Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group.

OBJECTIVE: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms. STUDY DESIGN: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch. RESULTS: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P <.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups. CONCLUSION: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio.

Pharmacokinetic and pharmacodynamic comparison of an osmotic release oral metoprolol tablet and the metoprolol conventional tablet.

Four double-blind, Latin-square studies were conducted to compare the pharmacokinetics and pharmacodynamic bioavailability of metoprolol OROS (oral osmotic) and the conventional tablet (CT) of metoprolol. Metoprolol OROS (7/95 mg or 14/190 mg) was administered once daily in doses equivalent to 100 mg of metoprolol CT given once, twice, thrice, and four times a day. In all four studies, lower peak plasma concentrations and longer times to peak were observed after metoprolol OROS than after metoprolol CT, indicating a controlled-release profile for metoprolol OROS. beta-Adrenergic blockade, as measured by reductions in exercise heart rate, was lower after metoprolol OROS than after metoprolol CT, but metoprolol OROS provided a smoother and more sustained beta-blockade. All four doses of metoprolol OROS at steady state produced relative pharmacodynamic bioavailability that ranged from 87% to 104% of that produced by equivalent doses of metoprolol CT.

What happens to tablets and capsules in the stomach: endoscopic comparison of disintegration and dispersion characteristics of two microencapsulated potassium formulations.

Previously we investigated gastric emptying and distribution of a capsule formulation of microencapsulated KCl and found the drug was usually present in clumps of KCl crystals held in place by gastric mucus. We therefore investigated whether a tablet formulation of microencapsulated KCl would have improved dispersion. We characterized the intragastric disintegration of capsules and tablets of microencapsulated KCl in 12 subjects. The capsule formulation floated in the gastric pool; one end would adhere to the gastric mucosa and the motion of the tethered capsule would pull the end of the capsule off. The KCl crystals would then be deposited in a mass. In contrast, the tablet formulation sank to the anatomically most dependent portion of the stomach. The tablet rapidly became soft and fragile but, if allowed to remain in one place and minimally disturbed, required a median of 12 min to lose its shape. If allowed to reach the gastric antrum, the tablet was quickly ground by the antro-pyloric pump and widely dispersed. Once liberated in the stomach, the microencapsulated KCl crystals were bound into a more-or-less cohesive mass. The differences between KCl formulations, once the crystals were released, was minimal although the larger crystals from the tablet formulation appeared less adherent and cohesive; they dispersed more in a reticulated pattern when the stomach was distended. We conclude that formulation of a drug in a microencapsulated multiple-unit dosage form does not guarantee wide dispersion nor absence of high local concentration of drug.