IntroductionHuman immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection.DiscussionFirst-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186.ConclusionsThis review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.

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This work was aimed at deliver curcumin to lungs by its incorporation into innovative vesicles glycerosomes and polymer-glycerosomes, the latter obtained combining glycerosomes with two polymers: sodium hyaluronate and trimethyl chitosan.

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A simple, rapid, and sensitive HPLC method based on 9H-fluoren-9-ylmethyl chloroformate derivatization for the quantification of sertraline in rat plasma has been developed, requiring a plasma sample of only 0.1 mL, which was deproteinized and derivatized for 5 min in two single steps. The obtained derivative was stable at room temperature and was determined by HPLC using a fluorescence detector. The analytical column was a C(18) column and the mobile phase was acetonitrile and water (80:20, v/v). Calibration curves were linear in the range of 10-500 ng/mL. The limit of detection was approximately 3 ng/mL, and the lower limit of quantification was established at 10 ng/mL. The bias of the method was lower than 10%, and the within day as well as between day, relative standard deviations were lower than 12%. This analytical method was successfully applied to characterize sertraline pharmacokinetics in rats following intravenous (t(1/2) = 213 ± 48 min, Cl = 43.1 ± 8.7 mL/min, V(d) = 11560 ± 1861 mL) and oral (C(max) = 156 ± 76 ng/mL, t(max) = 63.8 ± 16.3 min) administration of 2 and 5 mg, respectively.

One of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found. In vitro studies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT. In vivo human studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.

Between 22 and 45% of HIV-positive subjects are likely to report symptoms of depression. Considering this background, a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor efavirenz (EFV) and two antidepressants, sertraline (SRT) and nortriptyline (NT), was studied. Rats were administered EFV alone or together with the antidepressants, and changes in the plasma levels and pharmacokinetic parameters of EFV were analyzed. Additional in vitro experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effect of SRT and NT on EFV metabolism by determining the formation rate of the major EFV metabolite (8-OH-EFV). In vivo studies showed similar increases in the plasma levels of EFV when it was coadministered with SRT or NT. However, the studies using rat hepatic microsomes showed a more potent inhibitory effect of NT than of SRT on the metabolism of EFV, with values for the 50% inhibition constant (IC 50 ) and inhibitory constant (K i ) for NT about 9-fold lower than those for SRT. An equation was deduced that explains the similar in vivo effects of SRT and NT in spite of the different in vitro performance data. Using human hepatic microsomes, the strongest inhibitory effect was observed with SRT. In summary, pharmacokinetic interactions between EFV, SRT, and NT, associated with the inhibition of hepatic metabolism of EFV, have been detected in rats. Both antidepressants also inhibit EFV metabolism in human hepatic microsomes, but additional in vivo studies in humans are required to evaluate the clinical implication of this interaction. H uman immunodeficiency virus infection/AIDS (HIV/AIDS)is, at present, an incurable disease, and the use of antiretroviral therapy is essential to obtain durable viral suppression, improved immune function, and a good quality of life in infected individuals (1).Current treatment guidelines recommend the use of a drug combination consisting of at least three antiretroviral drugs of multiple classes, known as highly active antiretroviral therapy (HAART). Combining different anti-HIV agents has proven to be beneficial in terms of sustained efficacy and long-term safety, provided there are no significant negative pharmacokinetic drugdrug interactions. At present, preferred regimens of HAART consist of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) although other combinations are possible (2, 3).Efavirenz (EFV) is an NNRTI of human immunodeficiency virus type 1 (HIV-1) and is one of the preferred components of first-line antiretroviral regimens. It is widely used as a component of initial HAART (except in infected pregnant women) since it has demonstrated potent and sustained activity in HIV-infected patients as it induces a rapid suppression of the HIV-1 viral load and increases the CD4 cell count (1).In vitro studies with human hepatic microsomes, as well as in vivo studies, have demonstrated that EFV un...