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Tomas Cihlar - One of the best experts on this subject based on the ideXlab platform.
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nucleoside and nucleotide hiv Reverse Transcriptase Inhibitors 25 years after zidovudine
Antiviral Research, 2010Co-Authors: Tomas Cihlar, Adrian S RayAbstract:Twenty-five years ago, nucleoside analog 3'-azidothymidine (AZT) was shown to efficiently block the replication of HIV in cell culture. Subsequent studies demonstrated that AZT acts via the selective inhibition of HIV Reverse Transcriptase (RT) by its triphosphate metabolite. These discoveries have established the first class of antiretroviral agents: nucleoside and nucleotide Reverse Transcriptase Inhibitors (NRTIs). Over the years that followed, NRTIs evolved into the main component of antiretroviral drug combinations that are now used for the treatment of all populations of HIV infected patients. A total of thirteen NRTI drug products are now available for clinical application: eight individual NRTIs, four fixed-dose combinations of two or three NRTIs, and one complete fixed-dose regimen containing two NRTIs and one non-nucleoside RT inhibitor. Multiple NRTIs or their prodrugs are in various stages of clinical development and new potent NRTIs are still being identified through drug discovery efforts. This article will review basic principles of the in vitro and in vivo pharmacology of NRTIs, discuss their clinical use including limitations associated with long-term NRTI therapy, and describe newly identified NRTIs with promising pharmacological profiles highlighting those in the development pipeline. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010.
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Nucleotide HIV Reverse Transcriptase Inhibitors: tenofovir and beyond.
Current opinion in HIV and AIDS, 2006Co-Authors: Tomas CihlarAbstract:PURPOSE OF REVIEW This review describes the class of nucleotide HIV Reverse Transcriptase Inhibitors and summarises recent findings related to tenofovir and its oral prodrug tenofovir disoproxil fumarate, currently the only nucleotide approved for the treatment of HIV infection. In addition, novel strategies in the design of anti-HIV nucleotides and their prodrugs are discussed. RECENT FINDINGS A number of studies have demonstrated a potent and durable clinical efficacy of tenofovir disoproxil fumarate in combination with other antiretrovirals, particularly lamivudine or emtricitabine and efavirenz. The prophylactic antiretroviral effect of tenofovir and tenofovir disoproxil fumarate has been characterized in various animal models and is currently being evaluated in controlled clinical studies. In addition, efficacy of tenofovir disoproxil fumarate against hepatitis B virus has been established and is currently being explored in phase III trials. The identification of GS-7340, an alternative prodrug of tenofovir has raised the possibility of using phosphonoamidates as novel prodrugs allowing for an effective intracellular delivery of nucleotides. SUMMARY The concept of nucleotides as a novel class of antiretroviral therapeutics has been successfully validated through tenofovir disoproxil fumarate, a nucleotide prodrug that exhibits potent and durable clinical efficacy and favourable safety profile both in treatment-naive and experienced HIV-infected patients. Several novel nucleotide Reverse Transcriptase Inhibitors such as GS-9148, PMDTA, and PMEO have recently emerged from continuing preclinical drug discovery efforts.
Robert L. Murphy - One of the best experts on this subject based on the ideXlab platform.
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Combination nucleoside/nucleotide Reverse Transcriptase Inhibitors for treatment of HIV infection.
Expert opinion on pharmacotherapy, 2011Co-Authors: Maxwell O Akanbi, Kimberly Scarci, Babafemi Taiwo, Robert L. MurphyAbstract:Introduction: The combination of two nucleoside/nucleotide Reverse Transcriptase Inhibitors (N(t)RTIs) and a third agent from another antiretroviral class is currently recommended for initial antiretroviral therapy. In general, N(t)RTIs remain relevant in subsequent regimens. There are currently six nucleoside Reverse Transcriptase Inhibitors and one nucleotide Reverse Transcriptase inhibitor drug entities available, and several formulations that include two or more N(t)RTIs in a fixed-dose combination. These entities have heterogeneous pharmacological and clinical properties. Accordingly, toxicity, pill burden, dosing frequency, potential drug–drug interaction, preexisting antiretroviral drug resistance and comorbid conditions should be considered when constructing a regimen. This approach is critical in order to optimize virologic efficacy and clinical outcomes. Areas covered: This article reviews N(t)RTI combinations used in the treatment of HIV-infected adults. The pharmacological properties of each N...
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Nonnucleoside Reverse Transcriptase Inhibitors.
AIDS clinical care, 1997Co-Authors: Robert L. MurphyAbstract:The nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) are a structurally and chemically dissimilar group of antiretrovirals that are potent and
Kiat Ruxrungtham - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of nucleoside/nucleotide Reverse Transcriptase Inhibitors for the treatment and prevention of HIV infection.
Expert opinion on drug metabolism & toxicology, 2020Co-Authors: Piyanuch Wonganan, Wacharee Limpanasithikul, Suree Jianmongkol, Stephen J. Kerr, Kiat RuxrungthamAbstract:Despite dramatic increases in new drugs and regimens, a combination of two nucleoside/nucleotide Reverse Transcriptase Inhibitors (NRTIs) remains the backbone of many regimens to treat HIV. This ar...
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Resistance to Dual Nucleoside Reverse-Transcriptase Inhibitors in Children Infected with HIV Clade A/E
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004Co-Authors: Rangsima Lolekha, Kiat Ruxrungtham, Sunee Sirivichayakul, Umaporn Siangphoe, Chitsanu Pancharoen, Suchada Kaewchana, Wichitra Apateerapong, Apicha Mahanontharit, Tawee Chotpitayasunondh, Praphan PhanuphakAbstract:The prevalence of nucleoside Reverse-Transcriptase inhibitor (NRTI) mutations was determined among 95 human immunodeficiency virus-infected Thai children who were treated with dual nucleoside Reverse-Transcriptase Inhibitors. Almost all children had resistance to at least 1 NRTI, and approximately half of the children had resistance to multiple NRTIs. Cross-resistance to stavudine and azidothymidine was universal.
Gene D. Morse - One of the best experts on this subject based on the ideXlab platform.
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interactions between buprenorphine and antiretrovirals nucleos t ide Reverse Transcriptase Inhibitors nrti didanosine lamivudine and tenofovir
American Journal on Addictions, 2010Co-Authors: Jennifer Baker, Gene D. Morse, Petrie M Rainey, David E Moody, Elinore F MccancekatzAbstract:To improve outcomes among injection drug users with HIV and/or chronic hepatitis B, it is important to identify drug interactions between antiretroviral and opiate therapies. We report the results of a study designed to examine the interaction between buprenorphine and the nucleos(t)ide Reverse Transcriptase Inhibitors (NRTI) didanosine (ddI), lamivudine (3TC), and tenofovir (TDF). Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 27) participated in two 24-hour sessions to determine (1) pharmacokinetics of buprenorphine alone and (2) pharmacokinetics of both buprenorphine and either ddI, 3TC, or TDF. Among buprenorphine/naloxone-maintained study participants, no significant changes in buprenorphine pharmacokinetics were observed following ddI, 3TC, or TDF administration. Buprenorphine had no significant effect on NRTI concentrations. Concomitant use of buprenorphine with ddI, 3TC, or TDF results in neither a significant pharmacokinetic nor pharmacodynamic interaction. (Am J Addict 2009;19:17–29)
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Separation of phosphorylated nucleoside Reverse Transcriptase Inhibitors by capillary electrophoresis
Microchemical Journal, 2009Co-Authors: Melissa N. Dunkle, Gene D. Morse, Jill Hochreister, Robin Difrancesco, Luis A. ColónAbstract:Capillary electrophoretic (CE) conditions were established to separate multiple nucleoside Reverse Transcriptase inhibitor triphosphates (NRTI-TPs). These are the active drug forms of nucleoside Reverse Transcriptase Inhibitors (NRTIs) used to treat HIV-infected patients and two NRTIs are always used as part of a three or four drug regimen. Two buffer systems were suitable to separate multiple NRTI-TPs using CE. A carbonate/borate buffer under a positive applied voltage provided for the separation of six different NRTI-TPs of interest. A phosphate buffer, however, under suppressed electroosmotic flow conditions (i.e., low pH) and a negative applied voltage proved to be more effective than the carbonate/borate system. Addition of EDTA to the run buffer improved resolution and overall peak shape of the NRTI-TP. The established experimental conditions can be used to separate multiple NRTI-TPs in peripheral blood mononuclear cells (PBMCs) from human whole blood.
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Clinical Pharmacokinetics of Non-Nucleoside Reverse Transcriptase Inhibitors
Clinical Pharmacokinetics, 2001Co-Authors: Patrick F. Smith, Robert Dicenzo, Gene D. MorseAbstract:Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) Reverse Transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue Inhibitors of Reverse Transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or Inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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The nucleoside Reverse Transcriptase Inhibitors, nonnucleoside Reverse Transcriptase Inhibitors, and protease Inhibitors in the treatment of HIV infections (AIDS).
Advances in pharmacology (San Diego Calif.), 2013Co-Authors: Erik De ClercqAbstract:Abstract The majority of the drugs currently used for the treatment of HIV infections (AIDS) belong to either of the following three classes: nucleoside Reverse Transcriptase Inhibitors (NRTIs), nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs), and protease Inhibitors (PIs). At present, there are 7 NRTIs, 5 NNRTIs, and 10 PIs approved for clinical use. They are discussed from the following viewpoints: (i) chemical formulae; (ii) mechanism of action; (iii) drug combinations; (iv) clinical aspects; (v) preexposure prophylaxis; (vi) prevention of mother-to-child transmission; (vii) their use in children; (viii) toxicity; (ix) adherence (compliance); (x) resistance; (xi) new NRTIs, NNRTIs, or PIs in (pre)clinical development; and (xii) the prospects for a “cure” of the disease.
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Long-term exposure of HIV type 1-infected cell cultures to combinations of the novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of nonnucleoside Reverse Transcriptase Inhibitors.
AIDS research and human retroviruses, 2000Co-Authors: Jan Balzarini, Erik De Clercq, An Carbonez, Vikki Burt, Jörg-peter KleimAbstract:The novel quinoxaline GW420867X has been combined with a variety of nucleoside Reverse Transcriptase Inhibitors (NRTIs) and nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) in HIV-1(IIIB )-i...
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perspectives of non nucleoside Reverse Transcriptase Inhibitors nnrtis in the therapy of hiv 1 infection
Farmaco, 1999Co-Authors: Erik De ClercqAbstract:Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) have, in addition to the nucleoside Reverse Transcriptase Inhibitors (NRTIs) and protease Inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 Reverse Transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.
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the role of non nucleoside Reverse Transcriptase Inhibitors nnrtis in the therapy of hiv 1 infection
Antiviral Research, 1998Co-Authors: Erik De ClercqAbstract:Abstract Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) have, in addition to the nucleoside Reverse Transcriptase Inhibitors (NRTIs) and protease Inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than 30 structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 Reverse Transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are in preclinical or clinical development [thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097 and DMP 266 (efavirenz)]. The NNRTIs interact with a specific `pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, alone or in combination, are used from the start at sufficiently high concentrations. In vitro, this procedure has proved to `knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations of NNRTIs (nevirapine, delavirdine or efavirenz) with NRTIs (AZT, 3TC, ddI or d4T) and/or PIs (indinavir or nelfinavir) have been shown to afford a durable anti-HIV activity, as reflected by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-lymphocyte counts.