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)

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.
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PMID:Lopinavir. 1115 17

To determine whether some constitutional symptoms of influenza, such as headache, myalgia and nausea, could represent a viral infection of brain, muscle, and liver, we inoculated juvenile Balb/c mice intranasally with 103 plaque forming units of influenza B/Lee virus. Blood, brain, liver, skeletal muscle, and lung tissues were removed aseptically and assayed for infectivity by a plaque assay, viral RNA by reverse transcriptase-polymerase chain reaction (RT - PCR), viral antigen by immunoperoxidase staining, and histologic changes by light microscopy. Mice became ill 2 - 3 days post inoculation (PI). A productive viral infection of the lungs developed from days 1 - 8 with maxima of virus titers, pneumonia, and the number of immunoperoxidase staining lung cells occurring on days 2 - 6 PI. Virus isolation from blood was rare and viral RNA was detected intermittently in blood by RT - PCR. In many animals, a non-permissive or abortive infection of brain occurred from days 1 - 8 and peaked on days 3 - 4 PI. Viral RNA was detected in brain tissue and viral antigen was seen in cerebral endothelial cells but infectious virus was rarely isolated from brain. In liver, viral RNA was detected and viral antigen was seen occasionally in hepatocytes. In skeletal muscle, viral RNA was detected but neither infectious virus nor viral antigen was seen. A correlation existed between the severity of the illness, pneumonia, lung virus titer, viral antigen in lung cells, and extent of a non-permissive viral infection of brain and liver but not muscle. These studies demonstrate that following intranasal infection of influenza virus in mice, a viral pneumonia develops with subsequent intermittent viremia and non-permissive or abortive infection of brain, liver and muscle.
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PMID:Experimental influenza causes a non-permissive viral infection of brain, liver and muscle. 1117 25

(+)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (+)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals. In addition, (+)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (+)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (+)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t(1/2)) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (+)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (T(max)) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (+)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (C(max)), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (+)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (+)-calanolide A in healthy, HIV-negative individuals.
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PMID:Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. 1130 99

The nucleoside reverse transcriptase inhibitor 3TC (lamivudine) appears to induce unusually prolonged HIV suppression when used in combination with AZT, according to the results of four randomized clinical trials. The studies showed that 3TC and AZT had similar antiviral effects when used alone. However, investigators observed a substantial, prolonged increase in CD4 counts and a significant decrease in HIV RNA when the drugs were administered simultaneously. These benefits persisted in all study groups for the 24-week study period, and in several for the six-month follow-up period as well. The combination was well-tolerated by nearly 1000 AZT-naive and AZT-experienced subjects enrolled in these trials, with the most common adverse effects being nausea, vomiting and headaches. A possible explanation for the antiviral effect is suggested by the mutation at HIV codon 184 that is frequently observed in virions exposed to 3TC for extended periods of time. In vitro studies have shown that this mutation confers 3TC resistance. It may also counteract other mutations that would normally lead to AZT resistance, therefore enabling virions exposed to both drugs to remain effectively susceptible to AZT.
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PMID:Combination 3TC/AZT therapy shows promise. 1136 92

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

Abacavir sulfate (Ziagen) received accelerated approval for treatment of HIV infection from the Food and Drug Administration (FDA). It is the fifteenth approved anti-HIV drug. Abacavir, manufactured by Glaxo Wellcome, is currently the most powerful of the nucleoside analogue reverse transcriptase inhibitors (NRTIs). Side effects include nausea, vomiting, fatigue, headache, and diarrhea. A serious hypersensitivity reaction occurs in approximately 5 percent of patients taking the drug. Patients who experience this reaction can never take the drug again, because subsequent reactions can be fatal. Drug interactions may be minimal, as abacavir is not metabolized by the same enzymes that metabolize several other anti-retrovirals. Resistance is also discussed and clinical data from studies are presented.
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PMID:Abacavir sulfate (Ziagen). 1136 89

A study of Triangle Pharmaceuticals' non-nucleoside reverse transcriptase inhibitor, Coactinon, found that the drug significantly suppressed viral replication when used with d4T and 3TC. The manufacturer reported mild side effects, including nausea, headache, dizziness, diarrhea, and rash.
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PMID:Triangle Pharma Coactinon combo may suppress HIV. 1136 23

A substantial body of evidence provides support (but not definitive proof of efficacy) for the use of antiretroviral agents as postexposure prophylaxis for occupational exposures to HIV in the healthcare workplace. Despite the lack of definitive evidence of the efficacy of these agents in this setting, over the past decade this intervention has become the standard of care for healthcare workers who sustain occupational exposures to HIV. Administration of these agents--even for a relatively short 28-day postexposure course--is often fraught with difficulty. All of the agents currently used for postexposure prophylaxis regimens have substantial adverse effects, and significant adverse effects occur in more than two-thirds of individuals electing prophylaxis. This manuscript reiterates current US Federal Government guidelines for the administration of postexposure prophylaxis, specifically noting that zidovudine plus lamivudine (with or without a protease inhibitor) remains the recommended regimen. The paper summarises the significant toxicities associated with nucleoside reverse transcriptase inhibitors (primarily nausea, vomiting, diarrhoea and bone marrow suppression), non-nucleoside reverse transcriptase inhibitors (rash, fever, gastrointestinal symptoms and hepatitis, including hepatic decompensation necessitating liver transplantation) and protease inhibitors (nausea, vomiting, diarrhoea, abdominal pain, hyperglycaemia, hyperlipidaemia, headache and anorexia). As a class, the antiretroviral agents have an extraordinary number of drug interactions. The non-nucleoside reverse transcriptase inhibitors and the protease inhibitors are metabolised through the cytochrome P450 pathway, and the effects of concomitant administration of protease inhibitors with other agents in the same class are discussed, as well as the effects of concomitant administration of protease inhibitors with non-nucleoside agents. The potential for numerous and medically risky drug interactions emphasises the importance of planning antiretroviral prophylaxis in consultation with practitioners or clinical pharmacists who are skilled in the use of these agents and knowledgeable about the potential for significant drug interactions that could either reduce the benefit of prophylaxis or increase the potential for toxicity. Another common problem encountered by individuals managing postexposure prophylaxis programmes relates to the administration of chemoprophylaxis to a pregnant healthcare worker who has sustained an occupational exposure to HIV. We address what is known about the potential for toxicity and emphasise the recently published warning concerning the deaths of pregnant women and their offspring from lactic acidosis while receiving regimens containing stavudine and didanosine.
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PMID:Tolerability of postexposure antiretroviral prophylaxis for occupational exposures to HIV. 1148 Apr 91

A 48-year-old-man returned to the Netherlands from Sierra Leone and was admitted with nausea, crampy abdominal pain, myalgia, arthralgia, headache and watery diarrhoea. This was the first case of Lassa fever diagnosed in the Netherlands since 1980. Despite treatment with ribavirin, the patient died on the 16th day of illness. Prompt diagnosis of Lassa fever is critical for the timely administration of ribavirin which improves diagnosis considerably, and for the timely implementation of isolation measures. Recently, a reverse transcriptase polymerase chain reaction (RT-PCR) has become available for the rapid diagnosis of acute Lassa fever, which was implemented to diagnose this patient.
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PMID:[A man with fatal Lassa fever following a stay in Sierra Leone]. 1246 60

Nucleoside analog reverse transcriptase inhibitors (NRTI) have been used to treat HIV-infected patients for >10 years. Some severe adverse events have been attributed to mitochondrial dysfunction. Since 1991, cases of severe lactic acidosis have been reported in association with nucleoside therapy. Our objective was to report two cases of metabolic acidosis and hepatic steatosis in patients receiving stavudine (d4T) and to review the literature. A male and a female, 47 and 45 years of age, respectively, presented with abdominal pain, nausea, vomiting, and weakness after 9 and 6 months, respectively, of treatment with stavudine. At presentation, both patients had severe metabolic acidosis and liver failure. Ultrasonography showed hepatic steatosis (confirmed by biopsy in one case). All antiretroviral drugs were withdrawn and patients were treated with bicarbonate. Both patients developed fulminant liver dysfunction and multiple organ failure. We reviewed the literature and found 75 cases of lactic acidosis and hepatic steatosis associated with use of NRTI; 57 of these patients received d4T (76%). Of all cases reported in association with nucleoside therapy, 63% were females and mortality was 47%. General weakness, hepatic enzyme elevation, and liver steatosis are data that should alert physicians to this serious adverse event and to respond with prompt interruption of antiretroviral drugs and measurement of lactic acid in plasma. It is important to report serious adverse events in commercially released drugs to know prevalence in an exposed population. Physicians should be aware of risk and early signs of this serious adverse event.
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PMID:Metabolic acidosis and hepatic steatosis in two HIV-infected patients on stavudine (d4T) treatment. 1260 78


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