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)

Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV-1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first-line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI-based regimens over 1-2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such 'switch' strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI-associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI-based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV-1 transmission with a simple, cost-effective regimen.
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PMID:Clinical uses of non-nucleoside reverse transcriptase inhibitors. 1089 70

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz; other compounds are under evaluation. NNRTIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions with compounds utilizing the same metabolic pathway, particularly PIs, whose plasma levels are altered in the presence of NNRTIs. NNRTIs are drugs with a low genetic barrier, i.e. a single mutation in RT genoma induces a high-level of phenotypic resistance, preventing the use of NNRTIs as monotherapy. In naive patients, several trials have shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as second-line therapy. However, due to the rapid emergence of resistant virus to these compounds in case of incomplete viral suppression, NNRTIs should not be added to current failing antiretroviral regimen. The most common side-effect reported with nevirapine and delavirdine is rash. The incidence of rash is rather similar under these two compounds, but severe rash is less frequent with delavirdine. The most common adverse reactions reported with efavirenz are central nervous system complaints such as dizziness. Rash is reported less frequently than with nevirapine or delavirdine, and is usually mild. NNRTIs resistance mutations are located in the amino acid residues aligning the NNRTI-binding "pocket" site. High-level resistance is often associated with a single point mutation which develops within this site (especially codon groups 100 - 108 and 181 - 190). Patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations. NNRTIs should always be used as part of a potent antiretroviral therapy to insure suppression of viral replication, thus circumventing the rapid selection of cross-resistant variants.
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PMID:[Non-nucleoside reverse transcriptase inhibitors]. 1092 53

A hospital-acquired outbreak with febrile illness and/or rash occurred in our neonatal special care nursery (SCN) from September 1995 to September 1996. A total of 23 infants developed symptoms. We could not detect the etiological agents by routine virus isolation. In a retrospective study, however, enterovirus RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) from four out of six cerebrospinal fluid (CSF) samples and from two of 12 sera. Thus six out of 16 patients from whom samples were obtained were diagnosed retrospectively as having enterovirus infection. Furthermore, we detected the enterovirus genome from four of 20 serum samples obtained from patients who had other clinical symptoms, and from infants hospitalized without noticeable clinical illness during the same periods. This outbreak was caused by two different enteroviruses, which we assumed were echovirus type 7 (Echo 7) and coxsackievirus B3 (Cox B3), because of the sequence results. We demonstrated the clinical advantage of the analysis of nucleotide sequencing as supportive evidence of transmission.
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PMID:Diagnosis of horizontal enterovirus infections in neonates by nested PCR and direct sequence analysis. 1097 45

Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is effective when used as part of combination therapy to treat HIV-1-infected individuals and as monotherapy for prevention of mother-to-child HIV-1 transmission. Nevirapine pharmacokinetics are characterised by rapid absorption and distribution, followed by prolonged elimination. Nevirapine is generally well tolerated. The most common toxicity is rash, which is usually mild and self-limiting. The primary route of nevirapine elimination is through metabolism by the cytochrome P450 enzyme system. Nevirapine elimination accelerates during long term administration because of autoinduction of the enzymes involved in its elimination pathway. The recommended regimen for adults is nevirapine 200mg once daily for 2 weeks, followed by 200mg twice daily. Nevirapine elimination is prolonged in pregnant women during labour and in newborns. A regimen of a single 200mg oral dose administered to the mother during labour and a single 2 mg/kg dose administered to the newborn at 48 to 72 hours after birth maintains serum nevirapine concentrations above 100 microg/L (10 times the in vitro 50% inhibitory concentration against wild-type HIV-1) throughout the first week of life. This limited regimen has been shown to be extremely well tolerated and to reduce mother-to-child transmission by nearly 50% in mothers and infants receiving no other antiretrovirals. There are few data describing the safety and pharmacokinetics of nevirapine during long term use in pregnancy. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. Children should receive 4 mg/kg once daily for the first 2 weeks of therapy, followed by 7 mg/kg doses twice daily if below the age of 8 years or 4 mg/kg twice daily if older than 8 years. Alternatively, children may receive 150 mg/m2 across all ages, once daily for the first 2 weeks of therapy followed by the same dose twice daily.
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PMID:Nevirapine: pharmacokinetic considerations in children and pregnant women. 1106 14

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has the most common treatment limiting side effect of rash. Severe rash has been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men. In a multicenter, retrospective cohort study of all patients who received nevirapine over a 5-year period, severe rash was noted in 9 of 95 women and 3 of 263 men (risk ratio [RR], 8.31; 95% confidence interval [CI], 2.3-30.0; P=.005). Women were more likely to discontinue nevirapine therapy because of rash (RR, 4.5; 95% CI, 1. 9-10.5; P=.0005). After adjusting for age and baseline CD4 cell count in multivariate analysis, women had a 7-fold increase in risk for severe rash and were 3.5 times more likely to discontinue nevirapine therapy. In women of reproductive age for whom contraception may occur, nevirapine remains the NNRTI of choice. Recognition of sex differences in this severe adverse event will be important in prescribing nevirapine.
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PMID:Sex differences in nevirapine rash. 1171 1

As measles control and elimination campaigns progress, laboratory confirmation of clinically diagnosed measles cases becomes increasingly important. However, in many tropical countries collection and storage of clinical specimens for this purpose are logistically complicated. In this study it is shown that blood samples spotted on filter paper are suitable for the laboratory diagnosis of measles using a combination of reverse transcriptase PCR (RT-PCR) analysis and immunoglobulin M (IgM) detection. First, it was shown that in vitro measles virus (MV)-infected cells diluted in human blood and spotted on filter paper can be detected by RT-PCR. Small amounts of infected cells remained detectable after 25 weeks of storage of the filter paper at room temperature, 4 weeks at 37 degrees C, or 2 weeks at 45 degrees C. Subsequently, this RT-PCR was applied to filter paper blood samples collected from 117 clinically diagnosed measles patients in Sudan in 1997 and 1998. Prior laboratory diagnosis had confirmed 90 cases as acute MV infections, while 27 proved to be nonmeasles rash disease cases. Positive RT-PCR signals were detected in filter paper blood samples of 43 of the 90 confirmed cases (48%) but in none of the 27 nonmeasles cases. In addition, MV-specific IgM levels measured in reconstituted filter paper samples correlated well with those measured in plasma samples. Measles diagnosis based on the combination of filter paper RT-PCR and IgM detection had a sensitivity and specificity of 99 and 96%, respectively. An advantage of this diagnostic approach is that sequencing of RT-PCR products allows phylogenetic analysis of the MV strain involved.
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PMID:Combination of reverse transcriptase PCR analysis and immunoglobulin M detection on filter paper blood samples allows diagnostic and epidemiological studies of measles. 1113 82

At various times postonset of rash, 74 patients positive for measles virus-specific immunoglobulin M provided samples for detection of measles virus RNA by a reverse transcriptase PCR. Of lymphocytes, urine, throat swab, and serum specimens, throat swab specimens were optimal for detection of measles virus RNA during the first 2 weeks after the rash.
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PMID:Investigation of optimal specimen type and sampling time for detection of measles virus RNA during a measles epidemic. 1113 5

A reverse transcriptase-polymerase chain reaction assay was used to detect measles virus RNA in peripheral blood mononuclear cells, urine, and nasopharyngeal specimens from Zambian children during hospitalization and approximately 1-2 months after discharge. Of 47 children, 29 (61.7%) had prolonged measles virus shedding, as defined by detection of measles virus RNA in > or =1 specimen obtained 30-61 days after rash onset. Ten (90.9%) of 11 human immunodeficiency virus (HIV)-infected children had prolonged measles virus shedding, compared with 19 (52.8%) of 36 HIV-uninfected children (P=.02). Prolonged measles virus shedding did not correlate with levels of measles virus-specific antibody. HIV-infected children with measles may have a prolonged infectious period that potentially enhances measles virus transmission and hinders measles control.
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PMID:Prolonged measles virus shedding in human immunodeficiency virus-infected children, detected by reverse transcriptase-polymerase chain reaction. 1117 Sep 77

Nevirapine is a non-nucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of HIV infection. Severe rash, including the Stevens-Johnson syndrome (SJS), is the major toxicity of nevirapine and is described in the package labeling with a prominent, boxed warning. Though physicians treating large populations of patients with HIV are well aware of this complication, only one other report of nevirapine-associated SJS has been documented in the dermatology literature. We describe 2 cases of SJS related to nevirapine use and review the literature on this newly recognized association.
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PMID:Stevens-Johnson syndrome caused by the antiretroviral drug nevirapine. 1117 14

Most of the information available on stavudine (d4T) comes from studies in patients with advanced human immunodeficiency virus (HIV) disease to whom stavudine was administered as monotherapy. Herein, we summarize the results of adding 40 mg stavudine twice daily to previous therapies in patients with mild to advanced immunological disease (mean CD4 T cell count 178 cells/mm3; range 6-480 cells/mm3). In an intention-to-treat, prospective, open trial, 64 patients (84.4% men; mean age 35.2 years) were analysed. Their average time on previous antiretroviral therapy was 19.8 months (range 6-52). Plasma HIV RNA load fell by a mean of 0.64 and 0.74 log at 1 and 3 months, respectively, after the start of stavudine therapy (P <0.001 Sign rank test). The CD4 cell count increased by a mean of 25.1 cells/mm3 in the third month (P = 0.002 Sign rank test). Antiviral activity was independent of the CD4 cell count at baseline, but more pronounced declines in viral load were seen in patients with shorter periods of previous antiretroviral therapy and in those in whom stavudine was combined with didanosine or lamivudine rather than zidovudine. Ten (15.6%) patients discontinued the drug during the first 6 months of treatment because of the development of toxicity (neuropathy in six cases, hepatitis in two, oedema in one and rash in another); all but one of them had CD4 counts < 200 cells/mm3. Another two patients stopped treatment voluntarily. The remaining 52 patients tolerated the drug well for the first 6 months and had a high level of compliance with treatment. In conclusion, stavudine is generally well tolerated and has significant antiretroviral activity when it is administered to patients with extensive previous treatment with multiple reverse transcriptase (RT) inhibitors. It should be expected that the short-term favourable effects of stavudine on laboratory markers will further translate into a reduced progression of disease and improved survival.
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PMID:Short-term efficacy and safety of stavudine in pretreated HIV-infected patients. 1132 73


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