We have examined effects of the 20,23-dihydroxyvitamin D3 (20,23(OH)2D3), on differentiation and proliferation of human keratinocytes and the anti-inflammatory potential of 20,23(OH)2D3 from its action on nuclear factor-κB (NF-κB). 20,23(OH)2D3 inhibited growth of keratinocytes with a potency comparable to that for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Cell cycle analysis showed that this inhibition was associated with G1/G0 and G2/M arrests. 20,23(OH)2D3 stimulated production of involucrin mRNA and inhibited production of cytokeratin 14 mRNA in a manner similar to that seen for 1,25(OH)2D3. Flow cytometry showed that these effects were accompanied by increased involucrin protein expression, and an increase in the cell size and granularity. Silencing of the vitamin D receptor (VDR) by corresponding siRNA abolished the stimulatory effect on involucrin gene expression demonstrating an involvement of VDR in 20,23(OH)2D3 action. This mode of action was further substantiated by stimulation of CYP24 gene expression and stimulation of the CYP24 promoter-driven reporter gene activity. 20,23(OH)2D3 displayed several fold lower potency for induction of CYP24 gene expression than 1,25(OH)2D3. Finally, 20,23(OH)2D3 inhibited the transcriptional activity of NF-κB in keratinocytes as demonstrated by EMSA, NF-κB-driven reporter gene activity assays and measurements of translocation of p65 from the cytoplasm to the nucleus. These inhibitory effects were connected with stimulation of the expression of IκBα with subsequent sequestration of NF-κB in the cytoplasm and consequent attenuation of transcriptional activity. In summary, we have characterized 20,23(OH)2D3 as a novel secosteroidal regulator of keratinocytes proliferation and differentiation and a modifier of their immune activity.

Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV).We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C 24 ) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C max ) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P ‫؍‬ 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.Worldwide, the majority of human immunodeficiency virus (HIV) perinatal transmissions occur during labor and delivery. Zidovudine (ZDV), as administered in ACTG 076, substantially reduced HIV perinatal transmission (6, 30) but was too complex and expensive for use in resource-limited settings. HIVNET 012 demonstrated that single peripartum maternal and infant nevirapine (NVP) doses can provide effective singleagent therapy for prevention of mother-to-child transmission (PMTCT) of HIV in resource-limited areas of the world (13).This agent appeared optimal because of its strong potency, easy storage, and oral administration. However, there are concerns over the development of NVP resistance in women and infants who received this drug alone for prevention of perinatal transmission (8)(9)(10)(11)27). While development of NVP resistance can be mitigated by the use of short "tail" regimens in mothers (5,21,34) and the use of triple antiretroviral PMTCT regimens is becoming widespread, even in the developing world (28), knowledge about alternative peripartum antiretroviral strategies is needed. This is especially important for women who register late or not at all for prenatal care or who are diagnosed in active la...

Objective. To assess the risk of classical hysterotomy and surgical morbidity among women with a body mass index (BMI) greater than 40 kg/m2 who underwent a supraumbilical incision at the time of cesarean delivery. Methods. We conducted a retrospective cohort study in women having a BMI greater than 40 kg/m2 who underwent a cesarean delivery of a live, singleton pregnancy from 2007 to 2011 at a single tertiary care institution. Intraoperative and postoperative outcomes were compared between patients undergoing supraumbilical vertical (cohort, n = 45) or Pfannenstiel (controls, n = 90) skin incisions. Results. Women undergoing supraumbilical incisions had a higher risk of classical hysterotomy (OR, 24.6; 95% CI, 9.0–66.8), surgical drain placement (OR, 6.5; 95% CI, 2.6–16.2), estimated blood loss greater than 1 liter (OR, 3.4; 95% CI, 1.4–8.4), and longer operative time (97 ± 38 minutes versus 68 ± 30 minutes; P < .001) when compared to subjects with Pfannenstiel incisions (controls). There was no difference in the risk of wound complication between women undergoing supraumbilical or Pfannenstiel incisions (OR, 2.7; 95% CI, 0.9–8.0). Conclusion. In women with a BMI above 40 kg/m2, supraumbilical incision at the time of cesarean delivery is associated with a greater risk of classical hysterotomy and operative morbidity.

ObjectivesTo determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. MethodsTwenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante-and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). ResultsThe average NVP Area Under the Curve (AUC) was 56 AE 13 mcg*h/mL antepartum and 61 AE 15 mcg*h/mL postpartum. The typical parameters AE standard error were apparent clearance (CL/F) 5 3.51 AE 0.18 L/h and apparent volume of distribution (Vd/F) 5 121 AE 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median ( AE standard deviation) cord blood to maternal NVP concentration ratio was 0.91 AE 0.90. ConclusionsPregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.Keywords: HIV, nevirapine, non-nucleoside reverse transcriptase, pharmacokinetics, pregnancy IntroductionMother-to-child transmission of HIV-1 can be greatly reduced if the maternal viral loads are below the limit of detection at delivery [1]. To achieve this target, combination antiretroviral (ARV) therapy, consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), is recommended. Although efavirenz (EFV) is the preferred NNRTI in the general population, it has been found to cause severe central nervous system defects when given to primates during the Physiological and hormonal changes associated with pregnancy can have profound effects on drug disposition, including increased plasma volume and reduced plasma protein concentration, increased renal blood flow and modified metabolic enzyme activity. Several ARVs have been studied in pregnancy, with some exhibiting significant alterations in pharmacokinetics (PK), requiring drug dose modifications or avoidance [5,6].The antiviral effects of NVP are rapid, with significant reduction in plasma virus. However, development of viral resistance to NVP can occur with a single mutation in the HIV-1 reverse transcriptase gene [7]. NVP is metabolized primarily in the liver by the cytochrome P450 (CYP) 2B6 and 3A family enzymes [8,9]. Low NVP concentrations have been associated with inadequate viral suppression [10] and may also contribute to NNRTI resistance [11]. The PK of single-dose NVP to mothers at delivery have been described [12,13], but welldesigned PK studies of continuous NVP therapy in pregnancy have not been pub...