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)

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of evidence-based medicine, indinavir represents an important component of antiretroviral treatment strategies.
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PMID:Indinavir: a review of its use in the management of HIV infection. 1065 94

Current guidelines for the dosing of antiretroviral agents in HIV-positive patients with renal insufficiency including those requiring dialysis are limited, as revealed by a literature search performed using Health Knowledge Network MEDLINE and HealthSTAR. Pharmacokinetic and chemical aspects were taken into consideration to develop further recommendations. Results showed reverse transcriptase inhibitor dosage adjustment guidelines are available, but for patients receiving dialysis, guidelines are limited to zidovudine and didanosine. There are limited clinical data on dosage adjustments required for the use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Indinavir appears to require no dose modification. For nelfinavir, ritonavir and saquinavir, the chemical and pharmacokinetic characteristics along with the pathophysiology of renal dysfunction and dialysis suggest that these agents can likely be given at usual doses with close monitoring for toxicities. More data is required to make recommendations for use of NNRTIs in renal insufficiency. Combining the information from previous dosing guidelines and the pharmacokinetic data of antiretroviral agents allows for preliminary recommendations to be made until confirmed by definitive clinical data.
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PMID:The use of antiretroviral agents in patients with renal insufficiency. 1081 31

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.
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PMID:Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection. 1140 45

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

Studies are investigating drug interactions in dual protease therapies. Thus far, studies show nelfinavir has a beneficial effect on indinavir while indinavir has a limited effect on nelfinavir. Indinavir/nelfinavir studies are ongoing. Small European clinical trials indicate that while ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily) continue to be the only well-validated combination, nelfinavir (750mg bid) and saquinavir-soft gel capsule (800mg tid) may be an option. European studies also indicate that all dual protease inhibitor combinations, including ritonavir/saquinavir, should be used with at least one nucleoside reverse transcriptase inhibitor.
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PMID:Dual protease inhibitor therapy. 1136 54

Phase III data show that efavirenz (Sustiva, formerly DMP-266) is effective in suppressing viral load when used in combination with other treatments. A head-to-head comparison trial in volunteers with little or no previous antiretroviral experience shows that efavirenz may suppress viral load as well as Indinavir (Crixivan). Efavirenz is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI), and widespread consensus seems to accept it as a valid treatment for AIDS. The most noteworthy trial result showed that using it in combination with AZT plus 3TC suppressed viral load to below 400 copies in a significant number of volunteers, with few patients dropping out. Viral load remains low at 72 weeks, but not much information is available on those patients who were more heavily pre-treated. Other combinations also appear effective. DuPont Pharmaceuticals, the manufacturer, says common side effects include rash, nausea, diarrhea, headache, and insomnia, and cautions against widespread use in pregnant women. Efavirenz is unlikely to work in patients who have developed resistance to either Nevirapine or Delavirdine, two other NNRTI drugs.
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PMID:Efavirenz (Sustiva) may equal or exceed protease inhibitor in initial antiretroviral combination. 1136 99

Hydroxyurea obstructs HIV from reproducing, is effective when combined with nucleoside analogue reverse transcriptase inhibitors, and it is difficult for HIV to develop a resistance to it. The combination of Hydroxyurea and ddI may be effective in targeting the HIV virus that hides in resting cells. This is in contrast to most other anti-HIV drugs, which tend to target HIV in activated cells. Two studies are described that echo the benefits of combining Hydroxyurea with ddI. Another study employed the previous combination with Indinavir, and all participants achieved below 400 copies of HIV RNA. Observations of three individuals, who discontinued treatments subsequent to taking regimens including Hydroxyurea, indicate that they have maintained HIV RNA below the level of detection. These case studies are not necessarily a good representation of the people actually using Hydroxyurea. More research is necessary to determine the best way to utilize this drug.
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PMID:Hydroxyurea - new observations. 1136 14

Highly active antiretroviral therapies (HAART) that do not incorporate a protease inhibitor (PI) have received much attention in attempts to find effective treatment alternatives. HAART without PIs can extend the future options of some patients, to allow switching to a PI therapy later in treatment, or to avoid unpleasant side effects reported with some PIs. A study of combination therapy employing efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) showed encouraging results, as did a similar study employing abacavir. However, researchers are cautious about the ability of these drugs to sustain high antiviral activity over a long-term period. As a potent alternative to HAART, NNRTI's offer easier dosing and appear to have similar results, albeit in the short-term. Studies of Hydroxyurea have reported a positive antiviral response. However, one study indicated that the positive response came with significant side effects. The use of anti-HIV therapy in pregnant women and their newborns is the subject of another study, that assessed the safety of treatment and the possible side effects. Comparisons of protease inhibitor-containing regimens are also reviewed. Alternative two-drug combinations of Indinavir and Ritonavir, and abacavir and amprenavir are explored.
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PMID:Antivirals update. 1136 49

Merck has discontinued testing the twice-daily dosing of its protease inhibitor Crixivan (Indinavir) in combination with reverse transcriptase inhibitors (RTIs). Merck recommends that patients on the twice-daily dosing regimen be changed back to the original dosing schedule of 800 mg of Crixivan three times a day. The decision to discontinue the twice-daily dosing is based on an analysis of a study at the 24-week mark, which showed that dosing three times daily was more effective in reducing viral load to below detectable levels. The company will continue to study twice-daily dosing in combination with other protease inhibitors. Contact information is provided.
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PMID:Merck discontinues twice-daily dosing of Crixivan. 1136 14

Four protease inhibitors are compared: Saquinavir (Invirase, Fortovase), Indinavir (Crixivan), Ritonavir (Norvir), and Nelfinavir (Viracept). Key questions are answered on how dosages change when combined with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and other protease inhibitors. Information on administration and storage and the impact of each drug on disease development are reviewed. Drug interactions between protease inhibitors and other HIV drugs and non-HIV medications are described. Side effects are also discussed. Pediatric use is addressed, including suggested dosages. Contact information for each manufacturer is provided, along with approximate annual price for treatment.
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PMID:Protease inhibitors at a glance.... 1136 98


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