In-vitro and in-vivo characterisation of two sustained release formulations for the antidepressant rolipram.

Using the pellet technology two sustained release formulations for (dl)-rolipram (ZK 62 711; CAS 61413-54-5) were developed and characterised by in-vitro dissolution tests and in a cross-over study in healthy male volunteers. In-vitro, 50% release was achieved within 2.5 h for formulation A and within 4 h for B. In-vivo, Cmax values of 4.4 +/- 0.9 ng/ml (A) and 2.1 +/- 0.8 ng/ml (B) were observed 2.8 +/- 0.8 h or 10.3 +/- 3.7 h after oral intake of 3 mg (dl)-rolipram. The terminal disposition half-life in the plasma was similar for both formulations (12 +/- 13 h and 11 +/- 2 h). Expectedly, the relative bioavailability of formulation B was lower compared to A (72%). Using the pellet technology, formulations with an intended release profile can be tailored to suit by mixing pellets with different release characteristics within one dosage form.

Pharmacokinetics and endocrine effects of terguride in healthy subjects.

Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i.v. dose of 50 micrograms and on the first and seventh day of an oral treatment with 250 micrograms, 500 micrograms and 750 micrograms b.d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH)-stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i.v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml.min-1.kg-1. The oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6 beta-OH cortisol.

Pharmacokinetics of (+)-rolipram and (-)-rolipram in healthy volunteers.

Plasma levels of S-(+)-rolipram and R-(-)-rolipram in six healthy male volunteers were measured by radioimmunoassay after intravenous injection of 0.1 mg and oral administration of 1.0 mg of the pure enantiomers. Following i.v. treatment, plasma levels of both isomers declined in three phases, with half-lives of 0.2 h, 0.6-0.9 h and 6-8 h. Total clearance was 6 ml.min-1.kg-1. Oral administration of 1.0 mg gave a peak concentration of 16 ng.ml-1 after 0.5 h. Bioavailability of (+)-rolipram was 77% and of the (-) enantiomer it was 74%. There was no significant difference in Cmax, half-life, total clearance or bioavailability between the two enantiomers.

[Interaction studies with fluconazole, a new triazole antifungal drug]. / Interaktionsstudien mit Fluconazol, einem neuen Triazolantimykotikum.

Fluconazole is a new systemic antifungal agent from the class of triazoles. Its efficacy was documented in clinical studies of patients with candidosis and cryptococcosis. Due to the influence on human cytochrome-P-450-dependent enzymes, special attention should be paid, in the development of new antifungal agents, to the inhibition of the metabolization of other simultaneously given substances and to the inhibition of steroid hormone synthesis in the gonads and adrenal glands. The interaction studies carried out with frequently administered drugs such as oral contraceptives, cimetidine, warfarin, tolbutamide, and cyclosporin (transplantation patients) allow the concomitant intake of these substances with fluconazole. Concomitant anti-coagulant treatment requires a precautionary monitoring of prothrombin time; it may be necessary in individual cases to reduce the anticoagulant dosage. The intake of oral hypoglycemics of the tolbutamide type requires monitoring of blood glucose, although blood glucose lowering effects were not found. One interaction study carried out with phenazone showed the low metabolization tendency of fluconazole. Approximately 80% of the administered fluconazole dose appeared in the urine unchanged. Studies in male and female subjects with multiple doses of fluconazole (4 weeks) did not show any significant effects on the endocrinology and steroid synthesis in man.

Benzodiazepine receptor ligands: tools for memory research in clinical pharmacology.

In order to study the time course of amnesic effects of the benzodiazepine hypnotic lormetazepam, and their reversal by the benzodiazepine antagonist Ro 15-1788, a combined visual and auditory memory test was developed, which was designed to allow repeated assessments. Immediate recall as well as delayed free recall and recognition (1 h after drug) were investigated before and after intravenous lormetazepam (0.02 mg/kg) followed 15 min later by intravenous Ro 15-1788 (0.03 mg/kg) or placebo. A third group received placebo followed by Ro 15-1788. Results are based on ten subjects per treatment group and are compared with an age-matched control population (n = 20) without treatment. Immediate and delayed recall as well as recognition in both visual and auditory tests were impaired abruptly after intravenous lormetazepam. These effects were reversed instantaneously after Ro 15-1788, which had no marked effect on these parameters when given alone. Ratings by visual analog scales (1 h after drug administration) indicated concomitant sedation and impaired concentration after lormetazepam, which was attenuated by Ro 15-1788. By itself, Ro 15-1788 had no effect on these measures. Interestingly, the performance in delayed free recall of the visual memory test was significantly enhanced in the lormetazepam group prior to administration. Our results suggest that impaired acquisition of new information after lormetazepam is benzodiazepine receptor mediated and may be associated with a drug-induced enhancement of retrieval of information acquired before lormetazepam administration.

Clinical perspectives of beta-carbolines from first studies in humans.

First results from studies in healthy subjects with the beta-carbolines ZK 91 296, ZK 95 962 and ZK 93 426 are reviewed. ZK 91 296 and ZK 95 962, characterized as partial benzodiazepine agonists in preclinical research, were unable to induce some typical benzodiazepine effects like sedation when administered intravenously in high doses. ZK 95 962, reported to be effective in photoepileptic patients, was able to reverse lormetazepam-induced sleep as documented by EEG-parameters. The benzodiazepine receptor antagonist ZK 93 426 dose-dependently elicited alertness, restlessness and mild apprehension--symptoms opposite those known for the benzodiazepines. The activating effect of ZK 93 426 was confirmed by the results from e.g., self-rating scales and the logical reasoning test. In another placebo-controlled study comparing the effects of ZK 93 426 alone and in combination with lormetazepam vigilosomnograms obtained after ZK 93 426 alone clearly confirmed the activating effect. In combination with lormetazepam ZK 93 426 was able to reverse the benzodiazepine induced sleep. The attenuation of benzodiazepine effects was also evident from multiple sleep latency tests. Our results support findings from animal experiments which classify these beta-carbolines as benzodiazepine receptor ligands with partial agonist and antagonist properties. beta-Carbolines may prove to be beneficial drugs in the treatment of anxiety, convulsions and diseases with an impairment of cognitive functions as well as in the reversal of unwanted benzodiazepine effects.

Outcome of the glucagon test depends upon the prevailing blood glucose concentration in type I (insulin-dependent) diabetic patients.

The outcome of 97 paired glucagon and meal tests was related to the prevailing fasting blood glucose concentrations on the two test days. At blood glucose concentration less than 7 mmol/l both the C-peptide responses and the maximal (6 min) C-peptide concentrations during the glucagon tests were significantly lower than the corresponding values found during the meal tests. During the glucagon tests, a direct relationship was found between the responsiveness of the pancreatic beta-cells and fasting blood glucose values when these were between 3 and 7 mmol/l. No significant difference was found between the outcome of the two tests when the fasting blood glucose concentration was greater than 7 mmol/l. The results indicate that the outcome of the glucagon test in Type I patients depends upon the prevailing fasting blood glucose concentration and that the predictive value of the glucagon test as to how the beta-cells will respond to a meal during everyday life is low when fasting blood glucose is less than 7 mmol/l.

Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788.

A combined visual (pictures) and auditory (word lists) memory test developed to trace the course of information processing under pharmacological or other influences was validated in a group of 20 subjects (control group) and then applied to determine the amnesic effects of lormetazepam and the reversal of these effects by the benzodiazepine antagonist Ro 15-1788. Three groups of n = 10 subjects received either 0.02 mg/kg IV lormetazepam (groups B and C) or placebo (group A) followed 14 min later by 0.03 mg/kg IV Ro 15-1788 (groups A and C) or placebo (group B). The time course of memory performance in the three groups was investigated and compared across three consecutive 14-min phases: before (phase 1) and after (phase 2) the first intravenous administration, and after the second treatment (phase 3). Results were also compared with those of 20 subjects from a drug-free control group in order to verify the memory test. Lormetazepam clearly impaired immediate and delayed free recall as well as recognition in both visual and auditory tasks. These effects were completely reversed by Ro 15-1788, which alone had no clear effect on memory performance in this study. Psychometric scales indicated concomitant sedation and impaired concentration after lormetazepam alone. Interestingly, lormetazepam retrogradely enhanced performance in the visual test of delayed free recall. The impaired acquisition of new information after the administration of lormetazepam may be associated with an improvement of the consolidation process of information acquired before drug treatment.

Pharmacokinetics and pharmacodynamics in man of the dopamine antagonist ergot derivative, bromerguride.

The plasma levels and urinary excretion of the dopamine antagonist, bromerguride, were measured by radioimmunoassay in healthy male volunteers given 50 micrograms i.v. and oral doses of 1 and 2 mg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of bromerguride declined biphasically, with half-lives of 7 min and 1.2 h. The total clearance was 32 ml X min-1 X kg-1 and the apparent volume of distribution was 3.61/kg. The bioavailability of oral bromerguride was 29% after 1 mg and 25% after 2 mg. The drug was almost totally metabolized and less than 0.05% of the dose was excreted in urine in 24 h after oral administration. Plasma prolactin levels were increased in a dose-dependent manner for about 8 h. Side-effects were minimal, mainly being tiredness and headache in some of the volunteers.