Clonazepam pharmacokinetics: comparison of subcutaneous microsphere injection with multiple-dose oral administration.

Nine healthy volunteers participated in a 3-phase clinical pharmacokinetic study of the benzodiazepine derivative clonazepam. During phases I and II, subjects received the conventional oral dosage form of clonazepam, 0.5 mg 3 times daily, for 7 days. Multiple plasma samples were drawn on day 1 and day 7 of the trial and once daily during the washout period after the final dose. Based on nonlinear regression, mean kinetic variables for clonazepam were: absorption half-life, 24 minutes; elimination half-life, 40 hours; apparent oral clearance, 72 mL/min. The extent of accumulation at steady state relative to the first day of treatment averaged 3.3-fold, and was consistent with values predicted based on the elimination half-life. This finding suggests that once-daily dosage with clonazepam would be appropriate for many patients. In phase III of the study, subjects received a single 2.7 mg subcutaneous injection of a microsphere formulation of clonazepam, designed to produce a sustained-release profile. The maximum average plasma clonazepam concentration was 3.0 ng/mL, reached at 72 hours after dosage. Thereafter, plasma concentrations fell slowly over the 13-day sampling period, remaining above 1 ng/mL for 12 days. Overall systemic availability of clonazepam from the microsphere injection, relative to the conventional oral dosage form, was 1.05. Thus, the microsphere preparation of injectable clonazepam provides complete absorption from the injection site, with the intended slow-release pharmacokinetic profile.

Testosterone release from a subcutaneous, biodegradable microcapsule formulation (Viatrel) in hypogonadal men.

Men with hypogonadism require testosterone replacement for optimal health. In the United States, testosterone is currently administered by daily transdermal patches, topical gels or intramuscular injections every 1-3 weeks. Biodegradable polylactide-co-glycolide microcapsules are currently used for long-term drug delivery in humans. Such microcapsules that contain testosterone could provide a better means of long-term testosterone therapy. We therefore studied the pharmacokinetics and pharmacodynamics of testosterone release from testosterone microcapsules in men with hypogonadism. Fourteen men who had been treated previously with testosterone were enrolled in an open-label, prospective study of testosterone microcapsule administration. Subjects were enrolled if 2 consecutive serum total testosterone levels were lower than 8.7 nmol/L after a 4-week washout from testosterone therapy. Subjects were injected with a single dose of either 267 mg (n = 7) or 534 mg (n = 7) of (Viatrel) testosterone microcapsule, and serum total testosterone, dihydrotestosterone, estradiol, sex-hormone binding globulin, luteinizing hormone, and follicle-stimulating hormone levels were determined at days -14, -7, and 0 before the injection; at days 1, 2, and 7 after the injection; and then weekly thereafter for 8-12 weeks. Mean serum total testosterone levels peaked immediately following injection on day 1 at 25.2 +/- 2.6 nmol/L in the 267 mg group and 34.7 +/- 2.4 nmol/L in the 534 mg group. Total serum testosterone levels declined gradually and fell below 8.7 nmol/L at 42 days after injection in the 267 mg group, and 70 days after injection in the 534 mg group. Estradiol and dihydrotestosterone levels followed a similar pattern. Mean serum free testosterone also peaked immediately following injection on day 1 at 0.51 +/- 0.05 nmol/L in the 267 mg group and 0.97 +/- 0.08 nmol/L in the 534 mg group. No significant adverse reactions were seen, although 2 subjects complained of transient tenderness and fullness at their injection sites. We conclude that a single injection of 534 mg of testosterone microcapsules to men with hypogonadism normalizes serum hormone levels for up to 10-11 weeks, albeit with a pronounced early peak and a relatively long period of low-normal serum total testosterone. Subcutaneously administered testosterone microcapsules may provide a safe and convenient method for the long-term treatment of male hypogonadism or testosterone replacement in male contraceptive regimens.

Evaluation of polymer flock and metal alloy intra-tubal device in pigtail monkeys.

Two intratubal devices, one covered with a flock made from ethylene vinyl acetate and the other constructed of titanium-aluminum-vanadium alloy with an etched surface were evaluated after being placed in the Fallopian tubes of pigtail monkeys. In some instances, the devices were medicated with 10% silver nitrate or 50% quinacrine hydrochloride. The microflock device anchored in the tube mechanically, but there is no evidence that either the polymeric or metal alloy device formed an actual attachment with Fallopian tube epithelium. It is suggested that a mechanical design approach to ITDs might be more productive than one which assumes a tissue-device bond.

Use of transdermal melatonin delivery to improve sleep maintenance during daytime.

Oral melatonin (MEL) can improve daytime sleep, but the hormone's short elimination half-life limits its use as a hypnotic in shift workers and individuals with jet lag or other sleep problems. Here we show, in healthy subjects, that transdermal delivery of MEL during the daytime can elevate plasma MEL and reduce waking after sleep onset, by promoting sleep in the latter part of an 8-h sleep opportunity. Transdermal MEL may have advantages over fast-release oral MEL in improving sleep maintenance during adverse circadian phases.

An absorbable intravasal stent and a silicone intravasal reversible plug. Report of experiments on animals.

The high failure rate of vasovasotomy to restore fertility in vasectomized men prompted this investigation using guinea pigs as the experimental animals. The vasa were divided and absorbable intravasal stents were inserted into the lumens of the vasa at the site of anastomosis. The success or failure to secure patency and reestablish fertility was appraised by histologic sections, vasograms, semen analyses, and breeding tests. A second group of animals had silicone plugs equipped with a detachable central pin placed in both vasa. The design of this procedure was to produce an occlusive azoospermia which might be reversed by removing the central pin. Similar tests were used to establish the effectiveness of this reversible device in producing a temporary sterilization. The procedures were controlled by sham operations and insertion of plugs without pins.

PIP: Vasovasotomy with absorbable intravasal stents and reversible intravasal plugs was evaluated in guinea pigs. The stents were made of either starch, collagen, or polyester. The reversible plugs had removable stainless steel or nylon pins. The starch stents were completely absorbed within 2 weeks, and the collage stents were absorbed within 2 months. Patency of the vasa was confirmed by asogram in both g roups. 9 of 12 animals became azoospermic, on the average, 18 weeks aft er insertion of the stainless steel device. Approximately 33 weeks after removal of the pin, 5 of 9 animals successfully impregnated females. Azoospermia was observed in all 5 animals receiving plugs with nylon pins. 2 of these animals were able to impregnate females about 18 weeks after removal of the nylon pin. Animals receiving intravasal plugs without pins did not become azoospermic, and had an 80% successful breeding rate. A moderate inflammatory reaction of the vasa around the plug was observed.

Sustained-release naltrexone for alcoholism treatment: a preliminary study.

UNLABELLED: This 12-week study examined the bioavailability, tolerability, and potential efficacy of an injectable sustained-release preparation (SRP) of naltrexone (NTX). Twenty alcohol-dependent subjects took NTX 50 mg po daily for 2 weeks, followed by a 2-week, no-medication Washout Period, a 4-week Injection Period, and a 4-week Follow-up Period. Fifteen subjects (75%) received a single subcutaneous injection of 206 mg of sustained-release NTX, and five subjects (25%) received a placebo injection. All subjects also received eight weekly coping skills sessions during the Oral NTX, and the Washout and Injection Periods. RESULTS: After injection, NTX plasma concentrations exceeded a mean of 1 ng/ml for 21 days. Adverse effects produced by the SRP of NTX were comparable with those resulting from oral NTX therapy. Compared with placebo, the SRP of NTX significantly reduced the frequency of heavy drinking days during the Injection and Follow-up Periods. CONCLUSIONS: The results of this preliminary study support the potential clinical utility of the SRP of NTX for treatment of alcohol dependence.

An absorbable artificial vas deferens for vasovasotomy.

An absorbable artificial vas deferens is being developed in order to improve the relativley poor conception rates of vasovasotomy. The capillary device which is 0.4 mm I.D. by 0.7 mm O.D. and 15 mm long vas made from 3 absorbable polymers: starch, collagen, and a copolyester of lactide and glycolide. Preliminary evaluation of the device was made by implantation in the guinea pig was deferens immediately following vasectomy. Absorption of the starch and the copolyester occurred within 2-4 wks after implantation, whereas collagen required 3 mos and sometimes longer. Gross and histological examination showed little or no adverse effect on the tissues of the vas deferens, epididymes and testes. Active spermatogenesis continued in most cases and sperm count and motility remained essentially unchanged. Breeding studies with males implanted with the device for 5 mos have resulted in 12/13 prrgnancies with starch, 19/19 pregnancies with the copolyester and 9/11 pregnancies with collagen.