Objectives-To describe first dose and steady state antiretroviral drug exposure in the female genital tract. Design-Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.Method-Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA).Results-For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%).Conclusions-This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

The diffusion coefficients of sonicated calf-thymus DNA and an oligonucleotide fragment have been measured via an electrochemical strategy. The complex [Os(bpy)2(dppz)12+ (bpy = 2, 2'-bipyridine, dppz = dipyridophenazine) has been synthesized as a simple, single-electron intercalating redox couple. The free complex undergoes a kinetically reversible single-electron oxidation to the corresponding Os(II1) complex at an applied potential of 0.72 V vs Ag/AgCl, which is insufficient to achieve electrocatalytic DNA oxidation.Upon addition of DNA, the complex binds via intercalation to a two-base-pair site with binding constant Kb = 4 x lo6 M-I, as reflected in the changes in the photophysics of the Os(I1)-dppz chromophore. Changes in the voltammetric current upon binding reveal a slight limitation on heterogeneous charge-transfer kinetics (k = 5 x lov4 cm s-I) and a dramatic limitation on mass transfer of bound complexes. Normal pulse voltammetry gives diffusion coefficients of sonicated calf-thymus DNA and (dA)20*(dT)20 equal to 2.0 x cm2 s-I, respectively; each agrees with values reported for light-scattering experiments and theoretical calculation. and 1.2 xThe diffusion properties of biopolymers play an important role in many physiological For example, the recognition of a specific cleavage site by restriction enzymes is thought to involve initial, nonspecific electrostatic binding of the enzyme to DNA in a mode that is weak enough that diffusion of the enzyme is still f a~i l e .~ The weakly bound enzyme then diffuses along the DNA strand until reaching the cleavage locus and effecting site-specific cleavage. The importance of these processes clearly dictates a detailed understanding of the relative diffusion properties of molecules such as DNA and DNA-binding proteins. We report here on an electrochemical system for studying the diffusion properties of nucleic acids that can be performed on small volumes of sample at relatively low nucleic acid concentrations. These studies can be performed with commercially available potentiostats and analysis software.The discovery of both natural transition-metal-based antitumor agents such as iron-bleomycin (FeBLM)4*5 and synthetic platinum drugs6 has prompted intense investigation of the interactions and reactions of synthetic transition-metal complexes with nucleic acids. In particular, extensive efforts have been made to cleave DNA oxidatively in a site-specific manner with metal complexes in either an electronic excited or electrochemically potentiated high oxidation state.I0,' Electrochemical studies have been made of electrocatalytic cleavage reactions using FeBLM,' Mn porphyrins,I0 outer-sphere oxidants,I2 and complexes based on the Ru(IV)O~+/RU(II)OH~~+ ~o u p l e . '~-'~ An advantage of electrochemical cleavage reactions is that the current measured in electrolysis or in voltammetry should provide mechanistic information on the extent or rate of the cleavage reaction. However, because currents in solution electrochemistry are governed by mass transport, reliable inte...

This work describes a sensitive method for the simultaneous determination of 17 antiretroviral drugs including nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors, protease inhibitors and a nucleotide analog reverse transcriptase inhibitor in 50 microL of human plasma. This method employed high-performance liquid chromatography-tandem mass spectrometry with electrospray ionization. The analytes were monitored in multiple reaction monitoring mode and the polarity was switched from positive to negative to positive to detect all compounds after a single injection. A combination of liquid-liquid extraction and protein precipitation was used to extract all compounds, with at least 75% recovery for all analytes. Within- and between-day accuracies were at least 85% for 1-500 ng/mL for nelfinavir, indinavir and abacavir, 10-500 ng/mL for didanosine and stavudine and 5-500 ng/mL for all other compounds. This method is very effective for quantifying and screening antiretroviral drugs in clinical samples with limited (50 microL) volumes.

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

The alarmingly high frequency of potentially harmful errors uncovered in this study necessitates further investigation using larger sample sizes. Interventions to reduce and prevent these errors must be sought to eliminate the unintended harm associated with hospitalization.