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In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.

Background Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. Methods Three tenofovir rectal douches—220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C—were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. Results The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6–7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. Conclusions All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration. NCT02750540. [ABSTRACT FROM AUTHOR]

Byline: Lawrence S. Lee, MBBS, PhD (Division of Clinical Pharmacology, Department of Medicine, National University of Singapore); Stephen D. Wise, MBChB, FRCP (Lilly-NUS Centre for Clinical Pharmacology, National University of [...]

The steady-state pharmacokinetics (PK) interactions between atazanavir (ATV), ritonavir (RTV) and lopinavir (LPV) when coadministered at various doses are determined. An appropriate PK profile for ATV and LPV was indicated by the combination of ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily.

A hypothesis to test whether blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia is presented. It is concluded that most blips appear to represent random biological and statistical variation around mean HIV-1 levels below 50 copies/mL rather than clinically significant elevations in viremia.

The stability of nevirapine suspension over different storage conditions with a view to reduce mother-to-child transmission of HIV is discussed. It was found that in BaxaExcata-Med Oral Dispensers, nevirapine suspension is stable and pathogen free at varying conditions for six months.

Abstract Background Complementary and alternative medicine (CAM) use is prevalent among HIV-infected patients to reduce the toxicity of antiretroviral therapy. Ginseng has been used for treatment of hyperglycemia and insulin resistance, a common side effect of some HIV-1 protease inhibitors (PI). However, it is unknown whether American ginseng (AG) can reverse insulin resistance induced by the PI indinavir (IDV), and whether these two agents interact pharmacologically. We evaluated potential pharmacokinetic interactions between IDV and AG, and assessed whether AG improves IDV-induced insulin resistance. Methods After baseline assessment of insulin sensitivity using the insulin clamp technique, healthy volunteers received IDV 800 mg q8 h for 3 days and then IDV and AG 1g q8h for 14 days. IDV pharmacokinetics and insulin sensitivity were assessed before and after AG co-administration. Results There was no difference in the area-under the plasma-concentration-time curve after the co-administration of AG, compared to IDV alone (n = 13). Although insulin-stimulated glucose disposal per unit of insulin (M/I) decreased by an average of 14.8 ± 5.9% after 3 days of IDV (from 0.113 ± 0.012 to 0.096 ± 0.014 mg/kgFFM/min per μU/ml of insulin, p = 0.03, n = 11), M/I remained unchanged after co-administration of IDV and AG. Conclusion IDV decreases insulin sensitivity, which is unaltered by AG co-administration. AG does not significantly affect IDV pharmacokinetics.

Aim: The aim of this article was to present experiences from the field in the context of the International Council of Nurses' Leadership for Change™ programme, which celebrates 20 years of excellence in 2016 for developing the leadership and management capacity of nurses worldwide. Background: The programme was launched in 1996 in order to boost nurse participation in the healthcare policy‐making process, globally, and to foster within the nursing profession the requisite skills for nurses to lobby for and assume a greater responsibility in the leadership and management of health care services. Introduction: Over the course of two decades, the programme has been implemented in cooperation between ICN, national nurses associations, the World Health Organization, Ministries of Health and a variety of donor organizations such as the W.K. Kellogg Foundation and development agencies such as USAID and AUSAID. The programme has been implemented in more than 60 nations throughout Africa, Asia, Europe, the Middle East, Latin America and the Pacific Islands, to name a few regions. Methods: This article offers an overview of the impact that certified ICN LFC nurse trainers and their colleagues have had in the United Arab Emirates, Vietnam and the United States of America and is affiliated islands and the North Pacific Islands. Results: Twenty years of growth and empowerment are now the ongoing legacy of the ICN LFC Program, which has graduated and deployed nurse trainers around the world and achieved significant advances in the professional development of nurse leaders on an international scale. Implications for nursing and health policy: Nurse leaders can improve the health and well‐being of their nations in collaboration with consumers and other key stakeholders. Nurse leaders are critical in improving health systems, their work places and broader societal challenges through sound nursing practice, education, research and evidence‐based health and social policy change. [ABSTRACT FROM AUTHOR]