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)

Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (NPPIs). It is a sulphonamide-containing dihydropyrone, which is highly selective for the HIV protease enzyme and demonstrates potent in vitro activity against wild-type HIV-1 and HIV-2. The IC90 for TPV was 0.1 microM against clinical HIV isolates. Since CYP3A is the major cytochrome P450 isoform for the phase I metabolism of TPV, its exposure is markedly enhanced in the presence of ritonavir (RTV). In one clinical study, using the new self emulsifying drug delivery system (SEDDS) formulation of TPV, plasma concentrations in excess of 20 microM were maintained for 12 hours, allowing for twice-a-day dosing following administration of TPV 300 mg/RTV(r) 200 mg twice a day. The 20 microM target represents 10-fold the IC90 for multiple protease inhibitor (PI)-resistant strains. Both in vitro data and pharmacokinetic results indicate that TPV will be active in vivo against PI-resistant viruses, when given twice a day in combination with low dose RTV. Of 105 HIV viral isolates taken from patients who had been heavily pretreated with PI-based regimens: 90% were fully susceptible to TPV; 8% exhibited intermediate resistance; and 2% were more than 10-fold resistant. In patients who had failed at least two PI-based regimens, only 12.2% of the HIV isolates exhibited four to 10-fold reduced susceptibility to TPV after one year of treatment with a regimen containing the NPPI (Study BI1182.2). A reduction of approximately 1.5 log10 copies/mL in the plasma viral load (pVL) was observed in treatment-naive patients after 15 days of monotherapy with TPV (300 or 1200 mg twice a day) co-administered with RTV (200 mg twice a day) (TPV/r) in a dose-ranging study (Study BI1182.3). The safety and efficacy of TPV (500 or 1250 mg) plus ritonavir (100 mg twice a day) plus two new nucleoside reverse transcriptase inhibitors (NRTIs) was studied in patients failing their first PI-containing regimen (Study BI1182.4). Similar decreases in pVLs (1.44-1.79 log10 copies/mL) were observed after 16 weeks of treatment with either dose of TPV/r. Two doses of TPV/r plus efavirenz (EFV) and a new NRTI have been studied in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients who had failed two or more PI-containing regimens (BI1182.2). Between 50% and 78.9% of patients maintained a pVL < 50 copies/mL for 48 weeks. Clinical studies have shown that TPV/r-associated adverse events are generally gastrointestinal-associated, transient and mild. A phase II study will define the optimal dose of TPV/r for highly treatment-experienced patients. The safety and efficacy of this dose of TPV/r will be evaluated in two phase III studies that will enroll more than 1300 patients worldwide. Tipranavir's robust activity against PI-resistant strains results from its molecular flexibility, which allows it to fit into the active pocket of the protease enzyme in viruses that have become resistant to other PIs.
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PMID:Tipranavir: a protease inhibitor from a new class with distinct antiviral activity. 1456 64

Tipranavir is a new nonpeptidic protease inhibitor and belongs to the class of 4-hydroxy-5, 6-dihydro-2-pyrones. Chemically, tipranavir is based on coumarin and sulfonamide compounds, amongst others. It exhibits potent and specific activity against both HIV-1 and -2. Tipranavir 500 mg in combination with ritonavir 200 mg twice daily results in optimum viral load reduction and suppresses both wild-type and protease inhibitor-resistant virus. It is metabolized by the cytochrome P4503A4 enzyme and its pharmacokinetic parameters are enhanced when combined with ritonavir. Tipranavir is excreted primarily in the feces, with minimal excretion in urine. In early trials, tipranavir/ritonavir was demonstrated to be safe and well tolerated, with mild gastrointestinal side effects. Preliminary data indicate pharmacokinetic interaction with nucleotide reverse transcriptase inhibitors; however, no dose adjustments are recommended at this time. Virologic response is not adequate when combined with other ritonavir-boosted protease inhibitors, and is currently not recommended. As with other protease inhibitors, tipranavir interacts with fluconazole, atorvastatin, clarithromycin and rifabutin and absorption is reduced when taken with antacids and didanosine (enteric coated formulation). Phase III trials are underway to compare the efficacy of tipranavir/ritonavir with other antiretroviral agents.
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PMID:Tipranavir: a novel second-generation nonpeptidic protease inhibitor. 1575 54

Tipranavir is a novel nonpeptidic protease inhibitor (PI) with activity against wild-type and multidrug-resistant HIV-1 both in vitro and in HIV-infected patients. Tipranavir/ritonavir 500 mg/200 mg administered twice daily for 3 weeks to healthy volunteers produced a median (range) maximum plasma concentration and minimum plasma concentration of 79.1 (34.9-111.7) mg/L and 19.5 (0.43-42.8) mg/L, respectively. Concomitant administration with low-dose ritonavir significantly increases tipranavir plasma concentrations; therefore, the recommended dose is tipranavir 500 mg and ritonavir 200 mg twice daily. Tipranavir is a substrate and inducer of cytochrome P450 3A4 isoenzyme, thus is predisposed to interactions with other agents that are substrates, inducers or inhibitors of this enzyme family. Significant drug-drug interactions have been reported with co-administration of tipranavir/ritonavir and other PIs but not with the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine. Tipranavir/ritonavir 500 mg/200 mg twice daily in combination with an optimised background regimen was more effective than a ritonavir-boosted comparator PI plus an optimised background regimen. The adverse effect profile for tipranavir is similar to other boosted PI regimens and most commonly includes gastrointestinal complaints. Severe adverse events that require close monitoring include hepatotoxicity and lipid abnormalities. Tipranavir retains activity in many highly treatment-experienced patients with a large number of protease mutations. Therefore, this novel PI in combination with ritonavir represents an important new choice in the treatment of multiple-PI-experienced patients.
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PMID:Tipranavir: a novel nonpeptidic protease inhibitor of HIV. 1680 49

The virological response (VR) to a tipranavir-ritonavir (TPV-RTV)-based regimen had been shown to be associated with a number of mutations in the protease gene, the use of enfuvirtide (T20), and the TPV phenotypic inhibitory quotient (IQ). The role of the TPV genotypic IQ (gIQ) has not yet been fully investigated. The aim of our study was to evaluate the relationship between the TPV gIQ and the VR at 48 weeks to TPV-based salvage regimens. Patients placed on regimens containing two nucleoside reverse transcriptase inhibitors plus TPV-RTV 500/200 mg twice a day with or without T20 were prospectively studied. Regular follow-up was performed over the study period. VR, considered a viral load (VL) decrease of >or=1 log unit and/or the achievement of <50 copies/ml with no VL rebound of >0.5 log unit compared to the maximal VL decrease at week 48, was assessed. Thirty-eight patients who had received multiple drugs were included. At week 48 the VL decrease was -1.48 (interquartile range [IQR], -2.88 to -0.48), 15 patients (39.5%) had VLs of <50 copies/ml, and the CD4+ cell count increase was 37 cells/mm3 (IQR, -30 to +175). Twenty subjects (52.6%) achieved VRs. The TPV gIQ and optimized background score (OBS) were independently associated with higher VL decreases. The TPV gIQ and OBS were also independent predictors of a VR at week 48. TPV gIQ and OBS cutoff values of 14,500 and 2, respectively, were associated with a higher rate of VR. The TPV gIQ was shown to be able to predict the VR at 48 weeks to TPV-containing salvage regimens better than the TPV trough concentration or TPV-associated mutations alone. A possible TPV gIQ cutoff value of 14,500 for reaching a VR at week 48 was suggested. Further studies are needed in order to evaluate the calculation of TPV gIQ as a new tool for the optimization of TPV-based salvage therapy.
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PMID:Tipranavir (TPV) genotypic inhibitory quotient predicts virological response at 48 weeks to TPV-based salvage regimens. 1816 May 24

In recent years, increasing numbers of patients infected with HIV-1 non-B subtypes have been treated with modern antiretroviral regimens. Therefore, a better knowledge of HIV drug resistance in non-B strains is crucial. Thus, we compared the mutational pathways involved in drug resistance among the most common non-B subtypes in Italy (F, C, and CRF02_AG) and the B subtype. In total, 2234 pol sequences from 1231 virologically failing patients from Central Italy were analyzed. The prevalence of resistance mutations in protease and reverse transcriptase between non-B and B subtypes has been evaluated. Among patients treated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) and with thymidine analogues (TA) experience, TAMs1 M41L and L210W were less prevalent in CRF02_AG, while TAMs2 T215F and K219E were more prevalent in the F subtype. In NRTI-treated patients having experience with abacavir, didanosine, tenofovir, or stavudine the K65R mutation was mostly prevalent in the C subtype. In non-NRTI (NNRTI)-treated patients infected by the C subtype the prevalence of K103N was lower than in patients infected with other subtypes, while the prevalence of Y181C and Y188L was higher compared to subtype B. The prevalence of Y181C was higher also in subtype F as compared to subtype B. In patients treated with protease inhibitors, L89V was predominantly found in CRF02_AG, while the TPV resistance mutation T74P was predominantly found in the C subtype. Some differences in the genotypic drug resistance have been found among patients infected with B, C, F, and CRF02_AG subtypes in relationship to treatment. These results may be useful for the therapeutic management of individuals infected with HIV-1 non-B strains.
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PMID:Comparative analysis of drug resistance among B and the most prevalent non-B HIV type 1 subtypes (C, F, and CRF02_AG) in Italy. 2241 70