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)

The presence of human immunodeficiency virus (HIV) in the central nervous system (CNS) is associated with the development of HIV-1-associated dementia (HAD), a major cause of HIV-related mortality. To eradicate HIV in the CNS, anti-HIV drugs need to reach the brain and cerebrospinal fluid (CSF) in therapeutic concentrations. This involves passage through the blood-brain and blood-CSF barriers. Using a well established guinea pig in situ brain perfusion model, this study investigated whether nevirapine [6H-dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one,11-cyclopropyl-5,11-dihydro-4-methyl], a non-nucleoside reverse transcriptase inhibitor (NNRTI), could effectively accumulate in the CNS. [(3)H]Nevirapine was coperfused with [(14)C]mannitol (a vascular/paracellular permeability marker) through the carotid arteries for up to 30 min, and accumulation in the brain, CSF, and choroid plexus was measured. [(3)H]Nevirapine uptake into the cerebrum was greater than uptake of [(14)C]mannitol, indicating significant passage across the blood-brain barrier and accumulation into the brain (this was further confirmed with capillary depletion and high-performance liquid chromatography analyses). Likewise, [(3)H]nevirapine showed a great ability to cross the blood-CSF barrier and accumulate in the CSF, compared with [(14)C]mannitol. The CNS accumulation of [(3)H]nevirapine was unaffected by 100 muM nevirapine, suggesting that passage across the blood-brain barrier can occur by diffusion. Furthermore, coperfusion with 100 muM efavirenz [2H-3,1-benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-, (4S)-; another NNRTI] did not significantly alter CNS accumulation of [(3)H]nevirapine, indicating that the efficacy of nevirapine in the CNS would not be altered by the addition of this drug to a combination therapy. Together, these data indicate that this anti-HIV drug should be beneficial in the eradication of HIV within the CNS and the subsequent treatment of HAD.
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PMID:Nevirapine uptake into the central nervous system of the Guinea pig: an in situ brain perfusion study. 1642 47

Nevirapine (Viramune) belongs to the first generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Its efficiency is limited by drug resistant mutations, such as K103N and Y181C, so, the aim of this work was to design novel nevirapine analogues insensitive to the K103N and Y181C HIV-1 RT. 360 Nevirapine derivatives were designed using a combinatorial library design approach and these compounds were docked into the binding pocket of mutant HIV-1 RT enzyme structures, using the GOLD program. 124 Compounds having a GoldScore higher than that of nevirapine (55.00 and 52.00 for K103N and Y181C mutants, respectively) were first retrieved and submitted to a topological analysis with the SILVER program. Consequently, 31 compounds presenting a significant percentage of the surfaces buried upon binding (>80%) and exhibiting hydrogen bonds to either N103 or C181 residues of the HIV-RT were selected. To ensure that these compounds had hydrogen bonding interaction to either N103 or C181 residues, their interaction energies were estimated by quantum chemical calculations (QCCs). Finally, QCCs represent an alternative method for performing post docking procedure.
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PMID:Design of nevirapine derivatives insensitive to the K103N and Y181C HIV-1 reverse transcriptase mutants. 1664 57

Non-B HIV subtypes have been estimated to account for 88% of HIV infections in the world. These subtypes are particularly relevant in view of the availability of antiretroviral (ARV) drugs, since subtype-specific mutations are associated with drug-resistance in developing countries. Therefore, the pol gene sequences in HIV-1 isolates were examined from the three distinct groups of 39 infected patients from Ouagadougou in Burkina Faso: 17 patients who had not received any antiretroviral therapy (ART); 16 patients received ART, and 6 HIV-infected children, from infected mothers, received a single Nevirapine dose prophylaxis during birth. HIV-1 pol sequencing was successful for 29 samples. As expected, all patients presented the common (non-B subtype) M36I polymorphism and 26/29 (90%) the K20I mutation. Phylogenetic studies showed high predominance of recombinant HIV-1 strains: CRF06_cpx 16/29 (55.17%), CRF02_AG 9/29 (31.03%), A1 2/29 (6.89%), G 1/29 (3.44%), and CRF09_cpx 1/29 (3.44%). Two twins showed, 6 months after birth, a NNRTI-mutation (Y181C/Y). During the same period, the twin mother presented a different NNRTI-mutation (V106I), thus suggesting that the different blood drug concentration may determine a different drug-resistance pathway. Among 17 non-highly active antiretroviral therapy (HAART) patients, 3/17 (17.64%) presented virus with reverse transcriptase (RT) mutations [V118I: 1/17 patients (5.88%), V179E: 2/17 patients (11.76%)]. 10/17 (58.82%) presented virus with minor protease (PR) mutations [L63P: 5/17 patients (29.41%), V77I: 3/17 patients (17.64%), L10I: 2/17 patients (11.76%)]. 4/17 patients did not show any PR and RT mutations (23.52%). Among six HAART-treated patients, 6/6 and 3/6 had M36I and L63LP protease minor subtypes, respectively; and only two (33.33%) presented virus with K103N mutation. The low prevalence of drug-resistant associated mutations in Burkina Faso is encouraging. However, further studies with a larger cohort with a high non-B subtype prevalence are necessary to optimize ART in developing countries.
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PMID:Characterization of drug-resistance mutations in HIV-1 isolates from non-HAART and HAART treated patients in Burkina Faso. 1699 78

Tuberculosis associated with HIV infection continues to be an important problem throughout the world. Since the advent of HAART, the medication of HIV-infected patients who have to receive concomitant treatment for tuberculosis has become a difficult task. The two main problems faced by clinicians include the significant pharmacokinetic interactions between rifamycins, a cornerstone in antituberculosis therapy, and protease inhibitors and nonnucleoside reverse transcriptase inhibitors, which are essential components of antiretroviral combination regimens, as well as the best moment to initiate antiretroviral therapy in patients with tuberculosis. The therapy of choice for patients with no previous antiretroviral experience includes an antituberculous regimen with rifampin and an efavirenz-based antiretroviral regimen. No dose adjustments of these drugs seem to be necessary. Nevirapine can be an alternative to efavirenz in this situation. For patients who cannot take efavirenz, either due to resistance or intolerance, rifabutin and a boosted protease inhibitor can be coadministered, with the necessary dose adjustments. No definite recommendations can be given regarding the optimal timing of antiretroviral therapy, but a delay of two months after initiation of antituberculosis therapy would be advisable and seems to be safe in most patients.
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PMID:Antiretroviral therapy in AIDS patients with tuberculosis. 1707 82

Nevirapine and efavirenz are nonnucleoside reverse transcriptase inhibitors used in antiretroviral regimens to treat HIV infection. Therapeutic drug monitoring in patients on antiretroviral regimens that include these agents has been suggested to be beneficial in terms of efficacy and toxicity. Various analytical methods are available to quantify nevirapine and efavirenz concentrations. A previously published, nine-step, decision-making algorithm has been used to evaluate the utility of therapeutic drug monitoring of efavirenz and nevirapine. A relationship has been found between efavirenz concentrations and toxicity and between nevirapine concentrations and virological efficacy. For efavirenz, the recommended therapeutic range is 1-4 mg/L; for nevirapine, minimum trough concentrations of >3.4 mg/L have been suggested. Both drugs have demonstrated interindividual pharmacokinetic variability. The pharmacokinetic parameters of nevirapine vary in female patients, patients coinfected with hepatitis B virus, and patients from different geographical locations. The pharmacokinetic parameters of efavirenz have also been shown to vary depending on patients' race, baseline bilirubin level, and geographical location. Drug interactions and resistance mutations can also be confounders in the pharmacokinetic parameters of these drugs. Coinfection with hepatitis C can also contribute to increased drug concentrations. The risk of hepatotoxicity can be increased in the presence of elevated nevirapine concentrations. As patients with HIV-1 infection will be managed with different combinations of antiretroviral regimens over the course of their lives, the limitations of having only four drug classes from which to choose make it even more important to maximise the usefulness of each of these drug classes. The available evidence suggests that therapeutic drug monitoring of efavirenz and nevirapine may contribute to the clinician's ability to evaluate efficacy and safety in patients taking these drugs. Patients at risk of toxicity from drug interactions or disease interactions and patients who may be noncompliant may gain the greatest benefit from therapeutic drug monitoring of efavirenz and nevirapine.
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PMID:Efavirenz and nevirapine in HIV-1 infection : is there a role for clinical pharmacokinetic monitoring? 1725 84

Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens provide simpler and more easily tolerated treatment alternatives to protease inhibitor-based regimens, potentially improving adherence. Long-term viral suppression relies on adherence to a prescribed antiretroviral treatment regimen. Simplification of dosing schedules has prompted investigations into once-daily dosing regimens; nevirapine once-daily dosing strategies are currently under investigation. The DAUFIN study compared zidovudine/lamivudine 300 mg/150 mg plus nevirapine 200 mg twice daily with lamivudine 300 mg, tenofovir 245 mg and nevirapine 400 mg once daily. The study was stopped after early virological failure was observed in 8/36 (22.2%) once-daily patients. Baseline characteristics in once-daily patients with and without virological failure indicated significantly higher median plasma viral load and significantly lower median CD4+ cell counts. Presented nevirapine plasma trough levels were not stratified by virological failure or success. Resistance mutations accumulated while on treatment; high rates of K65R mutations and severe NNRTI resistance profiles might be indicative of ongoing viral replication caused by suboptimal nevirapine plasma trough concentrations under non-adherence to the treatment regimen. Non-B-subtype infection (subtype A or C not stated) was observed in 4/10 patients with virological failure. The DAUFIN study was prematurely stopped without predetermined cessation criteria, presented data are not complete, and results should be interpreted with caution. Nevirapine pharmacokinetics make it suitable for once-daily dosing. However, due to rash and concerns over liver toxicity, nevirapine once daily might best be administered in patients with undetectable viral load after initial treatment with nevirapine twice daily. The NODy study will evaluate the efficacy and safety of switching to nevirapine once daily compared with remaining on twice-daily treatment.
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PMID:Once-daily dosing of nevirapine in HAART. 1800 24

Nevirapine is a non-nucleoside reverse transcriptase inhibitor commonly used in human immunodeficiency virus-1 multidrug regimens and associated with life-threatening cutaneous reactions. Here, we report the successful use of intravenous immunoglobulin in a pediatric patient with Stevens-Johnson syndrome and highlight the risk of nevirapine usage in human immunodeficiency virus postexposure prophylaxis.
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PMID:Nevirapine-induced Stevens-Johnson syndrome in a pediatric patient. 1830 77

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against the human immunodeficiency virus type 1 (HIV-1), mostly to prevent mother-to-child HIV transmission in developing countries. One of the limitations of nevirapine use is severe hepatotoxicity, which raises concerns about its administration, particularly in the perinatal and pediatric settings. Nevirapine metabolism involves oxidation of the 4-methyl substituent to 12-hydroxy-NVP and the formation of phenolic derivatives. Further metabolism of 12-hydroxy-NVP by phase II esterification may produce electrophilic derivatives capable of reacting with DNA to yield covalent adducts, which could potentially be involved in the initiation of mutagenic and carcinogenic events. In the present study, we have investigated the reactivity of the synthetic model electrophile, 12-mesyloxy-NVP, toward 2'-deoxynucleosides and DNA. Parallel synthetic studies were conducted with 12-bromo-NVP and 3',5'- O-bis( tert-butyldimethylsilyl)-2'-deoxynucleosides, using palladium(0) catalysis. Multiple adducts from deoxyguanosine, deoxyadenosine, and deoxycytidine were isolated in the reactions with 12-mesyloxy-NVP and characterized by NMR and MS. The adduct structures consistently involved binding through C12 of NVP and N7 or N9 of deoxyguanosine; N1, N3, or N9 of deoxyadenosine; and N3 of deoxycytidine. Reactions conducted under palladium(0) catalysis yielded adducts through O (6) and N1 of deoxyguanosine, N1 of deoxyadenosine, and N3 of deoxycytidine. At least seven deoxynucleoside-NVP adducts were present in DNA reacted with 12-mesyloxy-NVP and enzymatically hydrolyzed. Four of these adducts were identified as 12-(deoxyadenosin-N1-yl)nevirapine, 12-(deoxycytidin-N3-yl)nevirapine, 12-(deoxyguanosin- O(6)-yl)nevirapine, and 12-(deoxyadenosin- N(6)-yl)nevirapine. One depurinating adduct, 12-(guanin-N7-yl)nevirapine, was identified in the thermal neutral DNA hydrolysate. If formed in vivo, some of these adducts would have considerable mutagenic potential. Our results thus suggest that NVP metabolism to 12-hydroxy-NVP may be a factor in NVP hepatocarcinogenicity.
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PMID:Synthesis and characterization of DNA adducts from the HIV reverse transcriptase inhibitor nevirapine. 1859 99

Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugs belonging to potent class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) widely used for the treatment human immunodeficiency virus (HIV) infection. It has been demonstrated that NVP and EFV are able to cross the blood-brain barrier and arrive at the central nervous system (CNS), causing important adverse effects related to their presence within this tissue. Considering that the exact mechanisms responsible for CNS toxicity associated with NVP and EFV remain unknown and that creatine kinase (CK) plays an important role in cell energy homeostasis, in the present work we evaluated CK activity in brain of mice after chronic administration of these drugs. Our results demonstrated that NVP and EFV significantly inhibited CK activity in cerebellum, hippocampus, striatum and cortex of mice. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity by NVP and EFV may be associated with neurological adverse symptoms of these drugs.
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PMID:Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity. 1881 73

Nevirapine and its synthetic analogues, a class of non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), have been the objective of numerous studies focused to prepare better and safer anti-HIV drugs. We developed a library of nevirapine analogues (47) using combinatorial design and with structural modification at X, Y and R substituents in the parent structure of nevirapine. Their molecular interactions and binding affinities with reverse transcriptase (3HVT and 1VRT) have been studied using the docking-molecular mechanics based generalized Born/surface area (MM-GB/SA) solvation model. Final screening of these analogues is based on absorption, distribution, metabolism and excretion (ADME) properties. The proposed NNRTI analogues dock in a similar position and orientation in the active site of RT as co-crystallized nevirapine. In addition a linear correlation was observed between the calculated free energy of binding (FEB) and pIC50 for the inhibitors with correlation coefficient R2 of 0.9948, suggesting that the docked structure orientation and the interaction energies are reasonable. The electrostatic energy terms estimated by GB/SA showed important role on prediction of binding affinity (R2 = 17.2 %). Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different resolution (2.9 and 2.2 A), we propose that structures with resolutions better than 3 A can be used to produce reasonable docking results. Few analogues showed high binding affinity and activity with RT in compare to co-crystallized nevirapine. These analogues also well qualify ADME properties and showed good druggable characters. The work addressed to modify the X, Y and R substituents in the nevirapine scaffold to prepare synthetic analogues for second generation drug development against RT.
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PMID:Docking-MM-GB/SA and ADME screening of HIV-1 NNRTI inhibitor: nevirapine and its analogues. 1903 62


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