Adrenal cortical function in abnormal newborn infants

Reynolds, John W.; Turnipseed, Marvin R.; Mirkin, Bernard L.

doi:10.1016/0022-4731(75)90050-3

Cited by 8 publications

(3 citation statements)

References 17 publications

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“…In the pregnant mother, 16α-hydroxy DHEA-S is exported to the placenta where it subsequently undergoes desulfation and a series of oxidations to ultimately form estriol, which is critically important in bringing the pregnancy to full term. , Women with low estriol levels are far more likely to give birth to premature and even stillborn infants . Furthermore, the level of 16α-hydroxy DHEA-S is an important indicator for normal growth and development of the neonate . Inhibition of CYP3A7, therefore, could cause irrevocable harm to the developing fetus.…”

Section: Introductionmentioning

confidence: 95%

“…28 Furthermore, the level of 16α-hydroxy DHEA-S is an important indicator for normal growth and development of the neonate. 29 Inhibition of CYP3A7, therefore, could cause irrevocable harm to the developing fetus. While the involvement of the hepatic CYP3A enzymes in the deleterious side effects of Kaletra has been postulated in previous studies, 7,8 to our knowledge no research has been conducted to examine the impact of CYP3A7 inhibition by lopinavir and ritonavir on endogenous DHEA-S metabolism.…”

Section: ■ Introductionmentioning

confidence: 99%

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Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Kandel

Lampe

2021

Chem. Res. Toxicol.

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Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC 50 = 0.0514 μM), while lopinavir is a much weaker inhibitor (IC 50 = 5.88 μM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a K I of 0.392 μM and a k inact of 0.119 min –1 , illustrating the potential for CYP3A mediated drug–drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.

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Section: Introductionmentioning

confidence: 95%

Section: ■ Introductionmentioning

confidence: 99%

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Kandel

Lampe

2021

Chem. Res. Toxicol.

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“…Human chorionic gonadotrophin (HCG) has been proposed as an adrenocorticotrophin controlling Cjo steroid hormone production by the human foetus and newborn while ACTH steroidogenic action may be confined primarily to stimulation of C?i steroid production (Lauritzen 8c Lehmann 1967;Lauritzen et al 1968;Reynolds et al 1975). During early extra-uterine life the adrenal of the human newborn may retain differential responsivity to HCG and ACTH with respect to Cjg and C21 steroid hormone production as judged by urinary excretion of their metabolites.…”

mentioning

confidence: 98%

The Effect of Acth and HCG on Adrenal Steroidogenesis in the Neonatal Baboon (Papio Papio)

Pepe

Townsley

1978

Acta Endocrinologica

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We have studied three, term newborn baboons (Papio papio) to determine whether differential responses to chorionic gonadotrophin (HCG) and ACTH exist with respect to cortisol (F), dehydroepiandrosterone (D), or dehydroepiandrosterone sulphate (DS) secretion as judged by the serum level of these hormones. Serum F, D and DS levels were measured by radioimmunoassay 30, 15 and 0 min prior to constant iv infusion (120 min) of (A) 12 IU ACTH, (B) 2000 USP Units HCG or (C) normal saline.Steroid concentrations measured on samples obtained during the infusion (30, 60 and 120 min) were averaged and compared with the average pre-treatment values. Statistical analyses were by analysis of variance with comparison of individual means by least significant difference procedure. Each animal was examined 6 times (day 1, 2, 3, 7, 8, 9 of life) receiving each treatment twice in a staggered schedule. Mean serum concentrations (\g=m\g/100 ml \m=+-\sd) of D, DS and F prior to treatment were 8.0 \ m=+-\ 3.8; 394 \ m=+-\196; 47.0 \ m=+-\18.7, respectively. ACTH, but not HCG, increased (P < 0.025) serum D, DS and F levels. The response of D and F to ACTH expressed as a per cent of pre-treatment values were similar #$x2266; 100 %) and greater (P < 0.05) than the mean DS percentage (29%) response. These results indicate that ACTH but not HCG is an adrenocorticotrophin in the baboon neonate.

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Ultrasonographic screening of neonatal adrenal apoplexy

Jójárt

Nagy

1992

International Urology and Nephrology

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A total of 1785 newborns were subjected in the course of 14 months to ultrasonographic screening. Adrenal bleeding among those born via caesarean section has not been recorded. Among 1490 born via vagina there were 14 (0.94%) with adrenal apoplexy and 80 were delivered with clavicular fracture (5.37%). There were 13 with unilateral bleeding. Hormone examination applied to one infant with bilateral bleeding confirmed adrenal insufficiency which normalized after three months. In the aetiology of neonatal adrenal apoplexy the dominant causative role is attributed to birth trauma.

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Adrenal cortical function in abnormal newborn infants

Cited by 8 publications

References 17 publications

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

The Effect of Acth and HCG on Adrenal Steroidogenesis in the Neonatal Baboon (Papio Papio)

Ultrasonographic screening of neonatal adrenal apoplexy

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