Aborto farmacológico dispensado a través de un servicio de telemedicina a mujeres de América Latina: complicaciones y su tratamiento / Medical abortion provided by telemedicine to women in Latin America: complications and their treatment

Objetivo: Analizar las complicaciones y los tratamientos declarados después de un aborto farmacológico con mifepristona y misoprostol dispensado a través de un servicio de telemedicina a mujeres que viven en América Latina. Métodos: Estudio observacional basado en el registro de consultas médicas de un servicio de telemedicina. Participaron 872 mujeres que usaron el servicio entre 2010 y 2011. Variables dependientes: total de complicaciones, hemorragia, aborto incompleto, total de tratamientos, evacuación quirúrgica y antibióticos. Variables independientes: edad, zona de residencia, privación socioeconómica, tener hijos/as, embarazos y abortos previos, y semana gestacional. Se ajustaron modelos de Poisson con estimación de la varianza robusta para estimar razones de incidencia (RI) y sus intervalos de confianza del 95% (IC95%). Resultados: El 14,6% de las participantes declaró complicaciones (6,2% hemorragia y 6,8% aborto incompleto). El 19,0% tuvo tratamiento postaborto (10,9% evacuación quirúrgica y 9,3% antibióticos). La privación socioeconómica aumentó en un 64% el riesgo de complicaciones (IC95%: 15%-132%), y dentro de estas un 82% el de aborto incompleto (IC95%: 8%-206%) y un 62% el riesgo de intervención quirúrgica (IC95%: 7%-144%). Los embarazos previos aumentaron el riesgo de hemorragia (RI=2,29; IC95%: 1,33-3,95%). Las mujeres con un embarazo de 12 semanas o más tuvieron un riesgo 2,45 veces mayor de tener tratamiento médico y 2,94 veces mayor de tomar antibióticos, comparado con embarazos de 7 semanas o menos. Conclusión: El aborto farmacológico proveído por telemedicina puede ser una opción segura y efectiva para la interrupción voluntaria del embarazo en contextos donde está legalmente restringido (AU)

Objective: To analyze reported complications and their treatment after a medical abortion with mifepristone and misoprostol provided by a telemedicine service to women living in Latin America. Methods: Observational study based on the registry of consultations in a telemedicine service. A total of 872 women who used the service in 2010 and 2011 participated in the study. The dependent variables were overall complications, hemorrhage, incomplete abortion, overall treatments, surgical evacuation, and antibiotics. Independent variables were age, area of residence, socioeconomic deprivation, previous children, pregnancies and abortions, and week of pregnancy. We fitted Poisson regression models with robust variance to estimate incidence ratios and 95% confidence intervals (95%CI). Results: Complications were reported by 14.6% of the participants: 6.2% reported hemorrhage and 6.8% incomplete abortion. Nearly one-fifth (19.0%) received postabortion treatment: 10.9% had a surgical evacuation and 9.3% took antibiotics. Socioeconomic deprivation increased the risk of complications by 64% (95%CI: 15%-132%), and, among these, the risk of incomplete abortion by 82% (95%CI: 8%-206%) and the risk of surgical intervention by 62% (95%CI: 7%-144%). Previous pregnancies increased the risk of complications and, specifically, the risk of hemorrhage by 2.29 times (95%CI: 1.33-3.95%). Women with a pregnancy of 12 or more weeks had a 2.45 times higher risk of receiving medical treatment and a 2.94 times higher risk of taking antibiotics compared with women with pregnancies of 7 or less weeks. Conclusion: Medical abortion provided by telemedicine seems to be a safe and effective alternative in contexts where it is legally restricted (AU)

Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii.

OBJECTIVE: To explain the role of mifepristone in medical abortions that results in fulminant and lethal septic shock due to Clostridium sordellii. DATA SOURCES: MEDLINE, PubMed, and Google Scholar databases were searched (1984-March 2005). Key search terms were mifepristone, RU38486, RU486, Mifeprex, medical abortion, septic shock, innate immune system, cytokines, and Clostridium sordellii. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included for the information related to the development of the understanding of the pathophysiology of mifepristone-induced septic shock due to C. sordellii. DATA SYNTHESIS: The mechanisms of action of mifepristone were incorporated into the pathophysiology of septic shock due to C. sordellii. Mifepristone, by blocking both progesterone and glucocorticoid receptors, interferes with the controlled release and functioning of cortisol and cytokines. Failure of physiologically controlled cortisol and cytokine responses results in an impaired innate immune system that results in disintegration of the body's defense system necessary to prevent the endometrial spread of C. sordellii infection. The abnormal cortisol and cytokine responses due to mifepristone coupled to the release of potent exotoxins and an endotoxin from C. sordellii are the major contributors to the rapid development of lethal septic shock. CONCLUSIONS: Theoretically, it appears that the mechanisms of mifepristone action favor the development of infection that leads to septic shock and intensifies the actions of multiple inflammatory cytokines, resulting in fulminant, lethal septic shock.

Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use.

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.

Methods of induction of labour.

Several research groups around the world reported on the use of the drug misoprostol in the medical management of miscarriage, abortion and induction of labour. This review examines the evolution of interest in this drug, with special emphasis on its role in induction of labour.

PIP: The induction of labor by prostaglandin agents has been a central research focus for the past 30 years, but their use has been compromised by the high incidence of gastrointestinal side effects. During the late 1970s, the research focus shifted to sequential vaginal administration of different prostaglandin analogues. Currently, the pharmaceutical industry is especially interested in the role of misoprostol in inducing uterine contractibility. Required first, however, is the determination of the correct dosage and frequency that will induce effective uterine contractions without producing uterine hyperstimulation and adverse effects on the fetal heart rate. Because of its thermostability, efficacy, and low cost, the therapeutic use of misoprostol is expected to increase throughout the world in the years ahead.

Methotrexate and misoprostol for abortion.

PIP: Methotrexate, a folic acid antagonist, is approved by the US Food and Drug Administration for use in rheumatoid arthritis, psoriasis, and various types of cancer, including choriocarcinoma, and has also been used to terminate ectopic pregnancies. Misoprostol, a prostaglandin, is approved for the prevention of gastric ulcers induced by nonsteroidal anti-inflammatory drugs. In France, the UK, and Sweden, misoprostol and another prostaglandin is used with mifepristone (RU486) to induce abortion in early pregnancy. Recent articles in the press have suggested that in early pregnancy, an intramuscular injection of methotrexate and oral or vaginal administration of misoprostol offers a medical alternative to a surgically induced abortion. This paper describes the mechanisms of action, pharmacokinetics, clinical use, and adverse effects of the two drugs. It is concluded that an intramuscular injection of methotrexate followed up to seven days later by the intravaginal administration of misoprostol can terminate an early intrauterine pregnancy. Headache, nausea, vomiting, diarrhea, and prolonged bleeding have occurred. However, in the few studies published to date, no serious complications have been reported.^ieng

Pharmacokinetic and tissue residue characteristics of fenprostalene, a prostaglandin F2 alpha analog, in swine.

Fenprostalene, a prostaglandin F2 alpha analog, can be used to induce parturition in swine. As part of the approval process for that indication, pharmacokinetic characteristics of the absorption and elimination of fenprostalene and the depletion of drug residues from the principal edible tissues of swine were studied. Blood samples, urine, and feces were collected from 8 gilts (body weight, 95 +/- 1.7 kg) for up to 72 hours after a single dose of 0.5 mg of 13,14-[3H]-fenprostalene in polyethylene glycol-400 was administered SC. At intervals of 24, 48, 72, and 168 hours after dosing, 2 gilts each were killed, and samples of liver, kidney, muscle, and abdominal fat were obtained for analysis. The mean (+/- SEM) maximal concentration of fenprostalene radioequivalents in plasma (0.41 +/- 0.05 nanogram-equivalents/ml; n = 8) was observed at 12 hours and decreased biexponentially, with half-lives of approximately 8 hours and 9 days. Mean cumulative recovery (n = 4) of the administered dose by 72 hours was 61.2 +/- 5.9% in urine and 18.5 +/- 2.6% in feces. The highest tissue fenprostalene concentration was in kidneys and liver, probably reflecting the role of those organs in excreting fenprostalene. Rates of depletion of fenprostalene equivalents from the injection site, kidneys, and liver were comparable with those previously observed in cattle. The composition of residue in the liver of 2 gilts slaughtered 12 hours after SC administration of [3H]-fenprostalene was examined in a second study. Results suggested that approximately 4% of the total residue was pharmacologically potent fenprostalene or the carboxylic acid form of fenprostalene.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of the antiprogesterone RU 486 in women during multiple dose administration.

Serum levels of RU 486 were measured by high performance liquid chromatography (HPLC) following oral intake of 12.5, 25, 50 and 100 mg twice daily (b.i.d.) for 4 days, 50 mg b.i.d. for 7 days, as well as a single dose of 200 mg of RU 486. The pharmacokinetics of RU 486 were not linear: when the daily dose of RU 486 was 100 mg or more, the serum levels were similar. The pharmacokinetic behaviour of RU 486 during the treatment period was similar between the study subjects, whereas the elimination phase pharmacokinetics showed wide individual variation. Also the mean elimination phase half-lifes (t 12) of RU 486 varied from 25.5 to 47.8 h in the groups of different regimen, yet the variation between different groups was not statistically significant. The areas under the concentration curves (AUC) were calculated. In the multiple dose study (mds) the AUC0----12h:s decreased when the administered dose of RU 486 was increased. The AUC0----12h seen after administration of 100 mg b.i.d. x 4d. (mean +/- SEM = 0.43 +/- 0.04 mumol/l x h/mg) was significantly (P less than 0.05) lower than the AUC0----12h:s obtained with administration of 12.5 mg b.i.d. x 4d. (1.49 +/- 0.37 mumol/l x h/mg), 25 mg b.i.d. x 4d. (1.09 +/- 0.15 mumol/l x h/mg), and 50 mg b.i.d. x 7d. (0.72 +/- 0.11 mumol/l x h/mg). The AUC0----infinity obtained by administration of a single dose of 200 mg of RU 486 (sds) was 0.67 +/- 0.21 mumol/l x h/mg. It is concluded that if multiple dose administration of RU 486 is preferred, daily administration of relatively small doses of RU 486 over several days seem to be advantageous.

The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran.

(R)-(+)-Pulegone, the major monoterpene component of the abortifacient mint oil, pennyroyal oil, is metabolized by hepatic microsomal monooxygenases of the mouse to a hepatotoxin. The formation of a toxic metabolite is apparently mediated by cytochromes P-450 of the phenobarbital class inasmuch as phenobarbital pretreatment of mice increases, whereas beta-naphthoflavone pretreatment decreases, the extent of hepatic necrosis caused by pulegone. Furthermore, two inhibitors of cytochromes P-450, cobaltous chloride and piperonyl butoxide, block toxicity. An analog of (R)-(+)-pulegone that was labeled with deuterium in the allylic methyl groups was found to be significantly less hepatotoxic than the parent compound. The results indicate that oxidation of an allylic methyl group is required for generation of a hepatotoxic metabolite. Menthofuran was identified as a proximate toxic metabolite of (R)-(+)-pulegone, and investigations with (R)-(+)-pulegone-d6 and 18O2 strongly indicate that menthofuran is formed by a sequence of reactions that involve: 1) oxidation of an allylic methyl group, 2) intramolecular cyclization to form a hemiketal, and 3) dehydration to form the furan.