Increasing Maternal Blood Pressure with Ephedrine Increases Uterine Artery Blood Flow Velocity during Uterine Contraction

Background: During labor, ephedrine is widely used to prevent or to treat maternal arterial hypotension and restore uterine perfusion pressure to avoid intrapartum fetal asphyxia. However, the effects of ephedrine on uterine blood flow have not been studied during uterine contractions. The purpose of the study was to assess the effects of ephedrine on uterine artery velocities and resistance index using the Doppler technique during the active phase of labor.

Methods: Ten normotensive, healthy parturients with uncomplicated pregnancies at term received intravenous ephedrine during labor to increase mean arterial pressure up to a maximum of 20% above their baseline pressure. Peak systolic and end-diastolic Doppler flow velocities and resistance indices were measured in the uterine artery before and immediately after administration of bolus intravenous ephedrine and after ephedrine washout. Umbilical and fetal middle cerebral arterial resistance indices and fetal heart rate were also calculated.

Results: After ephedrine administration, mean arterial pressure increased by 17 +/- 4%. End-diastolic flow velocity in the uterine artery at peak amplitude of uterine contraction was restored to 74% of the value observed in the absence of contraction. The systolic velocity was totally restored, and the uterine resistance index was significantly decreased, compared with the values in the absence of contraction. Between uterine contractions, ephedrine induced similar but less marked effects. Fetal hemodynamic parameters were not altered by ephedrine administration.     

The Tempofilter®: A Multicenter Study of a New Temporary Caval Filter Implantable for up to Six Weeks

multicenter study was conducted to evaluate a new temporary caval filter (TempofilterT) designed to be implanted for up to 6 weeks. A total of 66 patients with a mean age of 51.8 years were enrolled in the study. All had documented high risk of pulmonary embolism: severe deep venous thrombosis in 89.5% of cases and previous symptomatic pulmonary embolism in 65% of cases. Filter placement was performed in association with a surgical or obstetrical procedure in 68.5% of cases. The indication for filter placement was contraindication to or failure of anticoagulant therapy in 85% of the cases. The mean duration of implantation was 29.9 days. Pulmonary embolism was not observed during the implantation period. Partial thrombosis of the filter was observed in 15% of cases due to trapping of clots by the filter. Thrombosis did not hinder filter removal when attempted. Filter-related complications were minor. Filter migration occurred in only 7.5% of cases. Migration never led to complications and did not hinder filter removal. In all cases migration was due to specific, preventable causes. The results of this study show that the TempofilterT is not only safe and easy to use but also effective in preventing pulmonary embolism. A significantly longer maximum implantation time is a major advantage of the TempofilterT over conventional temporary filters. We believe that this filter can be used for temporary protection against the risk of pulmonary embolism particularly in young patients and in a surgical setting. (Ann Vasc Surg 1997;11:520–528.)     

Simultaneous occurrence of acute myelogenous leukemia and seminoma of the testis

Summary Simultaneous tumors are rarely encountered during the course of acute leukemias. We report on a case of seminoma of the testis that occurred during the evolution of acute myelogenous leukemia. To our knowledge, this stimultaneous association has not previously been described, but a causal relationship was not apparent in the present case. The likelihood of a common carcinogenesis existed, but direct exposure to carcinogens could not be established. Although the results of a physical examination and echography were normal at the time of diagnosis, we cannot exclude the presence of microscopic cancer of the testis. Since the dissemination pattern of seminoma is usually slower than that observed in this case and the disease remains limited to the lymph nodes for long periods following dissemination, the rapid development of the present case might have been attributable to the immunosuppression and the scrotal sepsis that occurred during the induction therapy. Immunosuppression might have stimulated the progression of a primary microscopic seminoma and the development of metastasis, whereas the scrotal sepsis and inflammation might have favored the occurrence of metastasis through bypass of the lymphatic barrier.     

Infants thinner at birth exhibit smaller kidneys for their size in late gestation in a sample of fetuses with appropriate growth

Fetal ultrasound measurements were employed to investigate the relationship between weight and ponderal index at birth and kidney size during the second (23 weeks) and third (32 weeks) trimesters of pregnancy in a sample of 25 normally growing fetuses. Kidney volume and kidney volume / fetal weight ratio at 32 weeks are significantly and positively related to both weight and ponderal index at birth, controlling for sex, gestational age at birth, and day of ultrasound measurement. A second‐degree polynomial relationship approximates the predictability of kidney volume fetal weight ratio at 23 weeks to that at 32 weeks, demonstrating shifting growth rates in fetal organ and body growth relationships during midgestation. Sex and parental size are suggested as contributing to these patterns. Females have a surge in renal growth between 23 and 32 weeks to catch up to earlier growing males, and maternal weight significantly predicts incremental growth in kidney volume and the kidney volume / fetal weight ratio at 32 weeks of gestation. The observation that fetuses relatively thin at birth have relatively smaller kidneys for their size in late gestation suggests that the influence of maternal weight on birth outcome may act through organ growth. Am. J. Hum. Biol. 14:398–406, 2002. © 2002 Wiley‐Liss, Inc.     

Characterization of dihydropyridine binding sites in the rat brain: hypertension and age-dependent modulation of [H](+)-PN 200-110 binding

The properties of [³H]dihydropyridine (DHP), nitrendipine and (+)-PN 200-110, binding to rat cerebral membranes were investigated. In normotensive Wistar-Kyoto (WKY) adult rats, the highest densities of [³H]DHP binding sites were found in the hippocampus. Frontal cerebral cortex and hypothalamus had intermediate levels and no specific binding of [³H]DHP and [¹²⁵I]iodipine could be detected in the brainstem membranes and more precisely in the nucleus tractus solitarius and in the locus coeruleus. Changes in the maximal number of DHP binding sites (B_max) were observed in spontaneously hypertensive rats (SHR) and in old Sprague-Dawley rats. In adult SHR, there was a significant increase in theB_max values of [³H](+)-PN 200-110 binding in the hippocampus when compared to the values obtained in WKY. There was no difference in theB_max values between young (3 weeks) prehypertensive SHR and age-matched WKY. In senescent (26 months) Sprague-Dawley rats, theB_max values of [³H](+)-PN 200-110 binding were significantly reduced (30%) in the frontal cerebral cortex and the hippocampus, as compared with the number of DHP binding sites found in mature Sprague-Dawley rats (15 weeks).     

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CL_int), as derived from the ratio of V _max/K_m, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml^*min^{-1 *}g^-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml^* mini^*g^-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml^*min^{-1 *} g^-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CL_int of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.