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The pharmacokinetics, metabolism, and excretion of a new antipsychotic drug, ziprasidone, were studied in four normal male volunteers after oral administration of a single 20 mg dose of a mixture of 14C- and 3H-labeled ziprasidone. Blood, urine, and feces were collected at various intervals for determination of total radioactivity and metabolic profiles. Eleven days after the dose, 20.3 ± 1% of the administered radioactivity was recovered in the urine and 66.3 ± 4.8% in feces. The absorption of ziprasidone was rapid, and the Cmaxfor ziprasidone and metabolites occurred at 2 to 6 hr postdose. Mean peak serum concentration of unchanged drug was 45 ng/ml and a mean AUC(0–t)of 335.7 ng · hr/ml. Mean peak serum concentration of total radioactivity (average of 3H and 14C) was 91 ng-eq/ml and a mean AUC(0–t)of 724.6 ng-eq · hr/ml. On the basis of AUC(0–t)values, ∼46% of circulating radioactivity was attributable to unchanged drug.

In this study, 194 imminent premature deliveries were treated. The pregnancies were in the 28th to 36th week. Uterine contractions were demonstrable in all patients and amniotic membranes were intact. All patients were treated with bedrest. Two betasympathomimetics were used in a double-blind study: Nylidrin hydrochloride (43 cases) and Isoxuprine hydrochloride (60 cases). A placebo was given to 41 patients, and ethyl alcohol to 50 patients. Intravenous and intramuscular treatment given in the hospital was continued with oral administration' at home, and follow-up examinations were repeated at short intervals. Taking a minimum birth weight of 2 500 g as the criteria of successful treatment, the success rate in the placebo group was 71%, in the Nylidrin hydrochloride group 86%, the Isoxuprine hydrochloride group 75% and the alcohol group 70%. When premature delivery was postponed 7 days, the pregnancy advanced, to the 37th week or later in 73, 77, 62 and 56% in their respective groups. The betasympathomimetics, especially the Nylidrin hydrochloride, were in every respect more efficient than placebo or alcohol. The therapeutic effect of alcohol was no better than that obtained with placebo. From the fetal point of view, the drugs used in the present study showed no adverse effects.

Over a period of 10 years, 645 patients were treated with six different betasympathomimetics because of threatening premature labor during the 24-36 weeks of gestation. Some 603 comparable patients were analysed with various parameters to find the most suitable criterion for assessing the efficacy of tocolysis and the best tocolytic agent. Delivery after 37 completed weeks proved clinically a sufficient criterion of a succesful therapeutic outcome. The various scores did not essentially facilitate comparison of various tocolytics. The combination buphenin (DilaverR) + verapamil (IsoptinR) proved to be the most suitable medication.

The pharmacokinetics, metabolism, and excretion of a new antipsychotic drug, ziprasidone, were studied in four normal male volunteers after oral administration of a single 20 mg dose of a mixture of 14C- and 3H-labeled ziprasidone. Blood, urine, and feces were collected at various intervals for determination of total radioactivity and metabolic profiles. Eleven days after the dose, 20.3 +/- 1% of the administered radioactivity was recovered in the urine and 66.3 +/- 4.8% in feces. The absorption of ziprasidone was rapid, and the C(max) for ziprasidone and metabolites occurred at 2 to 6 hr postdose. Mean peak serum concentration of unchanged drug was 45 ng/ml and a mean AUC(0-t) of 335.7 ng x hr/ml. Mean peak serum concentration of total radioactivity (average of 3H and 14C) was 91 ng-eq/ml and a mean AUC(0-t) of 724.6 ng-eq x hr/ml. On the basis of AUC(0-t) values, approximately 46% of circulating radioactivity was attributable to unchanged drug. Ziprasidone was extensively metabolized and only a small amount (<5% of the administered dose) was excreted in urine and feces as unchanged drug. Twelve metabolites in human urine and serum were identified by ion-spray LC/MS and LC/MS/MS with simultaneous monitoring of radioactivity. The major urinary metabolites were identified as oxindole-acetic acid and its glucuronide conjugate, benzisothiazole-3-yl-piperazine (BITP), BITP-sulfoxide, BITP-sulfone and its lactam, ziprasidone-sulfoxide, and sulfone similar to those identified in rats. In addition, two novel metabolic pathways (reductive cleavage and N-dearylation of the benzisothiazole ring) were identified for ziprasidone in humans. The metabolites resulted by these pathways were characterized as S-methyl-dihydroziprasidone, S-methyl-dihydro-ziprasidone sulfoxide, and 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one, respectively. Ziprasidone sulfoxide and sulfone were the major metabolites in human serum. The affinities of the sulfoxide and sulfone metabolites for 5-HT2 and D2 receptors are low with respect to ziprasidone, and are thus unlikely to contribute to its antipsychotic effects. Structures of the major metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Based on the structures of these metabolites, four routes of metabolism of ziprasidone were identified: 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at sulfur resulting in the formation of sulfoxide and sulfone, 3) reductive cleavage of the benzisothiazole moiety, and 4) hydration of the C=N bond and subsequent sulfer oxidation or N-dearylation of the benzisothiazole moiety. The identified metabolites accounted for >90% of total radioactivity recovered in urine.

The DHEA-S loading test was used to evaluate fetoplacental function in 105 pregnant women. The test gave 84% correct results in the 43 cases of fetoplacental deficiency. However, in the control group of 62 subjects it gave only 42% correct results. Measurement of estriol excretion in maternal urine is one of the biochemical tests routinely carried out on pregnancies at risk. The prognostic value of the test is, however, restricted by the big daily fluctuations in estriol excretion. Fluctuations of between 60% and 140% have been reported (12). In addition to the routine determination of estriol levels, the following tests are of importance for the biochemical evaluation of fetoplacental function: 15α-hydroxyestriol (7), pregnanediol (8), placen-tal lactogen (8), heat-stable alkaline phosphatase (8, 14), and finally, the test discussed in this publication, the dehydroepiandrosterone sulphate (DHEA-S) loading test (4). The present investigation evaluated the usefulness of this test in the early detection of danger to the fetus.

One hundred and eight patients with imminent premature labor in the 24-36th week of pregnancy and with intact membranes were allocated randomly to two groups. Fifty-four patients were treated with intravenous infusion of 12-50 μg/min of salbutamol (VentolineR) and 4 mg was subsequently given orally at 4-hour intervals. The weight of the newborn was over 2500 g in 72% of cases. The duration of pregnancy was prolonged by over seven days in 67%, and 37 weeks of pregnancy and more was achieved in 61%. The comparable figures for the control group treated with fenoterol, 3-4 μg/min and subsequently 5 mg orally at 4-hour intervals, were 78, 80 and 70% respectively.