid, Na-salicylate, Clofezone, Bumadizone and Dexamethasone the degenerative alterations in the injected knee joints were more severe than by applications of Chloroquine,D-penicillamine, Salicylamide and Indometacin. The degenerative effect on articular cartilage by the investigated drugs can be explained by their inhibitory potency on anabolic metabolism of connective tissue. The results of our animal experiments lead to the conclusion, that antiinflammatory drugs may also in man induce or accelerate degenerative joint diseases especially after long term treatment with high doses of these drugs.