A clinical and pharmacokinetic evaluation of tolmesoxide in hypertensive patients

The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and diuretic. After a 50 mg oral dose mean (+/- SD) peak plasma concentration of T was 1.13 +/- 0.29 micrograms/ml-1 and occurred 0.79 +/- 0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37 +/- 0.09 micrograms/ml-1 at 1.92 +/- 1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78 +/- 0.77 h and 10.78 +/- 7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50--200 mg t.i.d. During in-patient administration of 600--900 mg T daily (n = 6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n = 4) was associated with a significant fall in mean systolic but not diastolic by (lying -15/+1 mm Hg. standing -25/-8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean +/- SD) significantly from 55 +/- 5/min to 66 +/- 8/min following 900--1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600--900 mg daily eventually necessitated drug withdrawal. In its present form T is not recommended for the treatment of hypertension.