Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study.

OBJECTIVE: To assess the value of placental protein 13 (PP13) as an early marker of pre-eclampsia. DESIGN: Sequential blood samples were obtained from women with singleton viable pregnancies at 6-10, 16-20 and 24-28 weeks of gestation. Samples were tested for PP13 using a solid-phase sandwich enzyme-linked immunosorbent assay. Levels were expressed as multiples of the medians (MoM) of the unaffected population. The slope or rate of change in PP13 concentration per week of gestation was also calculated. SETTING: Thirty-five prenatal care community clinics. SAMPLE: In total, 1,366 women were recruited, and subsequently, 20 were diagnosed with pre-eclampsia, 41 with gestational hypertension and 1,178 were unaffected. MAIN OUTCOME MEASURES: Sensitivity and specificity of screening with PP13 at each gestational period and of PP13 level combined with the slope of PP13 between two testing periods. RESULTS: At 6-10 gestational weeks, PP13 levels were significantly lower among the pre-eclampsia group with a median 0.28 MoM (95% CI 0.15-0.39, P < 0.004). Using a cutoff of 0.40 MoM, the sensitivity was 80%, false-positive rate (FPR) was 20% and odds ratio was 16.0 (95% CI 5.3-48.4). Combining MoM of 6-10 weeks and slope between 6-10 and 16-20 weeks, the sensitivity was 78%, the FPR was 6% and odds ratio was 55.5 (95% CI 18.2-169.2). The gestational hypertension group was not different from the normal group. CONCLUSIONS: PP13 in the first trimester alone or in combination with the slope between the first and the second trimesters may be a promising marker for assessing the risk of pre-eclampsia.

Single-dose systemic oral fluconazole for the treatment of vaginal candidiasis.

OBJECTIVES: To evaluate the acceptance of fluconazole given in a single oral dose, for the safe, effective treatment of vaginal candidiasis. METHODS: A total of 428 patients who had a first or recurrent episode of vaginal candidiasis diagnosed clinically or by culture, were offered treatment with fluconazole by 40 primary care gynecologists who were unfamiliar with fluconazole treatment of vaginal candidiasis. The efficacy of this treatment was evaluated by both physicians and patients. RESULTS: Most of the physicians (72%) and most of the patients (69%) found the drug effective in relieving or at least alleviating the signs and symptoms of the disease. The majority of patients (83.5%) rated it better than other drugs they had received for vaginitis in the past. No recurrences were noted at the 6-week follow-up. CONCLUSIONS: Fluconazole has been found effective by physicians and patients. Both physician willingness to use it and patient compliance are satisfactory.

Criteria to assess in vivo performance of sustained release products: application to diltiazem formulations.

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.

[Sustained release verapamil in essential hypertension].

The efficacy of sustained release verapamil (Ikapress) was investigated in 237 hypertensive patients of both sexes in a multicenter trial in family practice. There were 4 groups: patients without previous treatment and those treated with nifedipine, with atenolol, or with a combination of drugs. After 4-7 days of washout, all those with diastolic pressures of 95 mm Hg or above received once daily 240 mg of verapamil for 8 weeks. 27 cases had to be withdrawn because of adverse effects: weakness in 10, constipation in 6, rash in 4, impotence in 3, and in 4, other reasons. In 177 blood pressure was brought under control after 4 weeks of treatment. An additional 33 were controlled after 4 weeks of 360 mg of sustained release verapamil. Response to treatment was similar in the 4 trial groups. Mean systolic and diastolic pressures fell 19 and 16 mm Hg, respectively, and mean pulse rate decreased by 5 beats/min. Constipation was the only side-effect reported by those who completed the trial. However, there was a significant reduction in initial scores for headache, dizziness, numbness and edema after 8 weeks of verapamil and all indices of quality of life were significantly improved. These included scores for general well-being, physical fitness, social activity, job fitness, sexual activity, sleep, concentration and mood. Scores for daytime sleepiness and fatigue also decreased significantly. Thus, sustained-release verapamil in a daily dose of 240-360 mg was shown to be an effective antihypertensive. It had few adverse effects and gave considerable improvement in quality of life.

Detection of genotoxic substances in cancer patients receiving antineoplastic drugs.

A short-term bacterial mutation test, the SOS Chromotest, has been used to detect the excretion in urine of genotoxic metabolites of antineoplastic drugs administered to cancer patients. In this test, the damage to the DNA of the test bacteria is expressed by the production of beta-galactosidase, which can be quantitatively assessed and is proportional to the concentration of the drug. Kinetic curves of excretion for adriamycin, bleomycin, dacarbazine, cis-platinum and vincristine and their mixtures have been constructed from standard curves relating the intensity of the beta-galactosidase response to the concentration of drugs dissolved in normal urine. Comparative data on extraction and concentration of the drugs from urine or serum by means of selective resin or silica columns are presented.

Transplacental passage of cefazolin in the first trimester of pregnancy.

The transfer of cefazolin, an antibiotic compound of the cefalosporin group, through the placental barrier was investigated in the first trimester of pregnancy. All cases were chosen from among women admitted for therapeutic abortion. The test group comprised 70 women, while there were 30 in the control group. The bacteriostatic activity was examined in the amniotic fluid, obtained by the vaginal route as well as the maternal blood, following the i.m. injection of 500 mg cefazolin. Our results indicate that the antibiotic cefazolin crosses the placental barrier, even during the first trimester of pregnancy. However, the concentrations obtained were considerably lower than those observed in the 2nd and 3rd trimesters.

Selected events following insertion of the Progestasert system.

The incidences of selected events were analyzed following insertion of the PROGESTASERT intrauterine progesterone contraceptive system (IPCS) and following its reinsertion after one year of use. Reinsertion did not interrupt the stabilizing or declining trends in incidences of P.I.D., removals for bleeding/pain, removals for other medical reasons, unplanned pregnancies, moderate/severe menstrual cramps and bleeding, and premenstrual/intermenstrual cramps. Comparison of the incidence of P.I.D. in the U.S. population with postinsertion incidence of P.I.D. in IPCS users indicates that the IPCS does not increase the likelihood that a woman will have P.I.D. over the likelihood that she would have it without use of the IPCS. The incidences of expulsions and intermenstrual spotting and bleeding rose temporarily after reinsertion to about half their previous peaks and then diminished markedly within two months, reverting to the levels and favorable patterns of change established during the first year.

PIP: Phase 3 clinical trials (carried out during 1972-1976) of the Progestasert IUD system are reported. In addition, reinsertion was made 1 year later, and side effects associated with both the initial and reinsertion are reported and compared. Reinsertion did not interrupt the stabilizing or declining trends in incidences of pelvic inflammatory disease, removals for bleeding/pain, removals for other medical indications, or removals for pregnancies. In addition, reinsertion did not affect trends pertaining to moderate/severe menstrual cramps/bleeding or premenstrual/intermenstrual cramping incidence. Incidence of pelvic inflammatory disease, when this series is compared with data for the U.S., was not increased among users of the Progestasert IUD system. However after reinsertion, the incidences of expulsions and intermenstrual spotting and bleeding did rise temporarily to about half their previous peaks with initial insertion, but they diminished markedly within 2 months of reinsertion and reverted to levels and favorable patterns of change which had been established during the first year of IUD use.

[Incidence of extrauterine pregnancies in IUD users (author's transl)]. / Grossesse extra-uterine et D.I.U.

PIP: In January 1979 the Food and Drug Administration (FDA) Published a report indicating that experimental clinical studies had demonstrated that conception by progesterone-releasing IUD (Progestasert) entailed more risk of ectopic pregnancy than contraception with other types of IUDs, and that such risk was similar to that of women not utilizing any contraceptive method. In this article the authors show that such indication is not correct, and that comparative studies and new epidemiological data clearly demonstrate that all IUD types carry the same risk of ectopic pregnancy. The FDA statement was probably based on data gathered under different protocols, from different patient populations, in very dissimilar conditions of study, and from badly chosen samples. Moreover, it appears that the FDA statement did not take into consideration other factors predisposing to ectopic pregnancy, such as endometritis and uterine fibroma.^ieng

The cyclical changes in the physical properties of the cervical mucus and the results of the postcoital test.

PIP: The effect of the postcoital test on the cyclic changes in the physi cal properties of the cervical mucus during the preovulatory period was investigated, and the results obtained in women who conceived during the period of investigation (fertile group) were compared with the results obtained in those who did not conceive (infertile group). 3007 postcoital examinations were performed within 72 hours after intercourse on 505 couples complaining of infertility. No significant differences were found in the amount, viscosity, and spinnbarkheit of the cervical m ucus or in the motility and drive of spermatozoa between 94 couples who conceived and 411 couples who remainded infertile. The number of spermatozoa per high power field was significantly higher in the fertile group as compared with the infertile when the amount of mucus increased. When estrogenic changes in the mucus first became apparent, the concentration of spermatozoa rose and their motility and drive improved. No further improvement was seen with further changes in the mucus. When white blood cells in the mucus appeared, both the motility and the drive of spermatozoa decreased significantly, but their number per high power field did not change. No significant changes were found to occur in either motility or drive during 72 hours after intercourse and in the number of spermatozoa per high power field during the first 24 hours. However, concentration of spermatozoa decreased significantly during Days 2 and 3. In 26 tests following the coitus presumably responsible for pregnancy, the concentration, motility, and drive of spermatozoa in mucus were not found to be different from those for the whole group of fertile patients. The wide range of distribution of the results in both groups indicates that the results of the postcoital test cannot be used as a reliable index of fertility in an individual couple.^ieng