Pharmacokinetics of 7 alpha-methyl-19-nortestosterone in men and cynomolgus monkeys.

Testosterone and its esters are widely used for androgen replacement therapy. In the prostate, testosterone ins 5 alpha-reduced to dihydrotestosterone (DHT), which leads to an amplification of its stimulatory activity in this and other tissues that have significant 5 alpha-reductase activity. While this amplification is essential during fetal development, it has potentially undesirable consequences during adult life. 7 alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that does not undergo 5 alpha reduction and is therefore being investigated for long-term clinical use because it is expected to be less stimulatory to the prostate. Since we anticipate using MENT acetate (MENT Ac) rather than MENT as the form of this androgen in humans, the bioavailability of MENT following the administration of MENT and MENT Ac was investigated in cynomolgus monkeys. Equimolar concentrations of MENT or MENT Ac were administered as a continuous subcutaneous infusion via Alzet osmotic pumps. Serum MENT levels were measured by radioimmunoassay (RIA) in blood samples collected daily for 4 days during steady state. The serum MENT levels were not significantly different in the two groups (11.3 +/- 1.6 vs. 13.1 +/- 1.2 nmol/L). This suggested that MENT Ac was rapidly converted to MENT in circulation. The hydrolysis of MENT Ac to MENT was confirmed by the in vitro incubation of MENT Ac with blood or plasma and the demonstration of MENT in products following separation by high-performance liquid chromatography (HPLC). Following the demonstration of the safety of MENT Ac in subchronic toxicity studies in rats and rabbits, a pharmacokinetic study was performed in men. In normal men, a single intravenous bolus of 500 micrograms of MENT led to peak serum MENT levels at 3 minutes after dosing (when the first samples were collected), followed by an exponential decline, reaching undetectable levels by 180 minutes. The average terminal half-life and the metabolic clearance rate (MCR) were calculated to be 40 minutes and 2,360 L/day, respectively. The results of the pharmacokinetic studies show that in both men and monkeys, the MCR of MENT is much faster than the values reported for testosterone. The faster MCR can be attributed, in part, to the finding that, in contrast to testosterone, MENT showed no binding to sex hormone binding globulin (SHBG).

Pharmacokinetics and pharmacodynamics of 7alpha-methyl-19-nortestosterone after intramuscular administration in healthy men.

7alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that is resistant to 5alpha-reductases and therefore less prone to over-stimulate the prostate. It is a good candidate for implant administration in long-term androgen replacement therapy for hypogonadal men or as part of a male contraceptive system. To investigate the pharmacokinetics of MENT after i.m. administration, single i.m. injections of 2, 4 or 8 mg of micronized MENT were given in aqueous suspension to 18 healthy men in two clinics. Blood was sampled frequently for 8 h and 1, 2, 3, 4 and 9 days after the injections. Serum MENT concentrations were determined by radioimmunoassay. Peak MENT concentrations were dose-dependent and were reached about 1-2 h after the injections. Doubling the dose of MENT resulted in an increase of 60% in peak serum MENT concentrations. The mean +/- SE clearance rate was 1790 +/- 140 l/day. The antigonadotrophic activity of MENT was investigated by giving six consecutive daily i.m. injections of 1, 2 or 4 mg of MENT to 24 healthy men in two clinics. Blood was sampled before each injection and up to 24 days after the last injection. Serum testosterone and gonadotrophin concentrations (determined by radioimmunoassay and fluoroimmunoassay respectively) decreased in a dose-dependent and statistically significant manner. The highest dose caused a 74% fall in testosterone, a 70% fall in luteinizing hormone, and a 57% fall in follicle stimulating hormone concentrations. MENT injections did not cause any side-effects. The results show that MENT is a potent antigonadotrophic agent in men.

[Population Council responsible for RU486 clinical trials in USA]. / Le Population Council responsable des essais cliniques du RU 486 aux USA.

PIP: As a result of the sudden political change that came with the Clinton Administration, RU-486's manufacturer, Roussel-Uclaf, and the Population Council agreed on April 20, 1992, on the manufacture and distribution of RU-486 in the US. In the US, there are less than 1.6 million induced abortions annually. From now on, US women will be able to have a choice between medical and surgical abortion. The Population Council and Roussel-Uclaf have had a contract since 1982. The Council is solely responsible for the phase 2 clinical trial of RU-486 in the US and other countries. It must present to the US Food and Drug Administration (FDA) an amendment allowing it to begin phase 3 clinical trials. The Council will also lead the US medical facilities in this study. It will identify partners for future production of RU-486 and its distribution in the US. It will also submit to FDA a New Drug Application (NDA). FDA will review the scientific literature on RU-486 and evaluate all data submitted by the Population Council. There are still obstacles to be surmounted. The Population Council must demonstrate good judgment when selecting the criteria for choosing a pharmaceutical firm before a Technical Committee which will be part of a group of players promoting women's health, scientific experts, and other interested parties. It must find the necessary funds to conduct the clinical trials and prepare the NDA. Phase 3 clinical trials in the US must have at least 2000 women. They will test RU-486's efficacy, safety, and acceptability among women choosing medical abortion over surgical abortion. Since the Council operates in almost all countries in the world, has innovated contraceptive research and development activities, and has been endorsed by the UN, product approval of RU-486 in the US will affect policy in all countries concerned about abortion.^ieng

Medical termination of early pregnancy with mifepristone (RU 486) followed by a prostaglandin analogue. Study in 16,369 women.

We report the results of a large-scale trial with mifepristone (RU 486) followed by the administration of a prostaglandin (PG) analogue for the medical termination of early pregnancy. Altogether, 16,173 patients from 300 centers were evaluated. 48 women (0.3%) were lost to follow-up prior to, and 416 (2.6%) after the PG administration, and therefore the efficacy was evaluated in 15,709 women. Overall, the success rate was 95.3%, with no statistical difference regarding the nature and dose of PG used. The median duration of bleeding was 8 days, being 12 days or less in 89.7% of the women. Bleeding was significant enough to necessitate a vacuum aspiration or a dilatation and curettage in 0.8% of the cases. A blood transfusion was necessary in 0.1% of the women (11 patients). Serious cardio-vascular side-effects were reported in 4 cases after the PG (sulprostone) injection: they consisted of one acute myocardial infarction attributed to a coronary spasm, and in marked hypotension in the other 3 women. All patients recovered uneventfully. In conclusion, RU 486 followed by a PG analogue provides an efficient and safe medical alternative to surgery for early pregnancy termination, provided that the recommended protocol is adequately followed and the contraindications to prostaglandins are respected.

PIP: Between May 1988 and September 1989, physicians administered 600 mg of RU-486 followed by either 1 mg gemeprost vaginal pessary or im injection of 0.125-1.0 mg sulprostone to 16,369 11-48 year old women attending 30 centers in France to evaluate this regimen's safety and efficacy and whether trained prescribers could adequately comply with recommended protocol. 13.6% patients whose gestational age was greater than the recommended 50 days, underwent RU-486 and prostaglandin (PG) analogue administration. 78% of 571 patients did not receive a PG analogue because they expelled the conceptus after RU-486 administration. The remaining 126 women did not receive RU-486 even though they had not expelled the conceptus. Clinicians administered to PG analogue to 88.4% of all women within the recommended 36-48 hours after RU-486 administration. The RU-486 and PG analogue regimen had a success rate of 95.3%. Women who received the PG analogue within the recommended time period had a higher success rate than those who received it either too early or too late (95.8% vs. 92.8% and 93.9%, respectively; p = .001). In those women who did not receive the PG analogue, RU-486's success rate was considerably lower (88.6%; p .001). The nature and does of the PG analogue greatly influenced expulsion within 4 hours after its administration (44.1% after 1 mg gemeprost vs. 57.3%, 55.8%, 73.5%, and 67.6% after 0.125, 0.25, 0.375, and 0.5 mg sulprostone respectively; p .001). The higher doses of sulprostone had a significant effect on duration of bleeding (e.g., 9.1 days for 0.5 mg vs. 7.1 days for 0.125 mg p .001). 89.7% of the women bled for no more than 12 days. The bleeding was so profuse in 0.8% of the cases that either vacuum aspiration or dilatation and curettage was needed. 11 women required 1-3 units of blood. 8.5% experienced at least 1 side effect, the most common being uterine cramps (1.6% of all cases). 4 women suffered from grave cardiovascular effects (myocardial infarction in 1 case, severe hypotension in 3 cases). As long as prescribers consider contraindications and follow the protocol, this regimen is a viable alternative to surgical abortion.

Cocaine use in persons on methadone maintenance.

Although cocaine use had increased dramatically among all levels of society over the past several years, its use by heroin addicts has existed for decades. To determine whether the prevalence or the pattern of cocaine use changes once an addict enrolls in methadone maintenance, a survey of cocaine use among persons in methadone maintenance therapy was conducted. Of the 613 persons surveyed, 229 (37%) chose to participate, with 33 (14%) considered invalid because of incomplete responses. Of the remaining 196 (86% of the participants), 64 (33%) indicated no cocaine use prior to methadone maintenance, and 132 (67%) reported some prior use. Once treatment had begun, 9 (14%) with no history of prior use admitted to at least one event within the last 6 months, and 55 (86%) reported no use. Of those reporting use prior to methadone maintenance, 41 (31%) stopped usage and 91 (69%) continued. Of the total participants, approximately half used cocaine at least once during methadone maintenance. Among those who used cocaine before and during methadone maintenance, the predominant route of administration was parenteral, 72 (54%) and 46 (51%) participants, respectively. It should be noted that there was a net gain of 17% of patients who stopped using cocaine as a result of entering methadone maintenance. Indices of cocaine use by random urinalysis over the preceding 6 months, for the entire clinic population, revealed only 86 (14%) to 110 (18%) patients to have urine samples positive for cocaine. Although cocaine use decreased on methadone maintenance, its use is still considerable, with the pattern of use differing from the recreational cocaine use in a non-narcotic-dependent population. Random urinalysis for cocaine appears to be an insensitive indication of prevalence of use.

[Sterilization as a reversible method: utopia or reality? (Author's transl)]. / Reversibilite de la sterilization; utopie ou realite?

PIP: Recent technological improvements in the field of microsurgery have made reversibility of sexual sterilization possible in a great number of cases. It appears that female sterilization can be reversed in almost 60% of cases, while male sterilization can be reversed in 70% of cases. Certainly the results are good, but it would be a mistake to be too optimistic. Success rates are not the same for every surgical team, and few patients know that reverse sterilization greatly depends on the technique used for sterilization. In conclusion, sterilization should be advised and performed only when both partners are absolutely sure not to desire any more children, and must still be considered as a permanent contraceptive method.^ieng

[Tubal ligation in U.S.A. (author's transl)]. / La ligature tubaire aux Etats-Unis.

PIP: Sterilization is the most popular contraceptive method among U. S. couples who have been married for more than 10 years; there are about 12 million sterilized couples in the U. S. Voluntary sterilization is legal in most U. S. states, and the consent of one's partner is not necessary. Average age of sterilization seekers is 30. Tubal ligation is usually performed through laparotomy or, especially in more recent times, laparoscopy. Hemorrhage is the most common complication, which can be easily corrected; intestinal or peritoneal burns, or ectopic pregnancy are very rare occurrences. Reversibility depends on the sterilization technique used; improved microsurgery techniques have made it possible in many instances. Hospital stay for tubal ligation was 4.2 days in 1975; today, tubal ligation can be done on an outpatient basis, under local anesthesia only. The largest number of sterilizations in performed in the Northern and in the South-West regions of the U. S., and there seems to be a relationship between educational level of the couple, and choosing sterilization as a permanent method of contraception.^ieng