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emotional support interventions showed reductions in cesarean (low SOE for doula support, moderate SOE for continuous emotional support) and instrumental deliveries (moderate SOE). For women choosing analgesia (epidural vs. combined spinal epidural, or epidural vs. patient-controlled intravenous analgesia), neither type nor timing affected cesarean delivery rates (moderate SOE). Conclusions The normal progress of labor given current practice is quite different from that originally described, although there is still uncertainty about the duration of “normal” labor in the absence of augmentation. Further work is needed to identify (1) the cesarean delivery rate that optimally balances maternal and neonatal outcomes and patient preferences, and (2) the best strategies to achieve this rate.Two study protocols were used to evaluate the reproductive, developmental, and general toxicity of 3'-azido-3'-deoxythymidine (AZT) and clarithromycin in Swiss (CD-1®) mice treated by oral gavage. For both studies, male mice (10 to 18/group) were dosed from study day 5 until the day prior to sacrifice on study day 25 or 26. Females were divided into two groups designated female-A and female-B mice. The female-A mice (20 to 28/group) were dosed from day 0 to sacrifice. They were cohabited with treated males on days 9 to 13 to test for effects on mating behavior, fertilization, and implantation. Caesarean sections were performed on presumed day 18 of gestation (days 28-32). The female-B mice (approximately 20/group) were cohabited with untreated males on days 0 to 4. Sperm-positive female-B mice were dosed during organogenesis on days 6 to 15 of presumed gestation and sacrificed on day 4 of lactation. [https://www.selleckchem.com/pharmacological_epigenetics.html Epigenetic inhibitors] In the initial study, doses of clarithromycin (500, 1,250, or 2,500 mg/kg) were approximately 2, 5, or 10 times combinations of AZT and clarithromycin. Combination therapy resulted in reduced pregnancy rates, reduced live litter size, increased numbers of resorptions, and declines in fetal and pup weights per litter. Fewer pups survived to postnatal day 4.Male and female B6C3F1 mice were dosed orally with AZT alone (100, 200, or 400 mg AZT/kg body weight per day), isoniazid alone (50, 100, or 150 mg/kg per day), or combinations of AZT and isoniazid for up to 94 days. Mice were evaluated for clinical signs, mortality, body and organ weights, sperm function and vaginal cytology, and hematology and clinical chemistry parameters. Core study mice, early-death clinical pathology mice, and females from the 400 + 150 mg/kg (AZT + isoniazid) clinical pathology group were necropsied and subjected to histopathological evaluations. The significant effects of treatment with AZT and isoniazid are summarized in the Abstract Table. The primary toxicity of AZT was bone marrow suppression. The hematopoietic toxicity was manifested by dose-related anemia, thrombocytosis, and a reticulocytopenia followed by reticulocytosis. Cellular depletion of the bone marrow was observed microscopically and was considered the major treatment-related effect. Increased pigmentation of the skin and a slight decline in epididymal sperm motility also occurred in mice treated with AZT alone. Administration of isoniazid alone resulted in slight hepatotoxicity manifested by hepatocellular hypertrophy and pigment deposition in the liver of male mice. Treatment with isoniazid also resulted in a slight increase in the duration of estrus. Administration of AZT in combination with isoniazid resulted in hematopoietic toxicity of greater severity than that resulting from the administration of AZT alone. The bone marrow suppression and anemia resulted in significant mortality in female mice treated with the highest combinations of AZT and isoniazid. Combination therapy also resulted in treatment-related declines in body weight, reticulocytopenia followed by reticulocytosis, thrombocytosis, leukopenia, neutropenia, lymphopenia, and a slight increase in the duration of estrus.Male and female Swiss CD-1® mice were dosed orally with AZT alone (200 or 400 mg/kg per day), pyrazinamide alone (300, 1,500, or 3,000 mg/kg per day), or combinations of AZT and pyrazinamide. The doses of AZT were equivalent to 2 and 4 times the therapeutic dose in humans, based on body surface area, and the doses of pyrazinamide were 2, 10, and 20 times the therapeutic dose for experimental tuberculosis in mice (Freireich et al., 1966; Grosset et al., 1992; PDR, 1999). Male mice (10 per group) were dosed from day 5 until the day prior to sacrifice on day 25 or 26. Females were divided into two groups designated female-A mice and female-B mice. The female-A mice (20 per group) were dosed from day 0 to the day of sacrifice. They were cohabited with treated males on days 9 to 13 to test for effects of treatment on mating behavior, fertilization, and implantation, and caesarean sections were performed on days 28 to 32. Female-B mice (20 per group) were cohabited with untreated males on days 0 to 4. Sperm-positivse in the duration of gestation. Combination therapy resulted in alterations in the above reproductive parameters of far greater magnitude than occurred with either compound alone. Other changes evident subsequent to combination therapy consisted of a decrease in the number of pregnant females that delivered litters, diminished litter size, an increase in the number of stillborn pups, and a decrease in the number of liveborn pups per litter. Combination therapy also resulted in diminished live litter size and an increase in the number of pup deaths during the lactation period. Significant numbers of gross external alterations did not occur following administration of either compound alone or in combination.Male and female B6C3F1 mice were dosed orally with AZT alone (100, 200, or 400 mg/kg), rifampicin alone (100, 200, or 400 mg/kg), or combinations of AZT and rifampicin for up to 94 days. Mice were evaluated for clinical findings, mean body weight, hematology and clinical chemistry parameters, and sperm function and vaginal cytology. All core study animals and the clinical pathology study animals that died early were necropsied and subjected to histopathological evaluations. A summary of the most significant toxicological parameters is presented in Table 1. AZT alone or rifampicin alone did not cause significant changes in body weights. Combination therapy with AZT and rifampicin caused marked and treatment-related decreases in body weights. The primary toxicity of AZT was bone marrow suppression manifested by macrocytic anemia, thrombocytosis, and reticulocytopenia followed by reticulocytosis. Bone marrow atrophy was observed microscopically and was considered the major drug-related effect. Administration of rifampicin alone resulted in both hematological toxicity and hepatotoxicity.