Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy

BACKGROUND: Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors. OBJECTIVES: The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals. METHODS: Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods. RESULTS: There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area. CONCLUSIONS: Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.     

YqTER deletion causes arrest of spermatogenesis in early puberty

We report a 12-7/12 year-old male with obesity, eunuchoid proportions, genetic stigmata of Turner's syndrome and mild developmental delay. We investigated whether cytogenetic alterations could be responsible for his phenotype. Conventional karyotype in 70 peripheral blood cells was 45,X(15%)/46,XYqh-(85%). Dual FISH on 1,000 nuclei revealed 8% of X0 cells (DXZ1 X-centromeric probe) and 92% of XY cells (DYZ3 Y-centromeric probe). We studied Y chromosome microdeletions by PCR. The patient showed a terminal Yq deletion from the 5I interval including the AZFb and AZFc regions. FSH, LH and testosterone (468 ng/dl) were within the normal range for his age. At Tanner IV pubertal development the spermiogram showed azoospermia and the testicular aspirate spermatic arrest. The present report suggests that Y chromosome deletions including AZFb and AZFc regions may cause spermatogenic arrest in early puberty.     

Non-Traditional Aromatic Topologies and Biomimetic Assembly Motifs as Components of Functional Pi-Conjugated Oligomers

This article will highlight our recent work using conjugated oligomers as precursors to electroactive polymer films and self-assembling nanomaterials. One area of investigation has focused on nonbenzenoid aromaticity in the context of charge delocalization in conjugated polymers. In these studies, polymerizable pi-conjugated units were coupled onto unusual aromatic cores such as methano[10]annulene. This article will also show how biologically-inspired assembly of molecularly well-defined oligopeptides that flank pi-conjugated oligomers has resulted in the aqueous construction of 1-dimensional nanomaterials that encourage electronic delocalization among the pi-electron systems.     

Hormonal influences of early postnatal indomethacin and ibuprofen in neonatal rats

ObjectiveIndomethacin and ibuprofen are administered to preterm neonates for symptomatic patent ductus arteriosus. The drugs suppress prostaglandins (PGs) which modulate growth and secretion of various hormones. We examined the hypothesis that early postnatal indomethacin and ibuprofen influence growth and GH-IGF-I-insulin and HPA axes in neonatal rats.DesignRat pups received IP injections of saline (Sal) on P1, P2, and P3; 10 mg/kg ibuprofen on P1 followed by 5 mg/kg on P2 and P3; or 0.2 mg/kg indomethacin on P1 followed by 0.1 mg/kg on P2 and P3. Serum and hepatic GH, GHBP and IGF-I; and serum corticosterone and insulin levels were determined.ResultsIbuprofen suppressed somatic growth in the sucking rats, but the effect was transient, resolving by P14. Indomethacin had an opposite, latent effect on body weight and liver to body weight ratios in weanling rats. Both indomethacin and ibuprofen had profound hormonal effects that differed in magnitude and timing. Indomethacin resulted in a sustained elevation in corticosterone levels at P21, while ibuprofen increased serum and hepatic GH levels. Both drugs suppressed GHBP in serum at P7 and P14; and liver at P4 and P7, but a rebound increase in serum GHBP was noted at P21 with Ibuprofen only. Both drugs increased serum IGF-I at P7. The effect remained sustained with indomethacin.ConclusionsThese results provide evidence for an involvement of PGs in the regulation of growth as well as the GH-IGF and HPA axes. Therefore, early postnatal exposure to PG inhibitors may further exacerbate postnatal growth restriction and ability to cope with stress.     

Orthotopic liver transplantation for acute liver failure secondary to autoimmune hepatitis in a child with autoimmune polyglandular syndrome type 1

Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal-recessive condition characterized by hypoparathyroidism, autoimmune Addison's disease, and chronic mucocutaneous candidiasis. Autoimmune hepatitis develops in 10-20% of affected patients and has a variable course ranging from asymptomatic chronic liver disease to lethal fulminant hepatic failure. Liver transplantation has been documented previously in only two patients. We report a 14-yr-old boy with APS-1 who developed acute liver failure secondary to associated autoimmune hepatitis. He did not respond to corticosteroid therapy and was successfully treated with an orthotopic liver transplant.     

Metabolic and target organ outcomes after total pancreatectomy: Mayo Clinic experience and meta‐analysis of the literature

Introduction Total pancreatectomy (TP) has been associated with substantial metabolic abnormalities and poor glycaemic control limiting its use. Because data reported to date are limited, we evaluated outcomes related to the diabetes mellitus obligated by TP. Methods A case series study of all patients who underwent TP from 01/01/1985 to 12/31/2006 at Mayo Clinic was conducted. TP cases were summarized according to perioperative procedures, mortality and morbidity after TP. To complement this retrospective examination, a survey was developed to measure DM treatment modality, target organ failure and complications in patients alive in 2007. We performed a meta‐analysis to compare our results with similar previous studies and provide overall estimates of outcomes. Results A total of 141 cases were studied (97 malignant diseases, 44 benign diseases). The median survival was much less for malignant pathology (2·2 vs 8·7 years, Log rank P = 0·0009). In 2007, there were 59 patients that were presumed alive and 47 (80%) responded to the survey. Mean HbA1c at last follow‐up was 7·5% with 89% of respondents on a complex insulin programme (mean daily insulin requirement 35 ± 13 units). Episodic hypoglycaemia was experienced by 37 (79%); 15 (41%) experienced severe hypoglycaemia. In contrast, diabetic ketoacidosis developed in only 2 (4%). Target organ complications and chronic diarrhoea developed in 13 patients (28%) each. Conclusion The primary factor determining survival after TP is the aetiology necessitating TP, i.e. pancreatic malignancy. Most respondents used complex insulin programmes, but hypoglycaemia continues to be a problem.