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 enormous resources spent on developing inhibitors of the HIV proteinase is finally proving worth while. The FDA in the USA approved saquinavir (Invirase, Roche) for treatment of AIDS in December 1995, and the presumably even more useful inhibitors, ritonavir (Norvir, Abbott) and indinavir (Crixivan, Merck) in March 1996. The clinical trials indicate that these substances are more efficient antiviral agents than the well known reverse transcriptase inhibitors (e.g., AZT or ddC). In the present article, the function of the HIV proteinase will be discussed, as well as the drug design strategies leading to the success. We believe that the combination of biotechnology and computer modelling is a potent tool for designing drugs, and that these proteinase inhibitors not only signal optimism in the treatment of AIDS, but also a new era in the development of therapeutics.
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PMID:[The HIV proteinase--a target for antiviral agents]. 897 9

While it appears that protease inhibitors in combination therapies are saving lives, questions continue: (1) which combinations of protease inhibitors and other antiretroviral agents are most effective in restoring immune function, (2) how these combinations can be used most effectively, and (3) what is the best time to start using them? An evaluation is presented on the immunological value of specific drug cocktail combinations and a comparison of the best and worst drug combinations and the reasons for this assessment. It indicates that Norvir is the most effective of all four protease inhibitors in preventing opportunistic infections, lymphomas, and cancers. D4T and 3TC are the safest and most effective of the nucleosides for preventing or remitting opportunistic infections when used with protease inhibitors. Rescriptor is the most therapeutic of the two non-nucleoside reverse transcriptase inhibitors in increasing absorption of protease inhibitors. The best drug combination therapies are listed as follows: Norvir plus Rescriptor; Norvir plus D4T; Norvir plus 3TC; Norvir, Rescriptor, and D4T; Norvir, Rescriptor, and 3TC; Norvir, D4T, and 3TC; and Crixivan or Viracept plus Rescriptor plus either D4T or 3TC. The worst drug combination therapies are listed as follows: AZT plus ddI (used in combination with a protease inhibitor); AZT or ddI or Combivir (used in combinations with a protease inhibitor); and any two protease inhibitors used together in any person with active hepatitis or elevated liver enzymes or impaired kidney function.
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PMID:An evaluation of drug cocktail combinations for their immunological value in preventing/remitting opportunistic infections. 1136 16

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

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

A non-nucleoside reverse transcriptase inhibitor, Sustiva (efavirenz, formerly DMP 266), received FDA approval for use by children and adults. Dosing is recommended at bedtime to avert side effects, which are described. People who receive the drug should avoid driving. Women should not become pregnant while taking this medication. Triple combination therapy with Sustiva and AZT/ Epivir (3TC) may be as effective as the combination of Crixivan with AZT/Epivir (3TC), preliminary trials showed. The drug costs about $4,000 a year. Contact information for obtaining financial assistance in the purchasing the drug is provided.
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PMID:Sustiva (efavirenz) is approved. 1136 71

St. John's wort, an herbal treatment for depression, should not be combined with certain drugs, including some antiretrovirals. St. John's wort can speed up the body's elimination of some drugs. When HIV medications are used, blood levels could drop low enough to allow resistance to occur. So far, St. John's wort has been tested only with the protease inhibitor indinavir (Crixivan), but it is likely to affect other drugs in that class and possibly non-nucleoside reverse transcriptase inhibitors. This warning follows a study by the National Institutes of Health (NIH) on dosing and blood levels of indinavir in HIV-negative test subjects. More information on the study is available on The Lancet's Web site. The text of the FDA's advisory letter is included.
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PMID:St. John's wort warning: do not combine with protease inhibitors, NNRTIs. 1136 7

Agouron Pharmaceuticals trial results suggest additional treatment options for people taking or considering taking Viracept in combination with other anti-HIV drugs. The clinical test results with Viracept and other drugs are presented. Viracept was tested for safety and efficacy with Fortovase (saquinavir soft gel), Norvir (ritonavir), Crixivan (indinavir), 1592 (abacavir), and non-nucleoside reverse transcriptase inhibitors.
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PMID:Protease inhibitor combos. 1136 48

Merck & Co. has recommended that patients taking the twice-daily dosage of the protease inhibitor Crixivan, in combination with reverse transcriptase inhibitors, switch to a regimen of 800 mg every 8 hours, or three times a day. The preliminary results of a trial indicated that only 64 percent of patients on the twice-daily dosage achieved undetectable levels of viral RNA, as compared to 91 percent of participants on the three times a day dosage. Additional trials will be conducted on the twice-daily dosage of Crixivan in combination with other protease inhibitors.
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PMID:Twice-a-day Crixivan study discontinued. 1136 2

Efavirenz is the lead compound of a series of benzoxazinones originally developed by DuPont Merck. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) under development for the potential treatment of viral infections, including HIV. In June 1998, the company submitted an NDA to the US FDA for the use of efavirenz (as Sustiva) for the treatment of HIV infection [289361]. In July 1998, DuPont purchased Merck's interest in DuPont Merck and the company's name changed to DuPont Pharmaceuticals. The two companies decided to continue to share marketing rights to Sustiva (to be marketed by Merck as Stocrin outside the US, Canada, and certain European countries) [291738]. As of October 1997, triple combination studies of efavirenz were ongoing, or planned, with nelfinavir, indinavir or ritonavir, or other retroviral inhibitors, for the treatment of opportunistic and pediatric viral infections [265945]. Efavirenz is also being evaluated as monotherapy and in combination with zidovudine (Retrovir, AZT) and lamivudine (Epivir, 3TC) (qv). Results of a study in eight HIV-infected patients, reported at the 12th World AIDS Conference in July 1998, showed that efavirenz administration, in dual and triple combinations, achieved HIV-RNA levels in plasma and cerebrospinal fluid (CSF) below the level of detection (fewer than 400 copies/ml) [290881,293994]. In March 1998, Merck signed a letter of intent with Trimeris to conduct a trial of efavirenz in combination with Trimeris's HIV fusion inhibitor, T-20, (qv). The trial will enroll up to 48 HIV-infected individuals at three sites in the US. All enrolled patients will be those who have begun to fail their existing triple combination therapy. Prior exposure to NNRTIs and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study were planned as a dose-optimization period to assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses of T-20. After completion of this period, subjects will be eligible to participate in an extension period of at least six months, during which T-20 will be administered in combination with efavirenz and two protease inhibitors [281696]. A 137-patient phase III study showed that efavirenz, in combination with zidovudine and lamivudine, caused significant reduction in viral levels and increased CD4 cell levels. The results were presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection (Hamburg, Germany, October 1997) [265945]. At the Fourth Conference on Retroviruses and Opportunistic Infections, in January 1997, data were presented from a clinical trial of efavirenz in combination with indinavir, which showed that, in 82% of the patients, viral load was reduced to undetectable levels, as measured by the Amplicor assay [231410]. Further retrospective analysis showed that the viral load was a significant predictor of long-term (over 52 weeks) viral suppression [265945]. A double-blind, phase II pilot study of efavirenz showed significant activity in HIV-RNA suppression and CD4 cell recovery when evaluated for two weeks alone, and even better results when used in combination with indinavir (Crixivan, qv); 80% of patients achieved HIV-RNA below level of quantification and CD4 cell count elevation averaging 140 cells/mm3. The study evaluated 16 patients for 12 weeks and is ongoing [219671,227966]. A total of 21 patients received indinavir (800 mg, eight hourly) for two weeks, followed by combination therapy with efavirenz (200 mg, once daily). Another group of nine patients received indinavir alone for 26 weeks, followed by the addition of stavudine (Zerit) and efavirenz. In combination use, indinavir dosing was 1.0 g every eight hours. At 26 weeks, approximately 40% of the patients receiving indinavir alonehad plasma levels below 400 copies/ml of HIV-RNA. After stavudine and efavirenz were added, and following 16 weeks of the triple combination, 83% of the patients had plasma levels below 400 copies/ml [247754].
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PMID:Efavirenz DuPont Pharmaceuticals Co. 1846 25


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