Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.
(49/2040)
DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg). (+info)
Management of women with recurrent genital herpes in pregnancy in Australia.
(50/2040)
OBJECTIVE: To document clinical practice for the management of recurrent genital herpes in pregnant women in Australia. DESIGN AND PARTICIPANTS: A questionnaire to all doctors associated with the Royal Australian College of Obstetricians and Gynaecologists. MAIN OUTCOME MEASURES: Policies for antenatal herpes screening, circumstances in which delivery by caesarean section was considered appropriate, and the use of aciclovir during pregnancy. The results were analysed by college status, sex, and whether the doctor worked in a public or private facility. RESULTS: 2855 (67.3%) obstetricians returned questionnaires. 696 (34.3%) stated that their hospital had a policy for managing recurrent genital herpes in pregnancy: 44.5% examined the genitalia and 33.8% took cultures during pregnancy. Fellows were more likely to examine the genitalia (87% v 37%, p < 0.001), and more likely to perform antenatal viral cultures than members (75% v 30%, p < 0.001). Doctors working at private hospitals were significantly more likely to take viral cultures than doctors in public hospitals (39% v 33% p < 0.05). Doctors were asked to consider five scenarios and judge whether caesarean section would be appropriate. 96% considered that a caesarean section was appropriate in women with active herpes at the onset of labour. In the case of a recurrence of genital HSV at the time of presentation with ruptured membranes longer than 4 hours, diplomats (79%) were significantly more likely to recommend a caesarean section than fellows (64%), members (63%), or trainees (49%) (all p < or = 0.001). Where there were positive viral cultures before the onset of labour fellows (45%) were more likely than members (29%) (p = 0.005), males (62%) were more likely than females (55%) (p = 0.03), and doctors working in private hospitals (69%) were more likely than those in the public sector (54%) (p < 0.001) to recommend caesarean section. CONCLUSION: There is considerable divergence of opinion regarding the appropriate management of recurrent genital herpes in pregnancy. The implementation of management guidelines would provide consistency of care. (+info)
Expression of cyclo-oxygenase types-1 and -2 in human myometrium throughout pregnancy.
(51/2040)
Human labour is associated with increased prostaglandin synthesis within the uterus. The aim of this study was to examine the expression of the two isoforms of the central prostaglandin synthetic enzyme, cyclo-oxygenase (COX-1 and COX-2) in human myometrium throughout pregnancy and to test the hypothesis that COX in the myometrium may play a role in labour onset. Expression of COX-1 and COX-2 at the mRNA level was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level using Western blotting. No significant changes of COX-1 RNA or protein expression were observed either with gestational age or labour. COX-2 mRNA and protein expression increased at term with significant up-regulation occurring prior to the onset of labour (P < 0.005). These data would suggest that up-regulation of COX-2, rather than COX-1, mediates increased prostaglandin synthesis in human myometrium at term. The increased COX-2 expression observed preceded labour onset, suggesting that COX-2 has a role in labour onset, rather than its presence merely a consequence of labour. (+info)
Recurrent cholestasis following ovarian hyperstimulation syndrome: case report.
(52/2040)
This is a case report illustrating a patient who developed recurrent cholestasis during a twin pregnancy following in-vitro fertilization (IVF) treatment. On the first occasion cholestasis developed unusually in the first trimester, and on the second occasion, it presented in the way that obstetric cholestasis (OC) is commonly seen in the third trimester. (+info)
Diabetes in pregnancy and cesarean delivery.
(53/2040)
OBJECTIVE: To evaluate the effect of diabetes during pregnancy on cesarean delivery and to determine whether the association between diabetes during pregnancy and cesarean delivery is mediated by birth weight. RESEARCH DESIGN AND METHODS: South Carolina 1993 birth certificates were matched through a unique identifier with infant and maternal hospital discharge records for the same year, yielding a total study population of 42,071 singleton births. Adjusted odds ratios (ORs) and 95% CIs were determined for the association between diabetes in pregnancy and cesarean delivery through multiple logistic regression, controlling for maternal age, race, education, number of prenatal care visits, length of gestation, birth weight, and a number of medical indications. RESULTS: Of the study population, 0.7% were pregnancies complicated by preexisting diabetes, 2.9% were pregnancies complicated by gestational diabetes, and 23.4% were cesarean deliveries. After controlling for confounders, including birth weight, cesarean delivery was strongly associated with both preexisting diabetes (OR [95% CI] 6.20 [4.47-8.61]) and gestational diabetes (1.71 [1.41-2.07]). The estimates remained essentially unchanged without birth weight in the model, and were substantially higher in analyses restricted to deliveries without common medical indications for cesarean delivery. CONCLUSIONS: Both preexisting and gestational diabetes increase the risk for cesarean delivery, independent of the effect of birth weight. The association is markedly greater among women without other medical indications for cesarean delivery. The increased risk of cesarean delivery for women with diabetes is mediated through other factors, which may include practice patterns and physician referrals to high-risk care. (+info)
Risk factors for the increasing caesarean section rate in Southeast Brazil: a comparison of two birth cohorts, 1978-1979 and 1994.
(54/2040)
BACKGROUND: Brazil has the highest caesarean section (CS) rate in the world (36.4% in 1996). METHODS: Risk factors for increasing CS rate were studied in two population-based cohorts of singleton live births in families residing in the municipality of Ribeirao Preto, State of Sao Paulo, Southeast Brazil. The first comprised births from June 1978 to May 1979 (6750 births-one-year survey) and the second births from May to August 1994 (2846 births-4-month survey). Multiple unconditional logistic regression modelling was used to control for confounding. RESULTS: The CS rate rose from 30.3% in 1978-1979 to 50.8% in 1994. In 1978-1979, socioeconomic, reproductive and demographic variables, and health service factors were associated with CS rate. In 1994, only reproductive, demographic and health service factors remained associated, e.g. hour of delivery (from 7 a.m. to 12 p.m.), attendance by the same physician for prenatal care and delivery, > or =4 prenatal visits, maternal age > or =30 years, 1-3 previous live births and birthweight 3500-3999 g. CONCLUSION: Caesarean section in Brazil is widely performed for non-medical reasons in which physician convenience plays an important role. There is an urgent need for public health interventions to reduce the CS rate in Brazil, mainly directed towards cultural beliefs and physician behaviour. (+info)
The infusion rate of mivacurium or atracurium for cesarean section compared with gynecological procedures.
(55/2040)
Mivacurium is mainly metabolized by plasma cholinesterase, whereas atracurium is removed by Hofman elimination. The purpose of this study was to compare the infusion rate of atracurium and mivacurium in maintaining surgical relaxation, and to compare their recovery indices between parturients and non-pregnant women. Muscle relaxation was maintained by the continuous infusion of relaxants to retain the first response of train-of-four (TOF) at 5% of control. When mivacurium was used, Bolus-T5 (duration from the end of mivacurium bolus injection to 5% single twitch recovery) was measured. After discontinuing the infusion, the recovery index was measured. The infusion rate of mivacurium, not atracurium, was significantly lower in parturients and Bolus-T5 of parturients was significantly longer than that of non-pregnant women. There was no significant difference in the recovery indices of both relaxants. The authors concluded that the infusion rate of mivacurium in maintaining muscle relaxation in parturients should be reduced compared to the rate in non-pregnant women and measuring Bolus-T5 may be helpful in determining the infusion rate to maintain muscle relaxation. (+info)
Involvement of calcitonin gene-related peptide in the modulation of human myometrial contractility during pregnancy.
(56/2040)
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and relaxes smooth muscle of a variety of tissues, but the effects of CGRP on human myometrial contractions and the changes in CGRP receptors (CGRP-Rs) in human myometrium have not been described. We report that CGRP induced dose-dependent relaxation in spontaneously contracting myometrium from pregnant women. This relaxation effect is diminished in myometrium obtained from patients during labor and in the nonpregnant state. CGRP-induced relaxations are inhibited by a CGRP-R antagonist (CGRP(8-37)), a soluble guanylate cyclase inhibitor (LY(83583)), and a nitric oxide synthase inhibitor (L-NAME). Both Western blotting and mRNA analysis showed that CGRP-Rs are present in human myometrium, and that the expression of these receptors is increased during pregnancy and decreased during term labor. Immunofluorescent staining revealed that CGRP-Rs are abundant in the myometrial cells of pregnant women who are not in labor, and are minimal in uterine specimens from women in labor and in the nonpregnant state. We conclude that increased CGRP-Rs in myometrium, and resulting enhanced myometrial sensitivity to CGRP, may play a role in maintaining human myometrium in a quiescent state during pregnancy, and that a decline in the CGRP-Rs at term could contribute to the initiation of labor. (+info)