Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.
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PMID:Etravirine for the treatment of HIV infection. 1866 9

Advanced immunosuppression from HIV infection can lead to gastrointestinal symptoms such as diarrhea, nausea, vomiting, dysphagia, weight loss, and abdominal pain. There is a complex, combined effect of HIV infection plus antiretroviral treatment on the incidence of gastrointestinal symptoms, and, for some trials, the majority of gastrointestinal adverse events may not be related to antiretroviral treatment. Antiretroviral treatment can lead to improvements in gastrointestinal symptoms for patients with advanced immunosuppression. This was observed in the TORO trials of enfuvirtide and the DUET trials of etravirine, which were conducted in highly treatment experienced patients with low baseline CD4 counts. While antiretroviral treatment can improve immune function, leading to fewer gastrointestinal symptoms, this could be counter-balanced by adverse gastrointestinal toxicity profiles from certain antiretrovirals. Ritonavir-boosted protease inhibitors show a range of gastrointestinal side effects; there are differences in tolerability within this class of antiretrovirals, influenced both by the dose of ritonavir used and the choice of boosted protease inhibitor. Overall, lopinavir/ritonavir and fosamprenavir/ritonavir tend to show the highest rates of drug-related grade 2-4 diarrhea, compared with atazanavir/ritonavir, darunavir/ritonavir, or saquinavir/ritonavir. Of the nucleoside analogs, zidovudine leads to a well-characterized problem of nausea. Issues relating to gastrointestinal complications are often subjective, reliant upon patient reporting and perception, along with clinician interaction and intervention. In trial publications, many different systems are used to present gastrointestinal adverse events. Most are based on the US Division of AIDS Grading Scale, ranging from grade 1 (mild) to grade 4 (life-threatening). Clinical trials most commonly report grade 2-4 gastrointestinal adverse events, which are at least possibly related to study medication. In future, it is important for clinical trials to report gastrointestinal adverse events in a consistent way. The percentage of patients with drug-related grade 2-4 events should be reported. In addition, the percentage with any grade 2-4 gastrointestinal adverse event should be included, since there could be subjectivity in the assessment of drug relatedness in open-label clinical trials. The percentage of patients who use medications to lessen the symptoms of diarrhea and other gastrointestinal adverse events should also be reported.
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PMID:Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. 1929 32