The effect-kinetics of the new benzodiazepine midazolam was evaluated in six subjects after single oral (7.5 and 15 mg) and intravenous (0.075 mg/kg) doses and infusion programs. The drug is bound to plasma proteins by 94%, and less than 0.5% is excreted unchanged in urine. Hepatic elimination is rapid: t1/2 beta is 2.4 +/- 0.8 hr (mean +/- S.D) and total body clearance is 283 +/- 43 ml/min (plasma) or 502 +/- 105 ml/min (blood). This substantial first-pass effect leads to bioavailability of only 44%, despite very rapid absorption (t1/2abs = 0.23 +/- 0.37 hr) after oral dosing. There is good intraindividual linear correlations (r between 0.68 and 0.97) between plasma levels and dynamic effects, as assessed by the d2 letter cancellation test and a sedation index formed from visual analogue scales.

A randomized, multicenter comparison of two intrauterine contraceptive devices (IUDs) was carried out. Nine hundred thirty-seven women were fitted with a copper-releasing IUD, the Nova-T, and 1821 women with an IUD that releases 20 micrograms of levonorgestrel daily. After 36 months, the cumulative gross rates of amenorrhea and hormonal side effects were significantly higher in the levonorgestrel-IUD users. The cumulative 36-month gross pregnancy rate was 3.7 for the Nova-T and 0.3 for the levonorgestrel IUD (P less than .001), demonstrating the levonorgestrel IUD's high contraceptive efficacy. For the first time, a protective effect of the levonorgestrel IUD against pelvic inflammatory disease as compared with the Nova-T was seen statistically. The cumulative 36-month gross rate of pelvic inflammatory disease was 2.0 in Nova-T- and 0.5 in levonorgestrel-IUD users (P less than .013). This significantly lowered incidence of pelvic inflammatory disease may help to solve one of the major concerns associated with intrauterine contraception.

1 The hypokalaemia-inducing effects of two widely used inhaled antiasthmatic 132-adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2 Each drug was administered in three different doses, 400, 600 and 800 ,ug, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 ,ug in 1 h). The treatments were given at 1 week intervals in random order in a single-blind fashion. 3 The concentration of potassium in plasma was dose-dependently reduced by both drugs with peak effects 75-90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average ± s.d. reductions of 1.13 ± 0.32 and 0.67 ± 0.25 mEq l-1, respectively, after the highest doses, P < 0.05). Concomitantly, decreases were noted in the amplitude of the T-wave on the ECG. 4 The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic 132-adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5 Plasma renin activity, noradrenaline in plasma and heart rate were also dosedependently increased by the treatments, whereas blood pressure remained unaltered.6 While the clinical significance of hypokalaemia induced by inhaled 132-adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non-bronchial effects.

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