Recombinant follicle-stimulating hormone: new biotechnology for infertility.

The frequency of infertility in developed countries is approximately 8-10%. New drugs are available for assisted reproduction techniques. Two recombinant follicle-stimulating hormone (FSH) products, follitropin-beta (Follistim in the United States, Puregon in Europe) and follitropin-alpha (Gonal-F), join compounds derived through transfecting nonhuman cell lines with genetic material capable of replicating identical amino acid sequences to human compounds. The cell line used for recombinant (r)-FSH production is the Chinese hamster ovary (CHO). Previously, the only agents that showed benefit in controlled ovulatory stimulation were derived from the urine of menopausal women. Those compounds contain additional substances, such as urinary proteins and various amounts of luteininzing hormone. The amino acid sequence of r-FSH is identical to that of human FSH, but the two recombinant products exist in many different isoforms and differ from each other and from human FSH due to varied carbohydrate side chains. Due to variation in the carbohydrate side chains, follitropin-beta in solution has a higher pH than urine-derived FSH, which enhances receptor affinity and therefore is a greater inducer of folliculogenesis. Follitropin-beta does not cause endogenous production of anti-CHO or anti-FSH antibodies, and is well tolerated.

Drug therapy during labor and delivery.

Situations related to labor and delivery that may require drug therapy are discussed, and treatment options are reviewed. The goal of labor induction and augmentation at term is to facilitate vaginal delivery of a healthy infant. The primary uterine stimulant used for this purpose is oxytocin. Low-, intermediate-, and high-dose protocols have been reported; augmentation requires approximately half as much oxytocin as induction does. Mifepristone has also been used for labor induction. Prostaglandins are the primary agents used for cervical ripening, but oxytocin, relaxin, and mifepristone have also been used. Mechanical dilators are available for cervical dilation, which may be necessary when prostaglandins are contraindicated. Oxytocin is the drug of choice for preventing postpartum hemorrhage; if it is not effective, methylergonovine or carboprost may be used to control the hemorrhage. Labor induction during the midtrimester may be necessary because of obstetrical or medical complications or fetal death. These situations call for aggressive dosing of uterine stimulants (e.g., high-dose oxytocin, intravaginal dinoprostone suppositories, carboprost, mifepristone). Drug therapy may be required for labor induction or augmentation, cervical ripening or dilation, and prevention or control of postpartum hemorrhage. Oxytocin is the most commonly used agent for labor induction or augmentation and for prevention of postpartum hemorrhage; prostaglandins are frequently used for cervical ripening. Aggressive dosing of uterine stimulants is required when labor must be induced during the midtrimester.

Methotrexate for treatment of unruptured ectopic pregnancy.

Clinical experience with and adverse effects of methotrexate for the treatment of unruptured ectopic pregnancy are described. Ectopic pregnancy is suspected in the presence of the following: positive results on pregnancy test (e.g., test for beta-human chorionic gonadotropin [beta-hCG]), lower abdominal pain, a normal or slightly enlarged uterus, and a mass on either side of the midline. When laparoscopy is required for diagnosis, surgical correction is done at the same time. However, use of serial beta-hCG titers, vaginal ultrasound examinations, serum progesterone concentrations, and dilation and curettage (when the pregnancy is confirmed to be nonviable) allows earlier detection of ectopic pregnancy without laparoscopy. If rupture has not occurred, i.v. or i.m. methotrexate is administered; usually, i.m. leucovorin is given, on alternate days, to prevent hematologic toxicity. Adverse effects of methotrexate include stomatitis, gastritis, and hepatic enzyme elevation. Use of a single-dose regimen of i.m. methotrexate without leucovorin has been associated with a lower frequency of toxicity. Selection criteria for patients are as follows: (1) an unruptured ectopic pregnancy less than or equal to 3.5 cm in greatest dimension on transvaginal ultrasound, (2) no active renal or hepatic disease, and (3) no evidence of leukopenia or thrombocytopenia. Intramuscular methotrexate therapy is a safe and effective alternative to surgery for the treatment of unruptured ectopic pregnancy.

Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients.

OBJECTIVES: The use of prophylactic antibiotics in the management of preterm premature rupture of the membranes has not been adequately studied. The purpose of this study was to evaluate the efficacy of oral erythromycin therapy in the prolongation of latency and reduction of infectious morbidity after preterm premature rupture of membranes. STUDY DESIGN: In this randomized, prospective, double-blind, placebo-controlled study, 220 women at 20 to 35 weeks' gestation were evaluated. Subjects received oral erythromycin 333 mg (n = 106) or indistinguishable placebo (n = 114) every 8 hours from randomization to delivery. RESULTS: Prolongation of latency was identified with erythromycin therapy (p = 0.02), particularly for those destined to have chorioamnionitis (p = 0.003) and those with oligohydramnios (p = 0.01). No decrease in the incidence of maternal or neonatal infectious morbidity was seen. CONCLUSIONS: Oral erythromycin delays, but does not prevent, the onset of clinical infection when administered to women with preterm premature rupture of membranes. This regimen does not decrease neonatal morbidity and mortality.

Oral nifedipine pharmacokinetics in pregnancy-induced hypertension.

The pharmacokinetics of oral nifedipine were studied in 15 women with pregnancy-induced hypertension in the third trimester of pregnancy to determine if the drug's disposition was different from that in nonpregnant patients. Peak serum concentrations of 38.6 +/- 18 ng/ml occurred at approximately 40 minutes after ingestion of nifedipine 10 mg. The terminal elimination half-life (mean 1.3 +/- 0.5 hrs) was shorter than that reported for normotensive volunteers and nonpregnant hypertensives after oral dosing. Mean +/- SD apparent elimination clearance of 2.0 +/- 0.8 L/hr/kg was more rapid than that in healthy volunteers (mean 0.49 +/- 0.09 L/hr/kg). Random serum concentrations were progressively higher in patients receiving larger daily doses. Nifedipine was detected in samples of fetal cord blood and amniotic fluid at concentrations approximately 93% and 53% those of simultaneous maternal vein samples, respectively. The findings indicate that nifedipine may achieve greater antihypertensive efficacy in pregnant women if administered at shorter intervals.

Nifedipine pharmacokinetics and pharmacodynamics during the immediate postpartum period in patients with preeclampsia.

Pharmacokinetic and pharmacodynamic parameters of oral nifedipine were studied in the immediate postpartum period in eight women with preeclampsia. Peak serum concentrations of 18 +/- 2.1 micrograms/L occurred 40 minutes after ingestion of nifedipine (10 mg). The terminal elimination half-life (mean = 1.35 +/- 0.3 hours) was found to be shorter than that reported for normotensive volunteers or nonpregnant hypertensive women (mean, 3.4 +/- 0.4 hours). A mean apparent oral elimination clearance of 3.3 +/- 1.3 L/hr/kg was more rapid than that found in normal volunteers (mean, 0.49 +/- 0.09 L/hr/kg) or in women with pregnancy-induced hypertension in the third trimester (mean, 2.0 +/- 0.8 L/hr/kg). Initial nadirs in mean arterial pressure were noted at 50 minutes after ingestion of nifedipine, with an average reduction in mean arterial pressure of 13.8 mm Hg. A dosing interval of every 3 to 4 hours is suggested when rapid-release nifedipine is used in the postpartum patient with preeclampsia.