Modulation of endocrine and transport functions in human trophoblasts by saquinavir and nelfinavir.

OBJECTIVES: The distribution of drugs to the maternal-fetal interface is influenced by the expression of various efflux transporters. Among these transporters, P-glycoprotein (P-gp) is responsible for the efflux of a great number of drugs such as protease inhibitors of the human immunodeficiency virus, thus reducing the chemical exposure of the fetus. STUDY DESIGN: The effects of saquinavir and nelfinavir were evaluated on human trophoblast functions and integrity by investigating their effect on human chorionic gonadotropin (hCG) secretion and on P-gp expression and functionality. RESULTS: Nelfinavir significantly reduced hCG secretion by 30% after a 48-h treatment but it had no effect on syncytia formation. Saquinavir had no effect on hCG secretion but significantly increased both expression (to a 2-fold extent) and functionality (by 17.9%) of P-gp, whereas nelfinavir only increased functionality (by 23.1%) with a dissociation of P-gp from caveolin-1. CONCLUSION: These results suggest that the effects of saquinavir and nelfinavir differ on trophoblast functions.

Contribution and limit of the model of perfused cotyledon to the study of placental transfer of drugs. Example of a protease inhibitor of HIV: nelfinavir.

OBJECTIVES: The perfused cotyledon model is a very useful method to study placental transfer of drugs. Here we studied placental transfer of the human immunodeficiency virus protease inhibitor nelfinavir using the non-recirculating dual human placental perfusion with a main goal to determining the clearance index of nelfinavir as related to maternal concentrations, and analyze the conditions under which ex vivo and in vivo data can be correlated. STUDY DESIGN: Thirteen human cotyledons, obtained after uneventful term pregnancies, were perfused in an open double circuit with nelfinavir (320-4436 microg/l) and a freely diffusing marker antipyrine 20 mg/l, in the presence of an albumin concentration of 2 g/l. Drug concentrations were determined by high-performance liquid chromatography. RESULTS: The mean clearance index of nelfinavir was very weak when maternal concentrations were under 500 microg/l (0.03+/-0.05). For maternal concentrations above 1200 microg/l, the mean fetal transfer rate was 14+/-3.4%, the mean clearance index was 0.39+/-0.10 and the fetal concentrations were between 133 and 671 microg/l. There was a good correlation between maternal and fetal concentrations (r=0.86; p<0.001). CONCLUSIONS: Our study with nelfinavir has achieved a good correlation between ex vivo and in vivo data. Our results also indicate that studies must be conducted under well defined conditions to obtain accurate and comparable data, underlining the fact that the ex vivo perfused cotyledon remains difficult to standardize as a model system.

Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery.

BACKGROUND: To provide anesthesia for cardiac surgery, hypnotics and opioids are frequently titrated on variables such as mean arterial pressure and heart rate. In this study conducted in patients scheduled to undergo coronary artery bypass grafting, propofol and sufentanil, both administered by computer-controlled infusion, were titrated on the Bispectral Index (BIS) values using a predefined algorithm. METHODS: After written informed consent, 110 patients, 95 men and 15 women aged 61 (9) yr [mean (SD)], were randomly allocated to receive predicted sufentanil effect site concentrations (Ce) of 0.5, 0.75, 1, 1.25, and 1.5 ng/ml, decreased by a third after sternotomy (groups 1-5). Target induction propofol concentration was 1.5 microg/ml and subsequently adjusted on BIS values. The following parameters were recorded: BIS values, predicted propofol Ce, the number of changes of propofol target, mean arterial pressure, heart rate, the number of bolus injection and doses of vasoconstrictor and vasodilator drugs, time to tracheal extubation, postoperative awareness and satisfaction scores, and cumulative morphine doses for the first postoperative day. RESULTS: One patient randomized to group 1 required 0.75 ng/ml sufentanil Ce instead of 0.5 ng/ml for increased BIS values on tracheal intubation. BIS values were similar in the five groups. The predicted propofol Ce values were different (P < 0.05; analysis of variance) among the five groups: 1.59 (0.47) to 1.23 (0.25) microg/ml in group 1 and group 4, respectively. Significantly fewer changes of propofol target were required in group 4 as compared to group 1. There were no differences among the five groups for mean arterial pressure, heart rate, time to tracheal extubation, awareness, satisfaction scores, and morphine requirements. CONCLUSION: These results suggest the BIS, as part of an algorithm that uses both the absolute BIS value and its increase following tracheal intubation, can be used to effectively titrate both propofol and sufentanil. A predicted sufentanil Ce of 1.25 ng/ml before and 0.8 ng/ml after sternotomy was associated with the lowest predicted propofol Ce and fewer changes of propofol target. Lower sufentanil concentrations required higher propofol concentrations and more frequent changes of the target propofol concentration and were associated with similar hemodynamic tolerance.

Molecular genetics of central nervous system malformations.

INTRODUCTION: Each of the processes involved in the development of the central nervous system is under genetic control and some mutations are responsible for severe malformations. For example, holoprosencephaly is associated with HPE genes, hydrocephalus with L1-CAM and lissencephaly with LIS-1. DISCUSSION: Molecular genetics has brought new insights into the etiology and pathogenesis of nervous system malformations and has provided new tools for accurate prenatal diagnosis.

Effects of electromagnetic fields on the immune systems of occupationally exposed humans and mice.

The authors examined immunological disorders in 6 individuals who had been exposed occupationally to environmental electromagnetic fields. Comparable effects on mice exposed in a similar environment were also investigated. The human subjects had worked 8 hr/day for 5 yr in a laboratory located above electrical transformers and high-tension cables, and in which there were low-frequency electromagnetic fields of 0.2-6.6 microtesla (microT). The 6 control subjects (matched for socioeconomic parameters, sex, and age) had worked away from the immediate vicinity of transformers and high-tension cables. The authors found statistically significantly lower total lymphocyte, CD4, and CD3 counts, and significantly increased natural killer (NK) cells, in exposed subjects vs. controls. Six months after exposure had ceased, total lymphocyte counts had increased, as had CD4, CD3, and CD19 counts (+13%, +28%, +22%, and +17%, respectively), and NK cell counts were decreased by 26% (not significant) in the same human subjects. In the second part of this study, 12 Swiss male mice housed in cages were exposed in the same room in which the human subjects had been exposed (i.e., 5-microT, 50-Hz magnetic field) for 109 days; 12 additional mice were used as unexposed controls. The total lymphocyte, leukocyte, polymorphonuclear neutrophil, CD4, and NK counts of the exposed mice at 109 days were significantly lower than those of controls. In addition, plasma glucose levels (at 30 days) and amylase activity (at 109 days) were significantly lower, whereas plasma sodium and chloride levels were significantly elevated at 109 days. Results from this study suggest that chronic exposure to a 0.2-6.6-microT magnetic field can lead to decreased immunological parameters (total lymphocytes and CD4 counts) in both humans and mice. The increase in some values once exposure was terminated suggests a causal relationship with exposure to electromagnetic fields, as do the changes in mice, particularly the changes in total lymphocyte and CD4 counts.

Effects of bupivacaine on mitochondrial energy metabolism in heart of rats following exposure to chronic hypoxia.

BACKGROUND: Adaptation to chronic exposure to hypoxia alters energy metabolism in the heart, particularly in the left ventricle, which undergoes a loss in oxidative capacity. Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. The purpose of this study was to compare the effects of bupivacaine on mitochondrial energy metabolism in heart of rats subjected to normoxic or hypoxic environments. METHODS: Male Wistar rats (n = 10) were subjected to hypobaric hypoxia (simulated altitude = 5,000 m, 380 mmHg) for 2 weeks. Control rats (n = 10) were maintained in an ambient normoxic environment. Mitochondrial metabolism (oxygen consumption and adenosine triphosphate synthesis) was assessed using saponin-skinned ventricular fibers. Bupivacaine (0-5 mM) was tested on both left and right ventricles of normoxic or hypoxic heart. RESULTS: In animals exposed to hypobaric hypoxia for 14 days, cardiac mass significantly increased, and the right-to-left ventricular ratio was approximately twofold (0.48 +/- 0.11 vs. 0.22 +/- 0.04, P < 0.05). Oxygen consumption and adenosine triphosphate synthesis were significantly lower in the hypoxic left ventricles but not in the right ones. The uncoupling effect of bupivacaine was more pronounced in the left ventricle from hypoxic heart than in the right ventricle; the bupivacaine-induced decrease in the adenosine triphosphate synthesis rate and in the adenosine triphosphate-to-oxygen ratio was significantly greater in the hypoxic left ventricle than in the normoxic one. CONCLUSIONS: Chronic hypoxia impairs cardiac energy metabolism in left ventricles and enhances the depressant effects of bupivacaine on mitochondrial functions.

Hemovigilance network in France: organization and analysis of immediate transfusion incident reports from 1994 to 1998.

BACKGROUND: Hemovigilance networks have been introduced in several countries to improve knowledge of blood transfusion-related morbidity and mortality. The general organization of the French network and its results from 1994 through March 1999 are presented here. STUDY DESIGN AND METHODS: The hemovigilance network relies on blood transfusion centers and hospital correspondents, who analyze unexpected and untoward blood transfusion-related effects and transmit a Transfusion Incident Report (TIR) to a national database (Transfusion Incident Reports Electronic Data Management [GIFIT]). RESULTS: As of March 1, 1999, the GIFIT database contained 24,234 TIRs related to incidents that occurred from the start of the hemovigilance network until December 31, 1998. The network was not fully implemented until 1996; but the reporting rate seems to have since stabilized at approximately 7000 per year (2.5 reports per 1000 blood components). The highest reporting rate is observed with platelet concentrates (4.02/1000), followed by RBCs (1.71/1000) and FFP (0.34/1000). Bacterial contamination quickly appeared as a major cause of morbidity and mortality (185 cases and 18 fatalities). However, a general trend of reduction in this type of incident was observed over time, which can be attributed to adoption of several preventive measures. In contrast, major ABO mismatchings during RBC transfusion remained at a constant rate throughout this period and accounted for six fatalities. After the implementation of universal WBC reduction, some incidents known to be related to WBCs, such as nonhemolytic febrile transfusion reactions (NHFTR) and HLA immunization, were dramatically reduced. CONCLUSION: Hemovigilance is an important tool not only to analyze blood transfusion incidents, but also to measure the effects of new processes or corrective actions at a national level.

Second trimester trisomy 21 maternal serum marker screening. Results of a countrywide study of 854,902 patients.

OBJECTIVES: In France, maternal serum marker screening is governed by specific legislation. We conducted a study of the countrywide trisomy 21 screening based on second trimester maternal serum markers. METHODS: We reviewed the medical records of 854,902 patients prospectively screened for second trimester maternal serum markers in the 60 authorized laboratories over the two-year period 1997-1998. All patients screened in France were included. The risk of trisomy 21 was calculated from the combination of maternal age and maternal serum markers. The same cut-off (1/250) was used in all laboratories. RESULTS: In 1998, 65% of pregnant women underwent maternal serum screening. In the 837,765 patients under 38 years of age who were screened, 54,321 (6.48%; 5% CI 6.42-6.53%) had a calculated risk >1/250. Of the 884 Down syndrome cases observed, 626 were detected by maternal serum markers (70.8%; 5% CI 67.8-73.8%). These good results can be explained by a strict quality control of all steps. For the 13,891 patients over 38 years of age, the Down syndrome detection rate was 98.9% for a 34% false-positive rate. CONCLUSIONS: Strict rules covering prenatal trisomy 21 screening are of benefit to patients, practitioners and laboratories alike, and ensure good quality control, a high trisomy 21 detection rate and a low amniocentesis rate.

Second trimester two-step trisomy 18 screening using maternal serum markers.

Trisomy 21 maternal serum marker screening has led to screening for other anomalies, including trisomy 18. Trisomy 18 is generally prenatally diagnosed because of major morphological defects. However, in up to 30% of cases ultrasound signs are unclear, and in most cases diagnosis is performed late in pregnancy. Of the different maternal serum markers, PAPP-A is now considered as the best for trisomy 18 screening. However, pregnancy-associated plasma protein A (PAPP-A) is of value in first trimester screening for trisomy 21, but not in the second trimester. We therefore propose a two-step screening strategy. Based on 45 trisomy 18 cases, we confirm the values of alpha-fetoprotein (AFP) (median 0.61 MoM), free beta-human chorionic gonadotrophin (beta-hCG) (median 0.24 MoM) and of PAPP-A (median 0.08 MoM). In the first step, a 0.5 MoM cut-off for AFP or for free beta-hCG resulted in detection of 37/45 trisomy 18 cases (82%) with a 10% false-positive rate. The second step consisted of the measurement of PAPP-A for all these false-positive cases. Using a PAPP-A cut-off of 0.5 MoM, all the 37 trisomy 18 cases were detected, but now with a 0.1-0.2% false-positive rate. Amniocentesis was only offered to these few patients. This two-step second trimester screening will be of value for patients who have not been included in first trimester screening based on nuchal translucency (NT) measurement combined with the first trimester markers, PAPP-A and free beta-hCG.

Antiplatelet agents in the perioperative period: expert recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) 2001--summary statement.

PURPOSE: Antiplatelet agents are administered to an increasing number of patients. Preoperative treatment with these agents represents a major problem for the anesthesiologist. The results of a French expert meeting on their perioperative management are reported. METHODS: Responses to questions formulated by the Organizing Committee were drafted by a group of experts and reviewed by a multidisciplinary. Reading Committee. Recommendations were classified (grade) according to the evidence level of the studies supporting them. PRINCIPAL FINDINGS: First, antiplatelet agents have a variable effect on hemostasis as far as bleeding risk is concerned. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) increase intra- and postoperative bleeding moderately, but not transfusion requirements. Very few data are available on clopidogrel and ticlopidin. Anti-glycoprotein (GP) IIb/IIIa agents may increase bleeding when surgery is required in proximity with their administration. Second, the common practice of withdrawing antiplatelet agents is now challenged because an increased incidence of myocardial infarction has been reported in patients in whom treatment was interrupted. Third, aspirin should not be withdrawn for most vascular procedures and in several additional settings. When a definite increase in intraoperative bleeding is feared, or when surgical hemostasis is difficult, aspirin, clopidogrel or ticlopidine can be replaced by short-acting NSAIDS, given for a ten-day period and interrupted the day before surgery. Platelet transfusion should only be given when overt bleeding is observed. Postoperatively, antiplatelet treatment should be resumed immediately after surgery (first six hours). CONCLUSION: Anesthesiologists should be aware of the indications, potential complications and means of substitution of these agents.