Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (C_max), area under the concentration-time curve to the last available concentration time point (AUC_0–t), and AUC extrapolated to infinity (AUC_0–inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the C_max, AUC_0–t, and AUC_0–inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The C_max, AUC_0–t, and AUC_0–inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02216331","term_id":"NCT02216331"}}NCT02216331.)     

Case Report: Conversion of a Low-Flow to High-Flow Priapism

Priapism is defined as an erection lasting for more than 4 hours and can be grouped into 3 distinct subtypes: ischemic (low-flow), stuttering and non-ischemic (high-flow). Herein, we present an interesting case of conversion from a low-flow to high-flow priapism after a distal shunting procedure. This is a rare phenomenon that has a paucity of documented cases. Diagnosis requires prompt clinical suspicion and confirmatory testing including penile cavernosal blood gases and Doppler ultrasound.Key Words: Priapism, Ischemic priapism, Non-Ischemic priapism     

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.METHODS. We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).RESULTS. Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.CONCLUSION. These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00990808","term_id":"NCT00990808"}}NCT00990808.FUNDING. Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).     

Antisense reduction of 11β-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet

We recently reported that inhibition of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) by antisense oligonucleotide (ASO) improved hepatic lipid metabolism independent of food intake. In that study, 11β-HSD1 ASO-treated mice lost weight compared with food-matched control ASO-treated mice, suggesting treatment-mediated increased energy expenditure. We have now examined the effects of 11β-HSD1 ASO treatment on adipose tissue metabolism, insulin sensitivity, and whole-body energy expenditure. We used an ASO to knock down 11β-HSD1 in C57BL/6J mice consuming a Western-type diet (WTD). The 11β-HSD1 ASO-treated mice consumed less food, so food-matched control ASO-treated mice were also evaluated. We characterized body composition, gene expression of individual adipose depots, and measures of energy metabolism. We also investigated glucose/insulin tolerance as well as acute insulin signaling in several tissues. Knockdown of 11β-HSD1 protected against WTD-induced obesity by reducing epididymal, mesenteric, and subcutaneous white adipose tissue while activating thermogenesis in brown adipose tissue. The latter was confirmed by demonstrating increased energy expenditure in 11β-HSD1 ASO-treated mice. The 11β-HSD1 ASO treatment also protected against WTD-induced glucose intolerance and insulin resistance; this protection was associated with smaller cells and fewer macrophages in epididymal white adipose tissue as well as enhanced in vivo insulin signaling. Our results indicate that ASO-mediated inhibition of 11β-HSD1 can protect against several WTD-induced metabolic abnormalities. These effects are, at least in part, mediated by increases in the oxidative capacity of brown adipose tissue.     

Wound infection,dressings and pain,is there a relationship in the chronic wound?

The focus on quality of life issues in wound care has justly taken a far greater importance. With the acceptance that pain can be a major factor to the patient, and in particular, pain at dressing change comes the opportunity for avoidance and/or reduction strategies. Whilst pain has been associated with wound infection for millennia, it is only much more recently that this has received due attention from research and clinical practice. In this study, the nature of pain, changes in pain and pain associated with infection are the focal points. A Delphi approach, now a frequently used tool in wound care research, has been used to obtain expert opinion on these aspects of management.     

The cross‐pin retained implant supported restoration: a study of gasket placement and leakage

Background: Advantages of cross‐pin retained implant supported restorations (ISRs) include predictable retrieval and predictable retention. Unlike direct to fixture (DTF) or cement retained restorations, the prosthetic design of a cross‐pinned restoration retains gaps at the interfaces between the crown, abutment and cross‐pin screw. These spaces permit leakage into the suprastructure and gasket placement has been recommended to prevent this leakage. Methods: Five different gaskets were assessed for their ability to prevent leakage into a cross‐pinned ISR. The gaskets tested were: cement admixture on the cross‐pin screw; cement admixture on the inner surface of the coping and the cross‐pin screw; cement admixture on the inner surface of the coping only; cement admixture placed 1 mm from the margin of the coping and a filler placed in the abutment chimney. Results: Only gaskets which sealed both the cross‐pin screw interface and the abutment‐crown interface prevented leakage. A filler placed in the abutment chimney prevented leakage into this space but did not prevent fluid accumulating between the coping and abutment. Conservative placement of cement at the margin of the coping failed to prevent leakage. Conclusions: Cement gaskets may effectively prevent leakage into a cross‐pinned ISR. However, the use of a cement as a gasket has to be weighed against the issue of predictable retrieval, cement extrusion and incomplete seating.