Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group.

OBJECTIVE: This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of three doses of sertindole (12, 20, and 24 mg/day) and haloperidol (4, 8, and 16 mg/day) in the treatment of psychotic symptoms for 497 hospitalized patients with schizophrenia. METHOD: The patients were randomly assigned to one of the medication groups and received treatment for 8 weeks. Changes in Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Brief Psychiatric Rating Scale, and Clinical Global Impression scores were used as evaluations of treatment efficacy. Three rating scales were used to assess extrapyramidal symptoms as well as the occurrence of adverse events and the use of medications related to extrapyramidal symptoms. RESULTS: Both sertindole and haloperidol were comparably effective in the treatment of psychosis, and all dose levels were significantly more effective than placebo. For the treatment of negative symptoms, only sertindole, 20 mg/day, was significantly more effective than placebo. For all extrapyramidal symptom measures, sertindole was clinically and statistically indistinguishable from placebo, and rates of extrapyramidal symptoms were not dose related. All dose levels of haloperidol produced significantly more extrapyramidal symptoms than placebo or sertindole. Adverse events associated with sertindole treatment were mild in severity. CONCLUSIONS: Sertindole is a new antipsychotic agent effective for the treatment of both the positive and negative symptoms of schizophrenia, with motor side effects that are indistinguishable from those associated with placebo.

A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia.

Sertindole is a novel antipsychotic agent with high selectivity for the mesolimbic dopaminergic pathway and nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine NE alpha 1 receptors. This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n = 205). Sertindole doses began at 4 mg/day and were increased to 8, 12, or 20 mg/day, depending on randomization. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Extrapyramidal symptoms (EPS) were assessed by movement rating scales, EPS-related adverse events, and use of anti-EPS medications. A dose-related improvement was observed for PANSS, BPRS, and CGI, with statistically significant mean differences (P < 0.05) between placebo and 20-mg/day sertindole (decreases from baseline of -5.8 versus -16.9 for PANSS, -4.8 versus -10.4 for BPRS, respectively). The differences in CGI final improvement score between placebo and 20-mg/day sertindole were 3.8 versus 2.9, respectively. EPS-related events were comparable in the placebo and sertindole groups. In conclusion, sertindole 20 mg/day was effective, well tolerated, and not associated with significant motor system abnormalities.

Relative bioavailability of almitrine bismesylate in humans.

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0.5 per cent (w/v) oral reference solution of almitrine bismesylate in d,l malic acid. The U.S. manufactured formulations were 85.88 and 87.85 per cent of the calculated mean area under the individual concentration-time curve for almitrine bismesylate reference solution compared to 88.40 and 88.86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176.3 ng ml-1 and 180.1 ng ml-1 compared to 196.3 and 200.1 ng ml-1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3.22, 3.33, 3.06, and 3.26 h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222.8 ng ml-1 and a mean time to peak plasma concentration of 2.68 h. Analysis of variance and multiple range comparisons (p less than 0.05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.

One year administration of almitrine bismesylate (Vectarion) to chronic obstructive pulmonary disease patients: pharmacokinetic analysis.

A double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50 mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen-phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p less than 0.01) between test day 14 and test day 360 (243 +/- 213 per cent and 199 +/- 170 per cent for predose and 3h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half-life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500 ng ml-1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700 ng ml-1. Mean accumulation was estimated to be 4.21 +/- 1.98 at one year.

Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans.

A single-blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen-phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0.96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200 mg dose. The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38.9 +/- 11.8 to 286.2 +/- 99.1 ng ml-1 for the 25 and 200 mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2.4 +/- 0.5 h to 2.8 +/- 0.8 h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268.2 +/- 132.8 to 436.4 +/- 191.4 ml min-1 for doses 50 and 200mg, respectively.