Article

Placental passage of angiotensin-converting enzyme inhibitors

Department of Obstetrics and Gynecology, University of Vienna, Austria.
American Journal of Obstetrics and Gynecology (Impact Factor: 3.97). 06/1996; 174(5):1450-5. DOI: 10.1016/S0002-9378(96)70587-2
Source: PubMed

ABSTRACT Placental passage of the angiotensin-converting enzyme inhibitors temocapril and enalapril was investigated in a placental perfusion model.
In an open system a placental lobe was perfused on both the maternal and the fetal side with a blood-free medium containing the test substances plus a reference substance on the maternal side. Six placentas were perfused with temocapril and five with enalapril. The drugs were measured by gas chromatography-mass spectrometry.
Both angiotensin-converting enzyme inhibitors crossed the human placenta in the maternal-fetal direction in similar quantities. Temocapril showed the same pharmacokinetic characteristics as enalapril.
This was the first study to quantify the placental transfer of angiotensin-converting enzyme inhibitors. These antihypertensive agents should not be taken during pregnancy, to avoid any potential hazards to the fetus.

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    • "Even if the placental transfer rate in humans is in the lower range of reported values, human fetal concentrations at maternal therapeutic doses would be above the therapeutic dose for newborns, which is 10 to 100 times lower than the adult dose, on a mg/kg basis [13]. Therefore, in the human, enalaprilat crosses the placenta in amounts pharmacologically significant for the fetus that are above the range needed to correct severe hypertension in children [13]. This is important because it shows that, within the maternal therapeutic dose range, the active metabolite could reach the fetus at concentrations sufficient to induce fetal hypotension . "
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    ABSTRACT: Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the second and third trimester of pregnancy in humans is associated with specific fetal and neonatal injury. The syndrome, termed “ACEI fetopathy” in humans, does not appear to have a similar counterpart in experimental animals. The present paper reviews pharmacokinetic and pharmacodynamic aspects of enalapril that are physiologically important during pregnancy and intrauterine development in humans and in experimental animal species with the aim of better understanding the comparability of the manifestations of enalapril developmental toxicity in animals and humans. The human fetus is at a disadvantage with regard to in utero enalapril exposure in comparison to some of the animal species for which gestational pharmacokinetic data are available. Important reasons for the higher vulnerability of the human fetus are its accessibility by enalapril and the earlier (relative to animal species) intrauterine development of organ systems that are specific targets of ACEI pharmacologic effect (the kidney and the renin-angiotensin system). In humans, these systems develop prior to calcarial ossification at the end of first trimester of pregnancy. The specific pharmacodynamic action of enalapril on these systems during fetal life is the chief determinant of the etiology and pathogenesis of ACEI fetopathy in humans. In contrast, in most of the studied animal species, these target systems are not developed until close to term when the fetus is relatively more mature (and therefore less vulnerable), so that the window of vulnerability is narrower in comparison to the human. Among animal species, the best concordance in fetal pharmacodynamics to the human is seen in the rhesus monkey, but further studies are necessary to determine if similar developmental pathology is induced in this animal model upon repeated administration of the drug during the relevant period of intrauterine development. Animal-human concordance of developmental toxicity is least likely in the rat because of greater disparities in enalapril availability to the fetus and the relative development of the kidney and skeletal ossification compared to that in humans.
    Reproductive Toxicology 09/2001; 15(5-15):467-478. DOI:10.1016/S0890-6238(01)00161-7 · 2.77 Impact Factor
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    ABSTRACT: Ziel dieser vorliegenden Studie war es, die Anwendbarkeit und Aussagekraft der sonographischen Grauwertanalyse zur Diagnose der Zervixinsuffizienz zu überprüfen und den cut-off-Wert der Graustufenanalyse zu ermitteln. Die Studie sollte zum einen klären, ob ein Zusammenhang zwischen einer Zervixverkürzung und Grauwertveränderungen der Zervix bestehen, zum anderen, ob die Grauwertanalyse mit den Ergebnissen der digitalen vaginalen Untersuchung, dem Bishop score korreliert. Zu diesem Zweck wurden 68 Patientinnen untersucht, die aufgrund einer drohenden Frühgeburt in der Universitäts-Frauenklinik Marburg therapiert wurden. Die Frauen wurden im Mittel in der 30+2. SSW in die Studie aufgenommen. Nach entsprechender Anamnese wurden die Frauen vaginal untersucht. Dabei wurden mikrobiologische Abstriche entnommen, der pH-Wert bestimmt, sowie durch digitale Untersuchung der Bishop score ermittelt. Die Ultraschalluntersuchungen führten wir mit dem Breitbandschallkopf (C 8-4v MHz) des HDI 3000 Ultraschallgerätes der Firma ATL™ durch. Wir bestimmten die Zervixlänge, und ggf. die Trichterlänge im Ultraschall-B-Bild. Daraufhin führten wir die Densitometrie durch, indem in der hinteren Muttermundslippe die Grauwertverteilung in der ROI (region of interest) mit konstanter Größe von = 1 cm untersucht wurde. Die Daten wurden in einer externen Workstation mit Hilfe der Software des HDILab von ATL™ Ultrasound, Bothell, USA ausgewertet. Die Zervixlängenmessung, sowie die quantitative sonographische Gewebetypisierung der Zervix uteri waren bei allen teilnehmenden Frauen möglich. Den cut-off Grauwert für eine drohende Frühgeburt definierten wir mit ≤ 6,54. Patientinnen, die eine signifikant verkürzte Zervixlänge (< 2,5 cm) aufwiesen, sowie einen erniedrigten mittleren Grauwert hatten, hatten im Verlauf häufiger eine Frühgeburt. 28 von 68 Patientinnen entbanden vor der 37. SSW. Das entspricht einer Frühgeburtsrate von 42,2 %. Die Zervixlängenmessung sowie die Grauwertanalyse erzielten vergleichbare positive und negative prädiktive Werte. Patientinnen mit Zervixverkürzung haben infolge eines reduzierten mittleren Grauwerts ein 8,5-fach erhöhtes relatives Risiko eine Frühgeburt zu erleiden. Frauen mit normaler Zervixlänge haben bei gleichem erniedrigtem mittlerem Grauwert dagegen nur ein 4,9-fach höheres Risiko vorzeitig zu entbinden. Die Studie zeigte weiterhin, dass der Bishop score zwar mit der Zervixlängenmessung korreliert, nicht jedoch mit dem mittleren Grauwert. Die Ergebnisse der Studie zeigen, dass die Grauwertanalyse eine hohe Sensitivität und Spezifität aufweisen und somit einen guten Prädiktor für eine Frühgeburt darstellt. Da die Grauwertanalyse ermöglicht sonographische Bilder zu quantifizieren und zu einer Objektivierung der visuellen Befunde führt, ist sie eine sinnvolle Ergänzung der B-Bild-Sonographie. Die in dieser Arbeit dargestellten Grauwertanalysen können als Diskussionsgrundlage für die quantitative Beurteilung von Ultraschallbildern in der Schwangerschaftsbetreuung dienen. Die Aussagekraft und Sicherheit der Bildbeurteilung kann dadurch erhöht werden. Insbesondere können durch das frühere Erkennen einer Risikopatientin Therapien zur Vermeidung einer drohenden Frühgeburt eingeleitet werden. OBJECTIVE: This study was to evaluate the predictice value of the uterine cervix tissue with the use of quantitative ultrasound grey level analysis and cervical length for preterm delivery. STUDY DESIGN: Sixty-eight patients with preterm labor between 20 and 35 weeks of gestation were included. When two-dimensional transvaginal ultrasound measurement of cervical length was completed, a region of interest of constant size was defined in the midsection of the posterior wall, and the tissue-specific gray scale was determined. Preterm delivery of <37 weeks of gestation was sought. RESULTS: Twenty-eight patients (41.2%) were delivered preterm. The risk for preterm delivery was increased significantly in patients with cervical length of ≤2.5cm (odds ratio, 7.67; 95% CI, 2.4-24.45), with Bishop score of ≥4 (odds ratio, 3.44; 95% CI, 1.21-9.75), and with decreased mean gray scale value (odds ratio, 12.13; 95% CI, 3.69-39.88). Parity and uterine contractions were not significant as predictors for preterm delivery, although the risk for preterm delivery increased with higher parity (odds ratio, 1.8; 95% CI, 0.68-4.79). The risk for preterm delivery remained nearly the same by uterine contractions (odds ratio, 0.92; 95% CI, 0.28-3.01). A mean scale value of ≤6.54 had the best cutoff value for the prediction of preterm delivery. For preterm delivery, a mean gray value ≤6.54 had a sensitivity of 82.1%, a specificity of 72.5%, a positive predictive value of 67.6%, and a negative predictive value 85.3%. Multiple logistic regression analysis indicated that, even when other variables are considered simultaneously, the mean gray scale value is the single best predictor of preterm delivery. CONCLUSION: Quantitative ultrasound tissue characterization of the uterine cervix predicts preterm delivery and provides additional information in the prediction of potential premature delivery.
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