Biomedical subjects

Dominique Cabrol

Publications and source records attributed to Dominique Cabrol.

27 records · Page 2Linked to original sources

PubMed2004

Tocolytic effects of intravenous nitroglycerin.

Currently available tocolytic agents have shown partial or transient efficacy on uterine contractions delaying delivery for 24 or 48 h without reduction in perinatal morbidity and mortality. These facts led us to study a new tocolytic compound. A double-blind dose finding study of the nitroglycerin tocolytic effect during preterm labor was conducted using a continual reassessment method among six different doses (0.2-1.2 mg/h for 2 h) in pregnant women who were unresponsive, intolerant to salbutamol, or with a contraindication to this therapy. Twenty-five pregnant women were included. The probability of success in stopping uterine contractions reached, for the maximal dose (1.2 mg/h), only a 54% rate (95% CI: 29-79%). Twelve patients complained of headaches and 16 experienced a decrease in arterial blood pressure suggesting that it would not be safe to increase the dose in order to obtain a higher success rate. The present study suggests that nitroglycerin is not as effective as expected in controlling uterine contractions during severe preterm labor in patients where beta2 agonists cannot be used.

Adult↗

PubMed2004

Pharmacokinetics of tocolytic agents.

Tocolytic agents are drugs designed to inhibit contractions of myometrial smooth muscle cells. Such an effect has been demonstrated in vitro or in vivo for several pharmacological agents, including beta-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, the aim of tocolysis is not only to stop uterine contractions or to prevent preterm delivery, but to prevent perinatal morbidity and mortality associated with preterm birth. The achievement of this goal has not yet been clearly demonstrated for any of the drugs available, and the use of tocolytic agents may appear controversial. Therefore, it is important to avoid maternal and fetal toxicity when tocolytic agents are used. During pregnancy, all steps of drug pharmacokinetics are altered. Absorption of drugs administered orally is limited because of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased. The metabolic activity of the liver is increased, accelerating the metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. These specific modifications have to be taken into account when using a drug in pregnant women. The aim of this review is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in pregnant women may affect the choice of optimal drug dosage and route of administration.

Adrenergic beta-Agonists↗

PubMed2004

Atosiban for preterm labour.

Oxytocin antagonists are synthetic analogues that have the nonapeptide structure of oxytocin. They act by competing with oxytocin for receptors in the myometrium. Animal experiments and pilot clinical studies have examined several agents and, of these, atosiban has been the object of extensive clinical trials. In a large placebo-controlled trial with >500 patients, atosiban reduced the number of premature deliveries over 7 days compared with placebo with no more adverse effects than placebo. In large multicentre studies comparing atosiban with beta-adrenoceptor agonists, the efficacy of the two medications was similar for pregnancy prolongation for 48 hours and for 7 days. The adverse effects, particularly cardiovascular, were considerably more frequent in the patients receiving beta-adrenoceptor agonists, who had to stop treatment significantly more often than the atosiban recipients. No fetal adverse effects were seen with atosiban and, in particular, no effect on baseline fetal heart rate, unlike with the beta-adrenoceptor agonists. Neonatal outcome did not differ significantly according to the treatment. The usefulness of maintenance treatment after the initial 48 hours has not been confirmed. Thus, the effectiveness of oxytocin antagonists appears to be similar to beta-adrenoceptor agonists and the former are not accompanied by measurable adverse effects. Oxytocin antagonists were designed specifically as tocolytics and have been validated by the European Drug Agency. They may be the treatment of choice for preterm labour, particularly in patients at risk of cardiovascular complications (e.g. multiple pregnancy, heart disease, etc.).

Adrenergic beta-Agonists↗

PubMed2003

Anti-inflammatory and utero-relaxant effects in human myometrium of new generation phosphodiesterase 4 inhibitors.

The anti-inflammatory and utero-relaxant effects of two potent phosphodiesterase 4 (PDE4) inhibitors of the latest generation: cilomilast (one of the most advanced PDE4 inhibitors in clinical development, reportedly more selective for PDE4D) and compound A (which displays 12-fold greater selectivity toward PDE4B and/or PDE4A than toward PDE4D) were evaluated in human uterine smooth muscle. We first established that these compounds exhibit greater efficacy in inhibiting total cAMP-PDE activity in pregnant versus nonpregnant myometrium (E(max) = 78.0% +/- 3.6% and 80.3% +/- 2.2% in pregnant versus 57% +/- 4.7% and 70.5% +/- 5.9% in nonpregnant women for compound A and cilomilast, respectively; P < 0.05 for both compounds), confirming the prominent participation of PDE4 isoforms in cAMP hydrolysis in the near-term pregnant myometrium. Using pregnant myometrial explants, we have shown that both these drugs and also rolipram, the prototype PDE4 inhibitor, produce concentration-dependent inhibition of lipopolysaccharide (LPS) induced tumor necrosis factor alpha (TNFalpha) release with similar potency in each case (pD2 = 8.0 +/- 0.5, 7.9 +/- 0.2, and 7.6 +/- 0.2 for compound A, cilomilast, and rolipram, respectively). The maximum inhibition produced is 65%. Pretreatment with forskolin or 8-bromo-cAMP mimics the PDE4 inhibitor effect. Furthermore, compound A and cilomilast both produce concentration-dependent inhibition of the spontaneous contractions of myometrial strips and are more potent in pregnant than in nonpregnant myometrium (pD2 = 7.3 +/- 0.7 and 8.1 +/- 0.3 in pregnant versus 6.2 +/- 0.9 and 6.6 +/- 0.1 in nonpregnant myometrium for compound A and cilomilast, respectively; P < 0.05 for both compounds). This demonstrates that the PDE4 isoforms involved in the mechanism of contraction are different in the pregnant and nonpregnant myometrium. Our study highlights the importance of developing PDE4 inhibitors for the pharmacological management of infection-induced preterm labor.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

Effect of amniotic fluid upon prostaglandin E2 and I2 production by cultured human myometrial cells.

OBJECTIVE: Our goal was to study the effect of amniotic fluid obtained at 16 and 39 weeks of gestation in normal human pregnancies upon prostaglandin production by human myometrial cells in culture. STUDY DESIGN: Amniotic fluid, sampled either at 16 weeks, during amniocentesis, or at 39 weeks, during caesarean section before labor, was fractionated by molecular-weight and then incubated with human myometrial cells in culture. We then used radioimmunoassay to measure PGE(2) and PGI(2) production. RESULTS: The "3-30 kDa" fraction of amniotic fluid sampled at 16 weeks significantly inhibited PGE(2) and PGI(2) production by human myometrial cells. When amniotic fluid was sampled at 39 weeks, it stimulated both PGE(2) and PGI(2) production, and the ">30 kDa" fraction increased levels of PGE(2) considerably more than of PGI(2) (420.0+/-88.0 ng/10(6)cells versus 188.2+/-21.4 ng/10(6)cells, P<0.001). CONCLUSION: Amniotic fluid contains substances whose effects in cultured myometrial cells vary according to gestational age and type of prostaglandin. These data suggest that the fetus plays a role in the regulation of myometrial activity during pregnancy.

Amniocentesis↗

PubMed2003

Contraction of cultured human uterine smooth muscle cells after stimulation with endothelin-1.

To our knowledge, the problem of how to maintain isolated smooth cells in a "contractile" phenotypic state without deviation after subculturing has yet to be resolved. The present study characterized the in vitro contractile response of human uterine smooth muscle cell to endothelin-1, which induces contractions in isolated uterine strips. Contractile effects were qualitatively investigated using silicone rubber substrata. Endothelin-1 was able to distort and reduce the wrinkles in the silicone surface. Contractions were also quantified by measuring the resulting change in the collagen lattice area. Endothelin-1 significantly increased the contractile response in a dose-dependent manner by selectively activating endothelin A receptors. When myometrial cells were cultured within collagen lattices, a microfilament-disrupting agent, cytochalasin B, abolished contractions, and no change was observed in smooth muscle alpha-actin immunostaining. Taken together, these observations show that the uterine smooth muscle cells are contractile and respond appropriately to a potent uterotonic agent. Based on these findings, a cultured uterine smooth muscle cell model, which could be used to elucidate the mechanisms controlling uterine activity, is proposed.

Collagen↗

PubMed2003

Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences.

Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in the VEGF family may explain the defective uteroplacental vascularization characterizing preeclampsia. We compared pregnancies complicated by early onset severe preeclampsia or intrauterine growth retardation to normal pregnancies. Maternal plasma, placentas, and placental bed biopsies were collected. The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds. Levels of VEGF-A, PlGF, and soluble VEGF receptor (VEGFR) were assessed in maternal plasma. In compromised pregnancies, elevated levels of VEGF-A and VEGFR-1 mRNAs may reflect the hypoxic status of the placenta. On contrast, the membrane-bound VEGFR-1 was decreased in the placental bed of preeclamptic patients. Preeclampsia was associated with low levels of circulating PlGF and increased levels of total VEGF-A and soluble VEGFR-1. Free VEGF-A was undetectable in maternal blood. Immunohistochemical studies revealed that VEGF-A and PlGF were localized in trophoblastic cells. Altogether, our results suggest two different pathophysiological mechanisms associated with preeclampsia. The first one is related to an overproduction of competitive soluble VEGFR-1 that may lead to suppression of VEGF-A and PlGF effects. The second one is the down-regulation of its membrane bound form (VEGFR-1) in the placental bed, which may result in the defective uteroplacental development.

Adult↗

PubMed2002

Breech presentation at term: morbidity and mortality according to the type of delivery at Port Royal Maternity hospital from 1993 through 1999.

OBJECTIVE: To compare neonatal morbidity and mortality at Port Royal Maternity between 1993 and 1999 for infants with a singleton breech presentation born after 37 weeks, according to planned mode of delivery. STUDY DESIGN: Retrospective study of 501 patients of whom vaginal delivery was planned in 322 (64%) or/and cesarean in 179 (36%). RESULTS: Severe neonatal morbidity was similar in the two groups (13/322, 4.0% versus 8/179, 4.5%; P=0.82); severe trauma morbidity was not significantly higher in the "planned vaginal delivery" group (3/322, 0.9% versus 1/179, 0.06%; P=0.16); there were no long-term sequelae. Mortality was not higher when vaginal delivery was planned. CONCLUSION: We have not found in this series any excess of morbidity or mortality attributable to vaginal delivery of breech presentations. This work does not indicate that we should change our obstetrical practice in the light of other recently-published studies.

Apgar Score↗

PubMed2002

Fertility after conservative treatment of placenta accreta.

OBJECTIVE: To report a pregnancy with vaginal delivery after a preceding pregnancy complicated by placenta accreta that was managed conservatively. DESIGN: Case report. SETTING: University medical center. PATIENT(S): A patient with placenta accreta that was managed conservatively. INTERVENTION(S): The placenta was left in situ and both uterine arteries were embolized. MAIN OUTCOME MEASURE(S): Preservation of reproductive capacity. RESULT(S): The patient had a term pregnancy with uncomplicated vaginal delivery. CONCLUSION(S): Pregnancy is possible after conservative treatment of placenta accreta. This treatment should be considered in the appropriate circumstances to preserve reproductive capacity.

Adult↗