Pharmacokinetics of the enantiomers of indoprofen in man.

Indoprofen, a non-steroidal analgesic and antiinflammatory drug whose activity and safety in man have been established in a large number of studies, has an asymmetric carbon atom and can therefore occur as either the (+) or the (-) enantiomer. As it has been shown that its pharmacological effects are almost entirely due to the (+) isomer (d-indoprofen), some pharmacokinetic properties of the latter have been studied in man in comparison with the racemic mixture given by oral administration, d-indoprofen is cleared from plasma and excreted in urine (as unchanged plus conjugated drug) at a slower rate than l-indoprofen. Moreover, no stereospecific inversion of d-indoprofen to the inactive enantiomer occurs after either single or repeated (one week) administration. The pharmacokinetic behaviour of d-indoprofen in the human organism appears to be the same after administration of the racemic form or of the dextro-enantiomer, when the latter is given at half the dose.

Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to intravenous tyramine in man.

1 Caroxazone is a new antidepressant drug with reversible MAO-inhibitory activity. 2 The pressor effect of intravenously injected tyramine has been evaluated in six male healthy volunteers before, during oral treatment with caroxazone 200 mg three times daily and at different time intervals after discontinuation of treatment. 3 Caroxazone produces a moderate tyramine supersensitivity. 4 The reversibility of MAO-inhibition produced by caroxazone is clearly reflected by the time-course of tyramine supersensitivity. In fact, tyramine potentiation does not accumulate with caroxazone cumulative dose, while it is correlated to drug plasma levels and disappears rapidly (half-life 1.5 days) upon discontinuation of treatment. 5 caroxazone seems to be safer and more manageable than all other clinically available MAO-inhibitors which produce irreversible inactivation of MAO.

Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to oral tyramine in man.

1 A double-blind, placebo-controlled study was carried out in order to investigate the effects of caroxazone, a new antidepressant drug endowed with a reversible short-lasting MAO-inhibitory activity in man, on the blood pressure response to tyramine administered by the oral route. 2 The study was carried out in 9 healthy volunteers who were randomly assigned to treatment with caroxazone 200 mg three times daily (7 subjects) or with indistinguishable placebo (2 subjects). 3 The sensitivity to tyramine was assessed in each subject both before and after the 7-9 days of treatment. 4. While placebo did not modify the pressor response to tyramine, the threshold dose of tyramine which induced a rise in systolic blood pressure was lowered by about four-fold in 6 out of the 7 subjects treated with caroxazone. In the seventh subject the observed potentiation of peroral tyramine was not quantitatively evaluable. 5 Challenges performed in three subjects after discontinuation of treatment with caroxazone show that the effects of the compound are short-lasting, since the sensitivity to tyramine seems to regain the baseline value within 1-2 days. 6 Even if caroxazone potentiates peroral tyramine to a relatively low degree, a tyramine poor diet is recommended for patients during caroxazone treatment. 7 The reversibility of the MAO-inhibitory action of caroxazone is confirmed by the rapid return to normal values in the response to tyramine after discontinuation of treatment. This property of caroxazone would allow patients to return to a free diet in much less time than the safety limit of 2 weeks recommended for the currently used irreversible MAO-inhibitors.

Effects of a new glucocorticoid, oxazacort, on some variables connected with bone metabolism in man: a comparison with prednisone.

The urinary elimination of calcium, other electrolytes, and hydroxyproline and the oral absorption of 47Ca have been evaluated in three groups of 8 patients before and during a 15-day treatment with prednisone at daily doses of 25 and 50 mg and with oxazacort, a new glucocorticoid, at a daily dose of 50 mg. The results obtained demonstrate that oxazacort in short-term teatment with a high dose has no significant effect on the urinary elimination of calcium and hydroxypyroline in experimental conditions in which prednisone produces statistically significant and clinically relevant increase, both when given at the same dose and when given at half that dose. On the other hand, the oral absorption of 47Ca is decreased by oxazacort, but less than by prednisone at the same dose. As the antirheumatic activity of oxazacort appears to be only slightly lower than that of prednisone (activity ratio of about 0.84: 1), these findings may have interesting therapeutic implications.

Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease.

The possible existence of kinetic interactions between rifampicin and isoniazid and the effect of the concomitant presence of an impaired liver function were investigated in man. In a first study normal healthy subjects and patients with chronic liver disease received, on three different occasions, a single dose of 600 mg rifampicin or isoniazid and of rifampicin and isoniazid associated in randomized sequences. The results have shown that in both groups the serum levels, half-life values, and urinary excretion of each drug given alone are not significantly different from those observed when the other drug is associated. Serum levels and half-life of rifampicin and isoniazid were significantly higher in patients with chronically impaired liver. In a second study, rifampicin and isoniazid were given in combination at the same doses as in the first study over a period of one week. The results have shown a trend to decrease in the serum levels of rifampicin of the healthy subjects and a trend to increase in the patients with chronic liver disease on day 7 of treatment. In both groups a reduction in the half-life of rifampicin was also observed. No changes in serum isoniazid concentrations were observed between day 1 and day 7 in the healthy subjects, whereas a significant increase was observed in the patients. No significant changes in the half-life of isoniazid were observed.