Nabumetone therapy of osteoarthritis. A six-week, placebo-controlled study.

Following a washout period, one hundred six patients with osteoarthritis were randomly assigned single daily doses of either 1,000 mg of nabumetone or placebo given at bedtime as part of a six-week, controlled, double-blind study. Forty-seven patients received nabumetone, whereas 48 patients were given placebo. Treatment groups were comparable for demographic characteristics, baseline efficacy assessments, and diagnostic criteria for osteoarthritis. Nabumetone-treated patients had absolute improvement, as well as relative improvement in comparison with placebo, both clinically and statistically. There were no clinical or statistical differences in safety variables between the two groups. When given once daily at bedtime, nabumetone was effective and had a good safety profile in patients with osteoarthritis.

Auranofin versus placebo in the treatment of rheumatoid arthritis.

In a six-month, multicenter, double-blind study involving 340 patients, auranofin, 3 mg twice daily, was compared with placebo in the treatment of adult-onset rheumatoid arthritis. All patients were continued on a therapeutic regimen of salicylates and/or a newer nonsteroidal anti-inflammatory drug. Patients in both treatment groups who completed six months of therapy with coded medications showed significant improvement in the clinical features of rheumatoid arthritis (that is, number of tender and swollen joints, severity of pain, grip strength and duration of morning stiffness); however, the mean improvement was greater in the auranofin-treated group. Fifty-two percent of the auranofin-treated patients compared with 24 percent of the placebo-treated patients (p less than 0.05) were judged by their physician to have shown marked or moderate improvement. Only in the auranofin-treated patients was there significant improvement from baseline in the laboratory parameters of disease activity: erythrocyte sedimentation rate, IgA, IgG, and IgM. After at least three months of therapy, 30 percent (46 of 152) of the placebo-treated patients but only 9 percent (13 of 152) of the auranofin-treated patients (p less than 0.05) withdrew from coded medication due to insufficient therapeutic effect. Study medication was discontinued by 5 percent (eight of 152) of the auranofin-treated patients and 3 percent (four of 152) of the placebo-treated patients because of adverse therapy events (p = 0.24). This study demonstrates the efficacy of auranofin when added to salicylates and/or nonsteroidal anti-inflammatory drugs in the treatment of rheumatoid arthritis.

A double-blind comparison of high and low doses of levamisole in rheumatoid arthritis.

A randomized, double-blind study was performed to compare the efficacy of 2 different regimens for levamisole in the treatment of rheumatoid arthritis over a period of six months. A dose of 150 mg once weekly was shown to be less efficacious than 150 mg on 3 consecutive days. Although the low dose produced fewer adverse effects, only subjective improvement was demonstrated. Only 14% of patients responded to the low dose, according to defined criteria, compared with 45% response to the high dose.

Basis of observed resistance of L1210 leukemia in mice: methotrexate, 6-thioguanine, 6-methylmercaptopurine riboside, 6-mercaptopurine, 5-fluorouracil, and 1-beta-D-arabinofuranosylcytosine administered in different combinations.

Schmid et al. (Cancer Treat. Rep., 60: 23-27, 1976) reported rapid emergence of resistance of L1210 leukemia cells in mice to two schedules of six antimetabolites and much slower development of resistance to a third schedule. Such rapid development of resistance to six drugs presents a striking puzzle, and one whose solution gives some insights into the basis for general emergence of drug resistance. Our approach was to examine the consequences of applying these drugs singly or in pairs and, from the results, to infer interactions in six-drug combinations. 6-Thioguanine (TG) and 6-mercaptopurine are the key drugs since, as shown by Schmid et al., resistance of leukemic cells appeared to six-drug combinations at the same time as did resistance to the purine analogs; sensitivity to the other drugs remained. We demonstrated that cells which emerged were resistant to both of the purine analogs, owing to a deficiency of the activating enzyme hypoxanthine-guanine phosphoribosyltransferase. TG resistance arose in the presence of TG because of an overgrowth of TG-resistance mutants that were present as one cell in 10(4) in the original L1210 population. L1210 cultures were prepared free of TG-resistant mutants. With these cells, TG administered shortly after inoculation was very effective in delaying their death. The cells that finally grew out were still TG sensitive. Simultaneous treatment with all the drugs greatly delayed appearance of TG resistance in vivo and in vitro. Methotrexate alone was responsible for this result, owing to its ability preferentially to kill TG-resistant cells. The other three drugs were not effective in delaying TG resistance. Methotrexate was effective only if it was added daily; one large injection was ineffective. Therefore, TG and methotrexate added daily for 6 days (simultaneous schedule) was the most effective drug regimen tested.

Crossover comparison of benoxaprofen and naproxen in osteoarthritis.

A total of 30 patients participated in a double-blind crossover trial to compare the efficacy and safety of benoxaprofen with naproxen in the treatment of osteoarthritis. Benoxaprofen, 600 mg administered once daily, was as effective as naproxen, 250 mg administered twice daily. Adverse reactions were mostly mild to moderate in severity and the incidence of the reactions was similar for the 2 study drugs. The advantage of the once-a-day dose regimen of benoxaprofen is discussed.

Clinical comparative evaluation of choline magnesium trisalicylate and acetylsalicylic acid in rheumatoid arthritis.

A multicentre double-blind comparison of choline magnesium trisalicylate (CMT) and acetylsalicylic acid (ACSA) compared the two medications for seven weeks in rheumatoid arthritis patients. Investigators measured the number of painful and swollen joints and the duration of morning stiffness, and assessed the overall condition of each patient. Both medications were highly effective in significantly reducing the severity of symptoms flaring after interruption of prior therapy. CMT achieved a greater reduction in the number of swollen joints than did ACSA (P less than 0.05). The incidence of adverse side-effects per patient was significantly less with CMT (P less than 0.05) (ACSA 32.1%; CMT, 16.3%. A larger percentage of ACSA patients (50.8%) reported adverse side-effects than did CMT patients 28.4%) (P less than 0.02).

Fenoprofen calcium in steroid treated rheumatoid arthritis: efficacy, safety, and steroid-sparing effect.

Twenty-one patients with active rheumatoid arthritis on maintenance corticosteroids were studied during a double-blind, crossover trial with fenoprofen. Fenoprofen showed significantly greater effect than did placebo on several subjective and objective measurements. In addition, patients were able to reduce their dose of corticosteroid to a level significantly lower than that during placebo periods. Though three patients dropped out of the study with gastrointestinal complaints while on fenoprofen, only one of these was believed to be drug-related. No serious adverse effects were encountered.

Ibuprofen or aspirin in rheumatoid arthritis therapy.

Ibuprofen is a nonsteroidal drug with analgesic, antipyretic, and anti-inflammatory properties that was recently introduced for use in antiarthritis therapy in the United States. In a year-long double-blind multiclinic trial in 885 patients with rheumatoid arthritis, ibuprofen was at least as satisfactory as aspirin, considering both efficacy and tolerance. In the majority of patients, daily doses ranged from 800 to 1,600 mg of ibuprofen and 3 to 6 gm of aspirin. The drugs did not differ greatly in providing relief from arthritis symptoms, but ibuprofen was definitely better tolerated, especially in regard to gastrointestinal complaints. Seven percent of the ibuprofen group dropped out of the study because of adverse reactions, as compared with 16% of the aspirin group; 17% of the ibuprofen group and 31% of the aspirin group had gastrointestinal symptoms.