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Biomedical subjects

J M Manson

Publications and source records attributed to J M Manson.

65 records · Page 4Linked to original sources
PubMed1979

Evaluation of teratogenicity and behavioral toxicity with inhalation exposure of maternal rats to trichloroethylene.

Female rats were exposed by inhalation to trichloroethylene (TCE) vapors at a concentration of 1800 +/- 200 ppm to determine whether exposure before mating and during pregnancy is more detrimental to reproductive outcome than exposure either before mating alone or during pregnancy alone. Four treatment groups were utilized in a two by two factorial design: exposure to TCE for 2 weeks before mating and during the first 20 days of pregnancy; TCE before mating and filtered air during pregnancy; filtered air before mating and TCE during pregnancy; and filtered air before and during pregnancy. Significant elevations in skeletal and soft tissue anomalies, indicative of developmental delay in maturation rather than teratogenesis, were observed in the group exposed during pregnancy alone. The mixed function oxidase enzymes, ethoxycoumarin and ethoxyresorufin, indicative of cytochrome P-450 and P-448 activities, respectively, were measured in maternal and fetal livers, as well as livers of non-pregnant females, and showed variable levels of activity not uniformly related to treatment or pregnancy. Behavioral evaluation of offspring indicated a lack of treatment effect in tests of general activity levels at 10, 20 and 100 days of age. However, a reduction in postnatal body weights was seen in offspring from mothers with pregestational exposure. No results indicative of treatment-related maternal toxicity, embryotoxicity, severe teratogenicity or significant behavioral deficits were obtained in any of the treatment groups.

Abnormalities, Drug-Induced↗
PubMed1977

Influence of cyclophosphamide and 4-ketocyclophosphamide on mouse limb development.

Many studies have been performed on the in vivo teratogenicity of cyclophosphamide, and there is uncertainty whether the parent compound or P-450 generated alkylating metabolite(s) is the proximal teratogen(s). We have examined the influence of cyclophosphamide and a metabolite, 4-ketocyclophosphamide, on mouse limb development. Pregnant mice were injected with 10, 15 or 20 mg/kg of cyclophosphamide on days 9 to 11 of gestation. Hindlimb buds were maximally sensitive to 20 mg/kg of cyclophosphamide at 9 A.M. on day 11, and the predominant malformations formed were preaxial ectrodactyly and hemimelia. Hindlimb buds of the same gestational age exposed to cyclophosphamide in vitro responded identically to controls in morphology and uptake of 3H-thymidine and 35SO4. Exposure to 4-ketocyclophosphamide in culture, however, resulted in the formation of limbs with a "hemimelic" appearance and distal limb reduction, and with reduced uptake of 3H-thymidine and 35SO4. These findings support the position that the P-450 generated metabolite(s), and not the parent compound, is the proximal teratogen(s).

Animals↗
PubMed1977

Effects of cytosine arabinoside on in vivo and in vitro mouse limb development.

When pregnant mice were exposed to 40 mg per kg of cytosine arabinoside (ara-C) on days 10 to 12 of gestation, adactylous limbs with large, distally located blisters were found when the fetuses were examined on day 18. Embryonic limbs exposed transplacentally under identical conditions and explanted to culture exhibited the same morphological abnormality as did limbs exposed directly in culture to 0.1 to 1 microgram per ml of ara-C. Two noncytotoxic analogues of ara-C, uridine arabinoside (ara-U) and hypoxanthine arabinose (ara-HX), had no influence on morphological differentiation of limbs in vitro. Ara-C alone caused a dose-related decrease in uptake of 3H-thymidine and 35SO4 in cultured limb buds. Production of this morphologically distinct malformation in vitro will allow detailed biochemical investigations on the effect of ara-C limb ectodermal-mesenchymal interactions.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Pharmacokinetic studies of enalaprilat in the in vitro perfused human placental lobule system.

The objectives of this study were to evaluate the transplacental kinetics and effects on placental function of the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, in the dually perfused human placental lobule system. When placed in the maternal perfusate at a high therapeutic serum concentration (150 ng/ml), enalaprilat was rapidly transferred from the maternal perfusate into placental tissue followed by a gradual release from the placenta into the fetal perfusate. Cmax and AUC values for enalaprilat in the maternal perfusate were approximately 3 times higher than in the fetal perfusate, and drug levels did not equilibrate between maternal and fetal perfusates during the 4-6 hours of perfusion. The more highly perfused regions of the placental lobule had higher drug levels than non-perfused areas. At the end of the perfusion period, the mean percent of total drug added in the maternal perfusate was 59%, with 23% in the fetal perfusate and the remainder (18%) in placental tissue. Despite the relatively high levels of drug found in placental tissue, there were no alterations in placental function as measured by fetal volume loss, fetal pressure, glucose utilization, lactate production, hCG release, net fetal oxygen transfer, and oxygen consumption. Results from this study clearly document placental transfer of enalaprilat in the perfused human placental lobule system. The lack of effect on placental function suggests that enalaprilat has no direct effect on fetoplacental vascular beds, and that fetal hypotension occurring from ACE inhibitor exposure may be due to direct effects on the fetal kidney and not to decreased perfusion of fetoplacental vascular beds; these findings require further validation in an in vivo model.

Area Under Curve↗
PubMedDate not supplied

Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy.

Pregnancy outcomes in women with inadvertent exposure to lovastatin and simvastatin during pregnancy have been examined based on reports submitted to the manufacturer as part of worldwide postmarketing surveillance. There were 134 reports of exposure during pregnancy in which pregnancy outcome was known. Among prospectively followed pregnancies with known outcome, the proportion of normal outcomes was 85%, congenital anomalies 4.0%, spontaneous abortions 8.0%, fetal deaths/stillbirths 1.0%, and miscellaneous adverse outcomes 2.0%. While the number of prospective reports available for evaluation were only sufficient to rule out a three- to fourfold increase in the overall frequency of congenital anomalies, these proportions do not exceed what would be expected in the general population. Based on findings from this interim evaluation, there is no relationship between exposure to therapeutic doses of these agents during pregnancy and the occurrence of adverse pregnancy outcomes.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Pharmacist's guide to pregnancy registry studies.

OBJECTIVE: To introduce the concept and design characteristics of pregnancy registries and to discuss opportunities for pharmacist involvement. DATA SOURCES: Previous and ongoing pregnancy registry studies that assess the safety of pharmaceutical agents in pregnant women were identified from the medical literature, Internet, abstracts from professional meetings, and personal communications. DATA EXTRACTION: The development and use of the pregnancy registry study for evaluating drug safety is described. Then, to illustrate the application of scientific principles to this unique study design, examples are given from previous and ongoing pregnancy registry studies. DATA SYNTHESIS: Pregnancy registry studies are increasingly used to assess the safety of drugs and other therapeutic agents during pregnancy. In a pregnancy registry, women who took the study drug while pregnant are identified soon after that exposure and followed until their pregnancy ends and its outcome is determined. Information is compiled from hundreds or thousands of pregnancies and used to make a safety assessment. CONCLUSION: Pharmacists can explain pregnancy registries to pregnant women and encourage enrollment. Also, pharmacists can use information derived from these studies to help patients and health care providers manage inadvertent drug exposures and optimize pharmaceutical therapy during pregnancy.

Data Collection↗