Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.

• MeSH
• HIV infekce * farmakoterapie   MeSH
• HIV reverzní transkriptasa metabolismus   MeSH
• HIV-1 * metabolismus   MeSH
• inhibitory reverzní transkriptasy MeSH
• látky proti HIV * chemie   MeSH
• lidé MeSH
• racionální návrh léčiv MeSH
• rilpivirin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

OBJECTIVES: The aim of this international multicentre study was to review potential drug-drug interactions (DDIs) for real-life coadministration of combination antiretroviral therapy (cART) and coronavirus disease 2019 (COVID-19)-specific medications. METHODS: The Euroguidelines in Central and Eastern Europe Network Group initiated a retrospective, observational cohort study of HIV-positive patients diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Data were collected through a standardized questionnaire and DDIs were identified using the University of Liverpool's interaction checker. RESULTS: In total, 524 (94.1% of 557) patients received cART at COVID-19 onset: 117 (22.3%) were female, and the median age was 42 (interquartile range 36-50) years. Only 115 (21.9%) patients were hospitalized, of whom 34 required oxygen therapy. The most frequent nucleoside reverse transcriptase inhibitor (NRTI) backbone was tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide (TAF) with lamivudine or emtricitabine (XTC) (79.3%) along with an integrase strand transfer inhibitor (INSTI) (68.5%), nonnucleoside reverse transcriptase inhibitor (NNRTI) (17.7%), protease inhibitor (PI) (13.7%) or other (2.5%). In total, 148 (28.2%) patients received COVID-19-specific treatments: corticosteroids (15.7%), favipiravir (7.1%), remdesivir (3.1%), hydroxychloroquine (2.7%), tocilizumab (0.6%) and anakinra (0.2%). In total, 62 DDI episodes were identified in 58 patients (11.8% of the total cohort and 41.9% of the COVID-19-specific treatment group). The use of boosted PIs and elvitegravir accounted for 43 DDIs (29%), whereas NNRTIs were responsible for 14 DDIs (9.5%). CONCLUSIONS: In this analysis from the Central and Eastern European region on HIV-positive persons receiving COVID-19-specific treatment, it was found that potential DDIs were common. Although low-dose steroids are mainly used for COVID-19 treatment, comedication with boosted antiretrovirals seems to have the most frequent potential for DDIs. In addition, attention should be paid to NNRTI coadministration.

• MeSH
• adenin terapeutické užití   MeSH
• COVID-19 * MeSH
• dospělí MeSH
• emtricitabin terapeutické užití   MeSH
• farmakoterapie COVID-19 MeSH
• HIV infekce * farmakoterapie   MeSH
• HIV séropozitivita * farmakoterapie   MeSH
• inhibitory reverzní transkriptasy MeSH
• látky proti HIV * terapeutické užití   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• SARS-CoV-2 MeSH
• tenofovir škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

BACKGROUND: There is currently no evidence suggesting that COVID-19 takes a different course in HIV-positive patients on antiretroviral treatment compared to the general population. However, little is known about the relation between specific HIV-related factors and the severity of the COVID-19 disease. METHODS: We performed a retrospective analysis of cases collected through an on-line survey distributed by the Euroguidelines in Central and Eastern Europe Network Group. In statistical analyses characteristics of HIV-positive patients, asymptomatic/moderate and moderate/severe course were compared. RESULTS: In total 34 HIV-positive patients diagnosed with COVID-19 were reported by 12 countries (Estonia, Czech Republic, Lithuania, Albania, Belarus, Romania, Serbia, Bosnia and Herzegovina, Poland, Russia, Hungary, Bulgaria). Asymptomatic courses of COVID-19 were reported in four (12%) cases, 11 (32%) patients presented with mild disease not requiring hospitalization, moderate disease with respiratory and/or systemic symptoms was observed in 14 (41%) cases, and severe disease with respiratory failure was found in five (15%) patients. The HIV-related characteristics of patients with an asymptomatic/mild course of COVID-19 were comparable to those with a moderate/severe course of COVID-19, except for the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in cART regimen (0.0% vs. 31.6% respectively, p = 0.0239). CONCLUSIONS: In our analyses HIV viral suppression and immunological status were not associated with the course of COVID-19 disease. On the contrary the cART regimen could contribute to severity of SARS-CoV-2 infection. Large and prospective studies are necessary to further investigate this relationship.

• MeSH
• antiretrovirové látky terapeutické užití   MeSH
• COVID-19 komplikace   virologie   MeSH
• dospělí MeSH
• farmakoterapie COVID-19 MeSH
• HIV infekce komplikace   farmakoterapie   virologie   MeSH
• inhibitory proteas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• průzkumy a dotazníky MeSH
• retrospektivní studie MeSH
• SARS-CoV-2 * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• východní Evropa MeSH

• MeSH
• farmaceutická chemie MeSH
• klinická chemie MeSH
• léčivé přípravky MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• chemie, klinická chemie
• farmacie a farmakologie
• biochemie

Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically as non-nucleoside reverse transcriptase inhibitors (NNRTI). There are at least 15 naturally occurring calanolides distributed mainly within the genus Calophyllum, but some of them are also present in the genus Clausena. Besides significant anti-HIV properties, which have been exploited towards potential development of new NNRTIs for anti-HIV therapy, calanolides have also been found to possess anticancer, antimicrobial and antiparasitic potential. This review article provides a comprehensive update on all aspects of naturally occurring calanolides, including their chemistry, natural occurrence, biosynthesis, pharmacological and toxicological aspects including mechanism of action and structure activity relationships, pharmacokinetics, therapeutic potentials and available patents.

• MeSH
• biologické přípravky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• pyranokumariny chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• biologický transport fyziologie   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• Caco-2 buňky MeSH
• dideoxynukleosidy metabolismus   farmakologie   MeSH
• inhibitory reverzní transkriptasy metabolismus   farmakologie   MeSH
• intestinální absorpce fyziologie   MeSH
• krysa rodu rattus MeSH
• lamivudin metabolismus   farmakologie   MeSH
• lékové interakce fyziologie   MeSH
• lidé MeSH
• membránové transportní proteiny metabolismus   MeSH
• nádorové buněčné linie MeSH
• P-glykoprotein metabolismus   MeSH
• potkani Wistar MeSH
• psi MeSH
• rilpivirin metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

• MeSH
• dospělí MeSH
• HIV infekce farmakoterapie   virologie   MeSH
• HIV-1 účinky léků   genetika   MeSH
• inhibitory HIV-proteasy farmakologie   MeSH
• inhibitory reverzní transkriptasy farmakologie   MeSH
• látky proti HIV farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mutace MeSH
• prevalence MeSH
• virová léková rezistence genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

OBJECTIVES: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. DESIGN: Multinational cohort study. METHODS: Individuals in EuroSIDA with virological failure (>1 RNA measurement >500 on ART after >6 months on ART) after 1997 were included. Adjusted odds ratios (aORs) for resistance testing following virological failure and aORs for the detection of resistance among those who had a test were calculated using logistic regression with generalized estimating equations. RESULTS: Compared to 74.2% of ART-experienced individuals in 1997, only 5.1% showed evidence of virological failure in 2012. The odds of resistance testing declined after 2004 (global P < 0.001). Resistance was detected in 77.9% of the tests, NRTI resistance being most common (70.3%), followed by NNRTI (51.6%) and protease inhibitor (46.1%) resistance. The odds of detecting resistance were lower in tests done in 1997-1998, 1999-2000 and 2009-2010, compared to those carried out in 2003-2004 (global P < 0.001). Resistance testing was less common in Eastern Europe [aOR 0.72, 95% confidence interval (CI) 0.55-0.94] compared to Southern Europe, whereas the detection of resistance given that a test was done was less common in Northern (aOR 0.29, 95% CI 0.21-0.39) and Central Eastern (aOR 0.47, 95% CI 0.29-0.76) Europe, compared to Southern Europe. CONCLUSIONS: Despite a concurrent decline in virological failure and testing, drug resistance was commonly detected. This suggests a selective approach to resistance testing. The regional differences identified indicate that policy aiming to minimize the emergence of resistance is of particular relevance in some European regions, notably in the countries in Eastern Europe.

• MeSH
• dospělí MeSH
• genotyp MeSH
• HIV infekce farmakoterapie   MeSH
• HIV-1 genetika   MeSH
• inhibitory HIV-proteasy terapeutické užití   MeSH
• inhibitory reverzní transkriptasy terapeutické užití   MeSH
• kohortové studie MeSH
• látky proti HIV terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• multivariační analýza MeSH
• neúspěšná terapie MeSH
• počet CD4 lymfocytů MeSH
• virová léková rezistence genetika   MeSH
• virová nálož účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Od druhé poloviny devadesátých let minulého století je hlavní léčebnou strategií HIV infekce tzv. kombinovaná antiretrovirová terapie. Jednou z tradičně používaných lékových skupin jsou inhibitory reverzní transkriptázy. Etravirin je zástupcem druhé generace nenukleosidových inhibitorů reverzní transkriptázy (NNRTI). Vzhledem k nutnosti kombinovat léky z různých terapeutických skupin, je každý nový léčebný přípravek možnou alternativou v případě nesnášenlivosti nebo neúčinnosti předchozí terapie. Etravirin je obecně charakterizován dobrou účinností, menším rizikem vzniku nežádoucích účinků a vyšší odolností proti vzniku rezistence v porovnání se zástupci první generace NNRTI.

Since the mid-nineties of the last century, combination antiretroviral therapy has been the main treatment strategy for HIV. Reverse transcriptase inhibitors are among the traditionally used drug classes. Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). Due to the need to combine drugs from different classes, each newly approved medicinal product is an option for patients with resistance or intolerance to previous therapy. Etravirine is generally characterized by high efficacy, a low risk of side effects and a higher resistance barrier in comparison with first-generation NNRTIs.

• MeSH
• aplikace orální MeSH
• HIV infekce * farmakoterapie   MeSH
• HIV-1 účinky léků   MeSH
• inhibitory reverzní transkriptasy * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• látky proti HIV farmakologie   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• pyridaziny * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• vysoce aktivní antiretrovirová terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. METHODS: HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. RESULTS: From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). CONCLUSIONS: MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs.

• MeSH
• dospělí MeSH
• heterosexualita statistika a číselné údaje   MeSH
• HIV infekce farmakoterapie   epidemiologie   přenos   virologie   MeSH
• HIV-1 účinky léků   MeSH
• homosexualita mužská statistika a číselné údaje   MeSH
• inhibitory proteas terapeutické užití   MeSH
• inhibitory reverzní transkriptasy terapeutické užití   MeSH
• intravenózní abúzus drog epidemiologie   virologie   MeSH
• látky proti HIV terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• riskování * MeSH
• riziko MeSH
• sexuální chování statistika a číselné údaje   MeSH
• virová léková rezistence * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH