Re-Directing an Alkylating Agent to Mitochondria Alters Drug Target and Cell Death Mechanism.

Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism.

PLoS One. 2013; 8(4): e60253
Mourtada R, Fonseca SB, Wisnovsky SP, Pereira MP, Wang X, Hurren R, Parfitt J, Larsen L, Smith RA, Murphy MP, Schimmer AD, Kelley SO

We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ?° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential. HubMed – drug

Prevalence of HIV-1 Drug Resistance among Women Screening for HIV Prevention Trials in KwaZulu-Natal, South Africa (MTN-009).

PLoS One. 2013; 8(4): e59787
Parikh UM, Kiepiela P, Ganesh S, Gomez K, Horn S, Eskay K, Kelly C, Mensch B, Gorbach P, Soto-Torres L, Ramjee G, Mellors JW,

A major concern with using antiretroviral (ARV)-based products for HIV prevention is the potential spread of drug resistance, particularly from individuals who are HIV-infected but unaware of their status. Limited data exist on the prevalence of HIV infection or drug resistance among potential users of ARV-based prevention products.A cross-sectional study of reproductive-aged women who presented to screen for an HIV prevention trial was conducted at 7 clinical sites in Durban, South Africa. CD4+T cell counts, HIV-1 RNA levels and population sequencing of the protease and reverse transcriptase genes were performed for all women with 2 positive HIV rapid tests. Resistance mutations were identified using the Stanford Calibrated Population Resistance Tool.Of the 1073 evaluable women, 400(37%) were confirmed as HIV-infected. Of those, plasma HIV-1 RNA was detectable in 365/400(91%) and undetectable(<40 copies/ml) in 35/400(9%) women. 156 women(39%) were eligible for antiretroviral therapy (CD4+T cell counts<350 cells/mm(3)) and 50(13%) met criteria for AIDS(CD4<200 cells/mm(3)). Of 352 plasma samples(>200 copies/ml) analyzed for drug resistance, 26(7.4%) had nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drug resistance mutations. Among those with resistance, 18/26 participants(62%) had single-class NNRTI resistance and 5/26(19%) had dual-class NRTI/NNRTI. Major mutations in reverse transcriptase included K65R(n?=?1), L74I(n?=?1), K103N(n?=?19), V106M(n?=?4), Y181C(n?=?2), M184V(n?=?4), and K219E/R(n?=?2). Major PI-resistance mutations were rare: M46L(n?=?1) and I85V(n?=?1). All participants were infected with subtype C virus, except one infected with subtype A.In women from Durban, South Africa screening for an HIV prevention trial, the HIV prevalence was high (37%) and HIV drug resistance prevalence was above 5%. This study highlights the potential challenges faced when implementing an ARV-based prevention product that overlaps with first-line antiretroviral therapy. Effective screening to exclude HIV infection among women interested in uptake of ARV-based HIV prevention will be essential in limiting the spread of ARV resistance. HubMed – drug

Stenting of left main coronary artery stenosis: A to Z.

Heart Asia. 2013; 5(1): 18-27
Dash D

For several decades, coronary artery bypass grafting (CABG) has been considered as the gold standard treatment of unprotected left main coronary artery (LMCA) disease. The marked improvement in technique and technology makes percutaneous coronary interventions (PCIs) feasible for patients with unprotected LMCA stenosis. The recent introduction of drug-eluting stents (DESs), together with advances in periprocedural and postprocedural adjunctive pharmacotherapies, has improved outcomes of PCIs of these lesions. Recent studies comparing efficacy and safety of PCIs using drug-eluting stents and CABG revealed comparable results in terms of safety and a lower need for repeat revascularisation for CABG. Patient selection for both the techniques directly impacts clinical outcome. Despite improvement in stent technology and operator experience, management can be challenging especially in LMCA bifurcation lesions and, therefore, an integrated approach combining advanced devices, tailored techniques, adjunctive support of physiological evaluation, and adjunctive pharmacological agents should be reinforced to improve clinical outcome. HubMed – drug