Twenty-one patients with rheumatoid arthritis were given indomethacin 25 mg t.i.d. by mouth for 3 weeks followed by indomethacin 25 mg t.i.d. plus a 100 mg suppository at night, after a 5-day period on placebo capsules. The mean (±S.E.) 24-hour creatinine clearance was 57.8 ± 5.7 ml/min in the placebo period and was not significantly altered during indomethacin therapy, 53.1 ± 5.5 ml/min in the oral period and 56.6 ± 6.4 ml/min in the oral plus suppository period (P > 0.1). In 6 volunteers, duplicate 2-hour creatinine clearances were performed after a single oral dose of 50 mg indomethacin. After placebo capsules the mean creatinine clearance was 133.7 ± 9.5 ml/min and after 50 mg indomethacin it was 126.5 ± 8.9 ml/min (P > 0.1). In 4 of the volunteers the mean creatinine clearance after 8 days on indomethacin 25 mg q.i.d. was 117.1 ± 5.3 ml/min (P > 0.1). Indomethacin plasma concentrations were in the usual range for the dose given. Indomethacin caused no reduction in the creatinine clearance in spite of causing significant inhibition of prostaglandin E synthesis.
Ten male patients with chronic stable angina pectoris completed a randomized, double-blind cross-over study, with matched placebo run-in period (P), to compare the effects of a long-acting preparation of propranolol (LA, 160 mg once a day) with that of conventional propranolol (CP, 40 mg four times a day) each given for 14 days. Response was assessed by symptom-limited bicycle ergometry, degree of ST segment depression, daily anginal attack rate and glyceryl trinitrin consumption (GTN). Heart rate and ventricular extra-systolic frequency (VES) were recorded by 24 h Holter monitor. Bicycle ergometry was performed and a trough blood sample taken for propranolol estimation on day 14 prior to the morning dose. Both formulations increased total work capacity (P 3412, LA 4095, CP 3697 kpm/min), reduced rate-pressure product (P 21896, LA 16011, CP 15609 mm Hg beats/min), and degree of ST segment depression (P 4.53, LA 2.48, CP 2.43), but without differences between the formulations. Daily anginal attack rate was reduced from 30 (placebo) to 7.5 (CP) and 14.5 (LA) (P less than 0.05 between treatment groups). There was a reduction in daily GTN consumption by both treatments. The heart rate and total number of VESs during 24 h was similar in the two treatment groups and was reduced in comparison with placebo. Both formulations were well tolerated. Long-acting propranolol is an effective and well-tolerated alternative to conventional propranolol in the treatment of chronic stable and stress-induced angina, and in reducing VES frequency.
A multicentre study of survivors of an anterior myocardial infarction is reported. The trial consisted of 720 patients and was a double-blind, placebo-controlled study with propranolol 40 mg three times a day. Trial entry was at two to 14 days (mean 8.5 days) and follow-up at one, three, and in most centres, six and nine months. The trial was designed to detect a 50 per cent reduction in mortality and this was not shown. The non-fatal reinfarction rate was similar in both groups. Subgroup analysis identified several prognostic risk factors for death, none of which interacted with treatment.
Fifteen patients with rheumatoid arthritis received indomethacin in three treatment schedules; indomethacin retard 75 mg twice daily; indomethacin capsules 50 mg three times daily; and indomethacin 100 mg suppository at night with 50 mg by mouth each morning. The study was a double‐blind, double‐dummy one with each treatment being given for 2 weeks after a washout period of 3 days. After the washout period, and at the end of each 2 week active treatment period, blood samples were taken during a dosage interval for assay of indomethacin concentrations in plasma. Clinical assessments were also performed. All three treatment period produced significant clinical improvements in the assessments compared with the placebo washout period. However, no differences were seen between the treatments. Side effects occurred with equal frequency in all three periods, and the anticipated reduction in central nervous system side effects during the indomethacin retard period was not seen. Plasma concentrations of indomethacin were significantly higher during indomethacin retard therapy with a peak concentration of 2500 +/‐ 25 ng ml‐1 during indomethacin retard therapy (mean +/‐ s.d.) and 1900 +/‐ 200 ng ml during conventional oral therapy. Indomethacin retard is as effective as the other formulations of indomethacin but appears to offer no significant advantages.
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