Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. 1032 Oct 27

Efavirenz (EFV, DMP-266) is a new antiretroviral agent belonging to the class of nonnucleoside reverse transcriptase inhibitors. It has recently been approved by the Food and Drug Administration in management of human immunodeficiency virus (HIV). Preliminary pharmacokinetic studies on EFV in healthy volunteers show that the drug may influence the metabolism of protease inhibitors. For the determination of EFV in human plasma, a validated and specific reverse-phase high-performance liquid chromatography (HPLC) method, with UV detection, was developed. We used 100 microL plasma sample for a liquid-liquid extraction with diethyl ether after basification. The mobile phase was a mixture of acetonitrile and water, pumped at a flow rate of 1.2 mL/min. Ultraviolet detection was carried out at a wavelength of 247 nm. Retention times for EFV and internal standard (IS) were 5.3 and 4.5 minutes, respectively, and there was no chromatographic interference from other commonly administered drugs. The limit of detection was 100 ng/mL. The described assay is a rapid and accurate method for measurement of EFV in plasma: the easy preparation and small sample size makes this assay highly suitable for pharmacokinetic studies and routine clinical analysis in patients with HIV. In addition, the reproducibility of the method is only moderately increased by including IS, so analyzing without IS may be an alternative.
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PMID:High-performance liquid chromatography method for analyzing the antiretroviral agent efavirenz in human plasma. 1036 51

Efavirenz (SUSTIVA, DMP 266, EFV) is a novel non-nucleoside reverse transcriptase inhibitor, which shows good inhibitory activity against HIV-1. The pharmacokinetics of efavirenz allow for once daily dosing without regard to meals of normal composition. Efavirenz is a mild inducer of CYP 3A4. Clinically significant drug interactions have been reported with medications that are metabolised via the cytochrome P450 enzymes such as indinavir and saquinavir. Results from the studies collated for submission (003, 006, 020, 024 and ACTG 364) have demonstrated the potency and durability of once daily efavirenz in combination with zidovudine (AZT) + lamivudine (3TC), indinavir (IDV), nelfinavir (NFV), IDV + 2 NRTIs, and NFV + 2 NRTIs. Efavirenz was recently approved for commercial use in the USA and has received marketing authorisation in Europe and Canada.
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PMID:Clinical history of efavirenz. 1062 35

Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.
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PMID:Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. 1133 79

DMP 266, a nonnucleoside reverse transcriptase inhibitor, has been effective as a monotherapeutic agent in reducing viral load. How long it remains effective is unknown, and resistance development is a problem. Two trials testing combinations with DMP 266 are beginning. One test using DMP 266 with indinavir is already considered flawed because indinavir is provided as a monotherapy first. Indinavir monotherapy is believed to help HIV resistance to evolve, especially in people with high baseline viral loads. Participants who are on the monotherapy risk not receiving the full benefit from indinavir and other protease inhibitors because they trigger similar resistance mutations.
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PMID:DMP 266: keep the drug but dump the trial? 1136 85

As combination therapy for treating HIV/AIDS grows, data on how these drugs interact becomes necessary and more complex. Information is provided on drug interactions using nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors, NNRTIs and nucleoside reverse transcriptase inhibitors, DMP 266 and indinavir, AZT and delavirdine, and ritonavir and saquinavir. New concerns for some combinations have arisen concerning AZT with d4T and nevirapine with indinavir. Trial results and questions about using these drugs are provided.
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PMID:Antiviral update. 1136 72

Dupont Merck announced that its experimental non-nucleoside reverse transcriptase inhibitor DMP 266 has shown viral load reductions to undetectable levels in eighty percent of study subjects. CD4 counts also increased among the study group. Other studies are underway to study DMP 266 at higher dosages and in combination with other drugs. Enrollment information is included.
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PMID:DMP 266 study opens at Jefferson. 1136 40

DMP 266, a non-nucleoside reverse transcriptase inhibitor (NNRTI) in the same general class as nevirapine or delavirdine, is undergoing clinical trials. Potential advantages of DMP 266 are that it is only taken once a day (making adherence easier for patients), there does not appear to be serious supply problems, and drug resistance appears to develop more slowly than other NNRTIs. Two Phase II trials, DMP 266-20 and DMP 266-006, are now recruiting protease inhibitor-naive persons. The company has decided to offer the drug to volunteers who complete either trial (each lasts 24 weeks) and wish to continue. Details about both trials and contact information are provided.
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PMID:DMP 266 trials recruiting, many cities -- protease inhibitor naive. 1136 23

DuPont Merck is conducting clinical trials of its new non-nucleoside reverse transcriptase inhibitor, DMP 266, at more than 100 hospitals. The drug is the first anti-HIV medication to be taken only once a day, and it shows significant viral load decreases when taken in combination with indinavir. Side effects include rash, sinusitis, upper respiratory infection, and diarrhea. Enrollment information is included. Merck will announce an expanded access program in September 1997.
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PMID:DMP 266 on the horizon. 1136 36

Results of a 48-week phase II trial of efavirenz (SUSTIVA, formerly DMP 266) in combination with indinavir resulted in an average viral load reduction of 2.38 out of a possible 2.49 logs. A comparison group, receiving only indinavir for 48 weeks, had a 1.89 log average reduction out of a possible 2.42 logs. Efavirenz, produced by DuPont Merck, is a non-nucleoside reverse transcriptase inhibitor that is effective against many HIV variants and resistance also develops slowly. Data from another study on efavirenz will be reported at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, October 11-15 in Hamburg, Germany. The additional number that is used to report viral load measurements is explained.
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PMID:Efavirenz (SUSTIVA, formerly DMP-266) 48-week data announced. 1136 90


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