Assisted vaginal delivery in low and middle income countries: an overview.

OBJECTIVE: To assess the use of assisted vaginal delivery (AVD) in low- and middle-income countries (LMICs), highlighting what level of care procedures were performed and identifying systemic barriers to its use. DESIGN: Cross-sectional health facility assessments. SETTING: Up to 40 countries in Latin America, sub-Saharan Africa and Asia. POPULATION: Assessments tended to be national in scope and included all hospitals and samples of midlevel facilities in public and private sectors. METHODS: Descriptive secondary data analysis. MAIN OUTCOME MEASURES: Percentage of facilities where health workers performed AVD in the 3 months prior to the assessment, instrument preference, which health workers performed the procedure, and reasons AVD was not practiced. RESULTS: Fewer than 20% of facilities in Latin America reported performing AVD in the last 3 months. In sub-Saharan Africa, 53% of 1728 hospitals had performed AVD but only 6% of nearly 10 000 health centres had done so. It was not uncommon to find <1% of institutional births delivered by AVD. Vacuum extraction appears preferred over forceps. Lack of equipment and trained health workers were the most frequent reasons for non-performance. CONCLUSIONS: The low use of AVD in LMICs is in contrast with many high-income countries, where high caesarean rates are also associated with significant rates of AVD. In many LMICs, rising caesarean rates have not been associated with maintenance of skills and practice of AVD. AVD is underused precisely in countries where pregnant women continue to face hardships accessing emergency obstetric care and where caesarean delivery can be relatively unsafe. TWEETABLE ABSTRACT: Many LMICs exhibit low use of assisted vaginal delivery where access to EmONC continues to be a hardship.

The effect of medication event reminder monitoring on treatment adherence of TB patients.

BACKGROUND: TB control remains a serious public health problem, compounded by poor treatment adherence, which increases the likelihood of onward transmission. We evaluated the effectiveness of medication event reminder monitoring (MERM) upon treatment adherence in a high TB burden setting.METHODS: We conducted an open-label parallel group randomised controlled trial among pulmonary TB adults. Participants were provided with a MERM device to store their medications. In the intervention arm, the devices were set to provide daily medication intake reminders. Primary outcome was the proportion of patient-months in which at least 6/30 doses were missed. Secondary outcomes included 1) the proportion of patient-months in which at least 14/30 doses were missed, and 2) the proportion of doses missed.RESULTS: Of 2,142 patients screened, 798 (37.3%) met the inclusion criteria and 250 participants were enrolled. The mean ratio (MR) for poor adherence between the intervention and control groups was 0.72 (95% CI 0.55-0.86). The intervention was also associated with a reduction in the proportion of patients missing at least 14/30 doses (MR 0.61, 95% CI 0.54-0.68) and the percentage of total doses missed (MR 0.75, 95% CI 0.68-0.80).CONCLUSION: MERM is effective in improving TB treatment adherence in a resource-limited environment.

Monoclonal antibody based radiopharmaceuticals for imaging and therapy.

The concept of personalized medicine has been steadily growing for the past decades. Monoclonal antibodies (mAbs) are undoubtedly playing an important role in the transition away from conventional medical practice to a more tailored approach to deliver the best therapy with the highest safety margin to a specific patient. In certain instances, mAbs and antibody drug conjugates (ADCs) may represent the preferred therapeutic option for several types of cancers due to their high specificity and affinity to the antigen. Monoclonal antibodies can be labeled with specific radionuclides well-suited for PET (Positron Emission Tomography) or gamma camera scintigraphy. The use of radiolabeled mAbs allows the interrogation of specific biomarkers and assessment of tumor heterogeneity in vivo by a single diagnostic imaging scan that includes the whole-body in the field-of-view. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of beta-minus radiation or alpha-particles as part of a radioimmunotherapy (RIT) approach. However, the path to develop, validate, and implement mAb-based radiopharmaceuticals from bench-to-bedside is complex due to the extensive pre-clinical experiments and toxicological studies required, and the necessity of labor-intensive clinical trials that often require multi-time-point imaging and blood draws for internal radiation dosimetry and pharmacokinetics. As more mAb-based radiopharmaceuticals have been developed and evaluated, the opportunities and limitations offered by mAbs have become better defined. Our aim with this manuscript is therefore to provide an overview of the recent advances in the development of mAb-based radiopharmaceuticals and their clinical applications in Oncology.

Prostate-Specific Membrane Antigen-Targeted Radiopharmaceuticals in Diagnosis and Therapy of Prostate Cancer: Current Status and Future Perspectives.

Prostate cancer is the most common cancer to affect men in the United States and the second most common cancer in men worldwide. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging has become increasingly popular as a novel molecular imaging technique capable of improving the clinical management of patients with prostate cancer. To date, several 68Ga and 18F-labeled PSMA-targeted molecules have shown promising results in imaging patients with recurrent prostate cancer using PET/computed tomography (PET/CT). Studies of involving PSMA-targeted radiopharmaceuticals also suggest a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and methylene diphosphonate bone scintigraphy) and 11C/18F-choline PET/CT. In addition, PSMA-617 and PSMA I&T ligands can be labeled with α- and ß-emitters (e.g., 225Ac, 90Y, and 177Lu) and serve as a theranostic tool for patients with metastatic prostate cancer. While the clinical impact of such concept remains to be verified, the preliminary results of PSMA molecular radiotherapy are very encouraging. Herein, we highlighted the current status of development and future perspectives of PSMA-targeted radiopharmaceuticals and their clinical applications.

[Audit of medical records]. / Audit des dossiers médicaux.

OBJECTIVE: TO assess the quality of medical records in a university teaching hospital in Africa. MATERIAL AND METHODS: We conducted a retrospective study at the Souro Sanou University Teaching Hospital of Bobo Dioulasso in Burkina Faso, by randomly selecting 480 medical records from 4 clinical departments (internal medicine, obstetrics & gynaecology, paediatrics and surgery). Items recorded were based mainly on those used by the French agency for the evaluation of health services (now the HAS). Ten physicians were also interviewed about medical file ergonomics file. Descriptive statistics were compiled from the data collected. RESULTS: Only 368 of the 480 records could be found. Two of the four departments had an adequate record room. Assessment of the overall quality of the files noted that: i) 95 to 100% of the records were in good physical condition; ii) the handwriting in the files was legible in 94 to 100% of the cases; iii) the identity of the staff members making file entries could be determined in 73 to 92% of the cases. A detailed examination of the content of the files revealed that: i) the patient's social and demographic characteristics (name, sex, age, residence, occupation, marital status and religion) were available in 26 to 99% of the cases; ii) the mode of admission was noted in 52 to 88%; iii) the reason for admission was stated in 83 to 100%; iv) the main diagnosis was reported in 68 to 100%; v) surgery notes were found for 93 to 100% of patients who underwent surgery; vi) the disposition on discharge was not found in 31% of the records; vii) the circumstances of death were not recorded for 77% of the patients who died. CONCLUSION: The quality of medical records at Souro University Teaching Hospital must be improved, through improving staff awareness and regular audits.

Fully automated preparation of 68Ga-PSMA-11 at curie level quantity using cyclotron-produced 68Ga for clinical applications.

68Ga-PSMA-11 is currently one of the most investigated PET agents for imaging both recurrent prostate cancer and relevant metastases; however, the production and distribution of 68Ga-PSMA-11 is limited to a supply of only a few daily doses when using a commercially available 68Ge/68Ga generator. 68Ge/68Ga generators deliver only a modest amount of activity, up to 1850 MBq (50 mCi), when new, but it decreases with time. Additionally, the production of 68Ga/68Ge generators has not been able to meet the increasing demand of 68Ga radiotracers. In response to the need for a more economically viable alternative, the focus of this study was to provide a simple and efficient method for producing 68Ga-PSMA-11, using cyclotron-produced 68Ga that is ready for routine clinical practice.

Predicting 3-year mortality based on the tumor necrosis factor alpha concentration in low-flux hemodialysis patients.

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine produced during acute inflammation. Few studies have evaluated the association between serum TNF-α and its receptors and their clinical outcomes in hemodialysis patients. However, a study assessing patients using a low-flux dialyzer reuse has not been conducted yet. The serum TNF-α concentrations of 319 prevalent hemodialysis patients (mean age, 45 ± 15 years; median duration of hemodialysis, 48 [interquartile range, 26-79] months; 185 males and 134 females) was examined to predict their 3-year mortality. The patients were divided into tertiles according to their serum TNF-α concentrations: T1 (n = 106; serum TNF-α concentration, <41.22 pg/mL), T2 (n = 106; serum TNF-α level, from 41.22 to 67.28 pg/mL), and T3 (n = 107; serum TNF-α concentration, ≥ 67.29 pg/mL). During the 36-month follow-up period, a total of 50 (15.7%) patients died from all causes. The Kaplan-Meier analysis revealed that the all-cause mortality in T3 was significantly higher compared to that in T1 and T2 (log-rank test, P < .001). The serum TNF-α level was a significant predictor for all-cause mortality (area under the curve = 0.887, P < .001, cutoff value, 89.812 pg/mL, sensitivity = 76%, specificity = 96.3%). The serum TNF-α level was a better predictor of mortality than the duration of hemodialysis and serum albumin, serum high-sensitivity C-reactive protein, and serum beta-2 microglobulin concentrations. The serum TNF-α concentration was a good predictor of the 3-year mortality in low-flux hemodialysis patients.

Clinical efficiency of a natural resin fluoride varnish (Shellac F) in reducing dentin hypersensitivity.

Previous in vitro permeability and scanning electron microscopic studies have demonstrated the effectiveness of a new natural based-resin varnish (Shellac F) in dentin permeability reduction and effective tubule occlusion. The aim of this randomized double-blind, controlled, split mouth 8-week clinical study was to evaluate the efficiency of Shellac F in reducing dentin hypersensitivity. Ten patients (eight women: two men) completed the study. A quadrant including at least one hypersensitive tooth (Visual Analog Scale - VAS = 15 mm to air blast) was considered as a unit and randomly assigned to different groups for Shellac F, Duraphat, Isodan. Three applications of each material were completed at days 0, 1 and 7. The subjective response was assessed by tactile and thermal/evaporative methods. Data were collected at baseline and after the first application, at 15 min, 1, 7, 14, 28 and 56 days. Analysis was based on Kruskall-Wallis test, Wilcoxon signed rank test and the method of the least square means. No statistically significant difference was noted between Shellac F and the two control materials. Regardless of the type of stimulus, Shellac F showed significant immediate and progressive continuous efficiency in reducing dentin hypersensitivity until 56 days (VAS of 14 +/- 12 mm and provoking pain force of 89 +/- 12 cN, respectively, compared with 38 +/- 23 mm and 41 +/- 10 cN at baseline), corresponding to a highly effective relief dentin hypersensitivity. Shellac F reduced dentin hypersensitivity and did not differ from the two desensitizing agents used as controls.

Prevalence of vulvovaginal candidiasis in pregnancy at three health centers in Burkina Faso.

INTRODUCTION: Pregnant women are more susceptible to vaginal colonization and infection by yeast. The role of Candida colonization in the occurrence of preterm birth is well established. The knowledge of local epidemiology and identification of risk factors for preterm birth is important for the prevention and management strategies. The purpose of the study was to determine the prevalence of Candida sp. in vaginal swabs of pregnant women. METHODS: Pregnant women attending routine antenatal visits in three primary health centres in Bobo-Dioulasso (Burkina Faso) were enrolled into a cross-sectional study carried out from February to April 2015. Vaginal swabs samples were taken from participants after obtaining oral consent. The swabs were inoculated into Sabouraud's glucose agar supplemented with chloramphenicol and incubated at 37°C for 24 to 48hours under aerobic conditions in order to perform fungal culture. The identification of the Candida species was done by culture on HiCrome Candida Differential Agar at 35°C for 48h for production of species-specific colors. RESULTS: A total of 229 pregnant women were included. The prevalence of vulvovaginal candidiasis (VVC) was 22.71%, (95% CI [17.45-28.69]). Candida albicans accounted for 40.39% and non-Candida albicans species for 59.61% of the isolates, with mainly C. glabrata (32.69%), C. tropicalis (15.38%) and C. krusei (11.54%). CONCLUSIONS: This study revealed a high prevalence of non-C. albicans species. The syndromic management guidelines for VVC in Burkina Faso will be revised to include a specific protocol for pregnant women.

Is misoprostol a safe, effective and acceptable alternative to manual vacuum aspiration for postabortion care? Results from a randomised trial in Burkina Faso, West Africa.

OBJECTIVES: Previous research has demonstrated the effectiveness of misoprostol for treatment of incomplete abortion; however, few studies have systematically compared misoprostol's effectiveness with that of standard surgical care. This study documents the effectiveness of a single 600 micrograms dose of oral misoprostol versus manual vacuum aspiration (MVA) for treatment of incomplete abortion in a developing country setting. DESIGN: Open-label randomised controlled trial. SETTING: Two university teaching hospitals in Burkina Faso, West Africa. POPULATION: Women of reproductive age presenting with incomplete abortion. METHODS: From April 2004 through October 2004, 447 consenting women with incomplete abortion were randomised to either a single dose of 600 micrograms oral misoprostol or MVA for treatment of their condition. MAIN OUTCOME MEASURE: Completed abortion following initial treatment. RESULTS: Regardless of treatment assigned, nearly all participants had a complete uterine evacuation (misoprostol = 94.5%, MVA = 99.1%; relative risk [RR] = 0.95 [95% CI 0.92-0.99]). Acceptability and satisfaction ratings were similar and high for both misoprostol and MVA, with three out of four women indicating that the treatment's adverse effects were tolerable (misoprostol = 72.9%, MVA = 75.8%; RR = 0.96 [95% CI 0.86-1.07]). The majority of women were 'satisfied' or 'very satisfied' with the method they received (misoprostol = 96.8%, MVA = 97.7%; RR = 0.99 [95% CI 0.96-1.02]), expressed a desire to choose that method again (misoprostol = 94.5%, MVA = 86.6%; RR = 1.09 [95% CI 1.03-1.16]) and to recommend it to a friend (misoprostol = 94.5%, MVA = 85.2%; RR = 1.11 [95% CI 1.04-1.18]). CONCLUSION: Six hundred micrograms of oral misoprostol is as safe and acceptable as MVA for the treatment of incomplete abortion. Operations research is needed to ascertain the role of misoprostol within postabortion care programmes worldwide.

Ultrastructural localization of the GTP-binding protein Go in neurons.

The ultrastructural localization of Go, a GTP-binding protein (G protein) highly expressed in nervous tissues, was performed in cultured fetal and adult murine neurons, using affinity-purified polyclonal antibodies against the alpha subunit of the Go protein (Go alpha). These antibodies recognized denatured Go alpha and both the native Go alpha-subunit and the Go alpha beta gamma heterotrimer. At the ultrastructural level, the positive immunoreactivity detected in cultured cells as well as in thin frozen sections, showed that Go was largely distributed in cell bodies and neuritic cytoplasm. Labelling was principally noted on the cytoplasmic face of the plasma membrane lining the cell body and the neurites, especially in 'cell-cell' contacts, but also in the cytoplasmic matrix, between endoplasmic reticulum and Golgi cisternae. No immunoreactivity was observed on the inner face of the pre- or postsynaptic membranes in both adult brain and in cultured neurons. This last finding strongly suggests that the Go protein is not involved in transducing chemical signals at the level of synapses, but more probably modulates the synaptic functions by controlling the activity of effectors localized outside of the synaptic densities.

Absence of fodrin (spectrin-like protein) under the pseudopod membrane in stimulated thyroid cells.

A fodrin-like protein purified from porcine thyroid cells and characterized by its properties identical to those of pig brain spectrin (F. Regnouf et al., Eur. J. Biochem. 153, 313-319 (1985)) has been localized by immunofluorescence and electron immunocytochemistry in porcine and rat thyroid. Fodrin-like polypeptides were detected in subplasmalemmal meshworks of microfilaments attached to isolated or in situ plasma membranes. In resting cells, fodrin was found under apical and basolateral membrane domains, whereas it was always absent under the pseudopod membrane domain induced by acute TSH stimulation in vitro, using monolayers of porcine cultured cells attached to collagen permeable substrates, as well as in vivo, using rats intravenously treated with TSH. Thyroid fodrin could be involved in exocytosis and membrane stabilization which occurs during the formation of pseudopods induced by TSH stimulation.

Low ventricular performance and high resistance in established hypertension in adults.

OBJECTIVE: To investigate the relationship between left ventricular performance and sympathetic nervous activity. DESIGN: We studied the alpha- and beta-adrenergic responsiveness of the subjects and assessed their left ventricular performance. METHODS: Fifty-four adult established hypertensive patients, all with apparent left ventricular hypertrophy, and 36 age-matched normotensive controls were studied. Thirty-four of the hypertensive patients were within the +/- 2SD confidence area of fractional shortening/end-systolic stress relation of the normotensive controls and are denoted subgroup A; 19 patients were below the lower limit and are denoted subgroup B. Isoproterenol and neosynephrine injection tests were used to assess beta- and alpha-adrenergic responsiveness, respectively. Intravenous infusion tests using regitine and isoproterenol were performed in 16 patients to assess the effects of sympatho-adrenergic responsiveness on changes in left ventricular performance. RESULTS: Afterload and left ventricular mass were similar in the two subgroups. Left ventricular performance and beta-adrenergic responsiveness in subgroup A were comparable with the corresponding levels in the normotensives, whereas in subgroup B both were markedly decreased. The regitine infusion test induced a fall of 25% in peripheral resistance from baseline, but no significant improvement in left ventricular performance. In contrast, isoproterenol infusion test resulted in striking improvements: left ventricular performance increased by 60%, afterload decreased by 48% and peripheral resistance fell by 50% from baseline. CONCLUSION: The diminished ventricular performance and high resistance observed in adult established hypertension may be due to synergic effects of significantly reduced beta-adrenergic responsiveness coupled with enhanced alpha-adrenergic responsiveness.

Treatment of malaria in Vietnam with oral artemisinin.

In this study, 638 patients with either Plasmodium falciparum or P. vivax malaria were treated with artemisinin (qinghaosu) that was isolated and formulated into tablets and capsules in Vietnam. In all cases, artemisinin treatment resulted in a rapid clearance of parasitemia and fever. Recrudescence rates were highest in those groups receiving treatment for five or less days (50%), but were between 10% and 23% for those groups receiving the drug for 5-10 days. A low recrudescent rate (9.5%) was also found when patients were treated with a combination of artemisinin for three days and tetracycline for five days. Thus, artemisinin represents a useful and economically feasible component of the malaria control program in Vietnam.

Choroidal ependymocytes in culture: expression of markers of polarity and function.

Long-term primary cultures derived from fetal mouse or rat choroid plexus were obtained in serum-supplemented media. Monoclonal and polyclonal antibodies to basolateral and apical membrane components were used to observe the expression of specific markers of polarity and function. Choroid plexus cultures and thin frozen sections of adult tissues were compared by immunocytochemistry. Two polyclonal antibodies directed against laminin and fibronectin were used on cultured choroid plexus and sectioned tissues, showing that fibronectin and laminin are located on the basolateral membrane domain in ependymocytes in vitro, as well as in vivo. Na(+)-K(+) ATPase was apically detected by light and electron microscopy with a monoclonal antibody (Mab H30) in both cultured cells and sectioned tissues. Double immunofluorescent staining with Mab H30 and affinity-purified polyclonal antibodies to the alpha subunit of G0 protein (G0 alpha) demonstrated the relatively similar distribution of the two antigens on the apical face of the choroidal tissue, both in vivo and in vitro. The distribution of these markers shows a typical differentiation with maintenance of polarized features in choroidal ependymocytes in culture, testifying that this cell culture system constitutes an interesting model for studying the functional characteristics of ependymal cells of the choroid plexus.

Incorporation of D-[3H]-glucosamine and L-[3H]-fucose into the developing rat cochlea.

The uptake of two tritiated carbohydrates, D-[3H]-glucosamine and L-[3H]-fucose, to the developing rat cochlea was examined using light and electron microscopic radioautography. Both carbohydrates, administered to in vitro developing rat cochleas, shared a similar ultrastructural labeling pattern on the microvilli and apical cell region and on the tectorial membrane (TM) fibrils. On embryonic day 18, the radiolabeling appeared on the apical surface of the undifferentiated epithelium that will develop into both spiral limbus and Kölliker's organ (KO), while on postnatal day (PD) 1, it was only located on the apical surface of the KO. When D-[3H]-glucosamine was administered in vivo to newborn rats, the radiolabeling was observed in the TM covering the KO at PD 3. Lastly, D-[3H]-glucosamine administered in vivo to PD 7 rats, appeared at PD 9 in the TM region lying just above the organ of Corti. The present findings support the previously suggested leading role of the spiral limbus and KO in the secretion of the TM during cochlear development. The secretion of carbohydrates, and probably of other matrix components, starts on the spiral limbus and KO region and progressively extends to the organ of Corti.

A 5-year clinical evaluation of Norplant implants in Senegal.

The principal objective of this 5-year clinical study of Norplant implants was to introduce these implants into the family planning program in Senegal and to determine their overall acceptability and safety in Senegalese acceptors. A total of 300 subjects were enrolled into the trial from August 1986 to July 1991. All the women were followed-up for 5 years or until the implants were removed. The pooled cumulative discontinuation rate was 40.8 +/- 2.91 per 100 women resulting in a continuation rate of 59.2 +/- 2.91 per 100 women. Thirteen subjects (4.3%) were lost during the follow-up. Seven pregnancies were reported throughout the 5 years leading to a cumulative pregnancy rate of 3.3 +/- 1.25 per 100 women. Menstrual problems were the reason most often given for early removal during the first 2 years. After year 2, desire for another pregnancy was the main reason for implant removal. The results presented in this study show that the Norplant implant system is a safe, effective, and acceptable method that meets the needs of the Senegalese family planning program.

PIP: A 5-year prospective, noncomparative clinical evaluation of Norplant implants was conducted to introduce these implants into the family planning program and to determine the acceptability among women users in Senegal from August 1986 to July 1991. Findings showed that the pooled discontinuation rate was 40.8 +or- 2.91 per 100 women, resulting in a continuation rate of 59.2 +or- 2.91 per 100 women. During follow-up, 13 (4.3%) subjects were lost. Throughout the 5 years, 7 pregnancies were reported leading to a cumulative pregnancy rate of 3.3 +or- 1.25 per 100 women. The most common reason for early removal during the first 2 years was menstrual problems, while the main reason for removal in the second year was the desire to have a child. Overall, the Norplant implant system is a safe, effective, and acceptable method that is suitable for the Senegalese family planning program.

Anti-implantation activity of antiestrogens and mifepristone.

To develop a better postcoital contraceptive, the following antiestrogens were tested for their anti-implantation activity in the rat: anordrin, anordiol, tamoxifen, ICI 182,780, and RU 39411. The compounds were administered orally or subcutaneously (s.c.) to female rats on days 1, 2, and 3 of pregnancy. All the antiestrogens tested were 100% effective in preventing blastocyst implantation. The lowest effective doses when administered orally were 10, 1.25, 0.062, 6.0 (partially effective), and 0.01 mg/kg/day, respectively. The estimated median effective doses (ED50) were 5.60, 0.40, 0.035, 5.40, and 0.0074 mg/kg/day, respectively. When administered s.c., the minimum effective doses in preventing blastocyst implantation in all animals were 2.0, 0.1, 0.1, 0.1, and 0.01 mg/kg/day, respectively. Anordrin, anordiol, and ICI 182,780 were more potent when administered s.c.; whereas tamoxifen and RU 39411 were effective at similar doses when administered parenterally or orally. RU 39411 was the most potent among the antiestrogens tested and should be evaluated as a potential postcoital contraceptive. The administration of mifepristone, an antiprogestin, at a dose of 8 mg/kg/day blocked blastocyst implantation in all treated animals; whereas at a dose of 4 mg/kg/day or lower, the drug was ineffective. These findings confirm that estradiol and progesterone are essential for blastocyst implantation in the rat. The capacity of mifepristone to potentiate the anti-implantation activity of the antiestrogens was also determined. The combination of a non-effective dose of each of the antiestrogens (anordrin, anordiol, and tamoxifen), and RU 39411, with mifepristone at a non-effective dose, prevented pregnancy, demonstration that an antiprogestin and antiestrogen act synergistically in blocking blastocyst implantation in the rat. The antiestrogen compounds whose anti-implantation activities were potentiated by mifepristone were found to possess significant estrogenic activity, when assayed by measuring the increase in the uterine weights of ovariectomized rats. The only exception was ICI 182,780, which showed no estrogenic activity in the uterine weight bioassay and did not act synergistically with mifepristone in blocking blastocyst implantation. Estradiol was effective in preventing pregnancy at a dose of 1 microgram/kg/day. The combination of non-effective doses of estradiol and mifepristone did not prevent pregnancy. The findings that mifepristone potentiates the anti-implantation activity suggests that the synergistic effect may be a unique property of this class of antiestrogens.

PIP: In New York, female and male rats copulated on the afternoon of proestrus as part of a study aiming to determine whether antiestrogens alone or in combination with mifepristone (RU-486) will block blastocyst implantation in the rat. This study is part of research efforts to develop a better postcoital contraceptive. The antiestrogens included RU39411; ICI 182,780; anordrin; anordiol; tamoxifen; and estradiol. The laboratory researchers treated the rats orally or subcutaneously on days 1, 2, and 3 of pregnancy. They killed them on day 8-9 to examine the uteri for the presence or absence of implanted embryos. All the antiestrogens effectively prevented blastocyte implantation. Using the measurement mg/kg/day, the lowest effective oral dose was 10 for anordrin; 1.25 for anordiol; 0.062 for tamoxifen; 6 (80% effective) for ICI 182,780; and 0.01 for RU 39411. These antiestrogens' estimated median effective doses were 5.6, 0.4, 0.035, 5.4, and 0.0074 mg/kg/day, respectively. In all animals, the minimum effective doses administered subcutaneously were 2, 0.1, 0.1, 0.1, and 0.01 mg/kg/day, respectively. Anordrin, anordiol, and ICI 182,780 were more effective during subcutaneous administration while tamoxifen and RU 39411 were as effective at similar doses during parenteral or oral administration. The most potent antiestrogen was RU 39411. This antiestrogen should be evaluated as a potential postcoital contraceptive. An 8 mg/kg/day dose of RU-486 blocked blastocyst implantation in all rats. The 4 mg/kg/day dose was completely ineffective. RU-486 augmented the activity of anordrin, anordiol, tamoxifen, and RU39411 synergistically, resulting in prevention of pregnancy at non-effective doses of RU-486 and the antiestrogens. These same antiestrogens also exhibited significant estrogenic activity as determined by an increase in uterine weights of ovariectomized rats. Estradiol prevented pregnancy at a dose of 1 mcg/kg/day. RU-486 did not potentiate estradiol. These findings suggest that the synergistic effect of anordrin, anordiol, tamoxifen, and RU39411 may be unique to these antiestrogens.

Comparative effectiveness of three antiprogestins alone and in combination with anordiol in terminating pregnancy in the rat.

The effectiveness of mifepristone, onapristone, and ORG 31806 alone or in combination with anordiol to terminate pregnancy in the rat was evaluated. ORG 31806 at a dose of 2 mg/kg/day, mifepristone at 4 mg/kg/day, and onapristone at 8 mg/kg/day, terminated pregnancy in all treated animals. Anordiol, an antiestrogen, at a dose of 5 mg/kg/day, terminated pregnancy in all treated animals. Anordiol acted synergistically with all three antiprogestins terminating pregnancy in the rat. The antiprogestins at doses that were either partially effective or non-effective became 100% effective when administered with a non-effective dose of anordiol. Thus, combination of ORG 31806 (1 mg/kg/day) plus anordiol (0.31 mg/kg/ day), mifepristone (1 mg/kg/day) plus anordiol (0.62 mg/ kg/day), and onapristone (2 mg/kg/day) plus anordiol (2.5 mg/kg/day) terminated pregnancy in all treated animals. These combinations of the antiprogestins and anordiol decreased significantly the serum progesterone levels but not serum 17 beta-estradiol levels. The present results indicate that the most potent combination was ORG 31806 plus anordiol.

PIP: The pregnancy termination potency of varying doses of mifepristone, onapristone, and ORG 3806--alone and in combination with the estrogenic/antiestrogenic compound anordiol--was evaluated in adult rats. The antiprogestins and anordiol alone were administered to pregnant female rats on days 7, 8, and 9 of pregnancy and the presence or absence of embryos in utero was determined on day 16. ORG 31806 at a dose of 2 mg/kg/day, mifepristone at 4 mg/kg/day, and onapristone at 8 mg/kg/day terminated pregnancy in 100% of animals; 5 mg/kg/day of anordiol was required. Anordiol acted synergistically with all three antiprogestins. Antiprogestin doses that were either partially effective or ineffective became 100% effective when administered with a noneffective dose of anordiol. The combination of ORG 31806 (1 mg/kg/day) and anordiol (0.31 mg/kg/day) had the most potent pregnancy termination activity. The administration of antiprogestins in combination with anordiol at doses that effectively terminate pregnancy was associated with a significant, persistent reduction in serum progesterone, but no change in serum estradiol levels. The effectiveness of ORG 31806 and anordiol in terminating pregnancy should be evaluated in a non-human primate model to determine its potential clinical use.