Gene/Protein Disease Symptom Drug Enzyme Compound
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 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

OBJECTIVES: Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers. METHODS: In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured. RESULTS: In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (>/= grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations. CONCLUSIONS: Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.
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PMID:Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers. 1938 36

Most ritonavir-boosted protease inhibitor (PI)-based antiretroviral regimens offer comparable levels of virological efficacy. Thus, the tolerability of the regimen becomes a distinguishing factor with implications for patient quality of life (QoL), treatment adherence, and clinical outcome. This article describes results from the CASTLE study (comparing once-daily atazanavir/ritonavir [ATV/RTV] with twice-daily lopinavir/ritonavir [LPV/RTV], both in combination with fixed-dose tenofovir/emtricitabine, in treatment-naive HIV-infected patients) and an evaluation of the impact of gastrointestinal (GI) complications of treatment on patient QoL, as measured by the irritable bowel syndrome (IBS) QoL questionnaire (IBS-QoL). Changes in IBS-QoL from baseline over time (to week 24) were classified as: "Improvement" (> or =2-point positive change from baseline), "No change" (<2-point change), or "Worsening" (> or =2-point negative change). Data were collected on GI adverse events (AEs) and use of GI medications. Of the 599 patients with IBS-QoL-evaluable data through week 24, fewer patients in the ATV/RTV group than in the LPV/RTV group experienced grade 2-4 treatment-related GI AEs including diarrhea (3% versus 10%), nausea (5% versus 7%), and vomiting (<1% on both arms). Nearly three times as many patients receiving LPV/RTV used GI medications. ATV/RTV was associated with an increase in overall IBS-QoL scores and more patients receiving ATV/RTV than LPV/RTV experienced improvement in IBS-QoL through week 24. In contrast to LPV/RTV, ATV/RTV treatment was associated with earlier and more positive improvements in QoL scores across CD4 sub-groups. Differences in the health-related QoL profile between ATV/RTV and LPV/RTV may be important when selecting PI-based antiretroviral regimens.
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PMID:Gastrointestinal tolerability and quality of life in antiretroviral-naive HIV-1-infected patients: data from the CASTLE study. 2046 43

Antiretroviral drugs have been recommended for postexposure prophylaxis (PEP) after high-risk sexual exposures for more than a decade. Three drug regimens could offer the highest levels of protection, particularly if the infectious source is taking medication, but drug intolerance has often led to suboptimal adherence. The current study evaluated a novel 3-drug PEP regimen, consisting of raltegravir, tenofovir DF, and emtricitabine. Of 100 participants enrolled in this study at a Boston community health center that has had a comprehensive PEP program for more than a decade, 85 were evaluable at 3 months and none became HIV infected. Fifty seven percent of those enrolled completed the regimen as prescribed, and 27% took their medicine daily, but sometimes missed the second daily dose of Raltegravir. The most common side effects reported included nausea or vomiting (27%), diarrhea (21%), headache (15%), fatigue (14%), abdominal symptoms (including pain, gas, or bloating) (16%), and myalgias or arthralgias (8%), all of which were mild and tended to be self-limited, not resulting in drug discontinuation. The side effects were significantly less common than those reported by historical controls, who used a 3-drug PEP regimen including zidovudine, lamivudine, and a ritonavir-boosted protease inhibitor. Raltegravir, tenofovir DF, and emtricitabine may be useful as a 3-drug regimen for PEP.
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PMID:Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence. 2226 17

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.
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PMID:A review of the toxicity of HIV medications. 2396 94

Ebola virus disease (EVD) has been a great concern worldwide because of its high mortality. EVD usually manifests with fever, diarrhea and vomiting, as well as disseminated intravascular coagulation (DIC). To date, there is neither a licensed Ebola vaccine nor a promising therapeutic agent, although clinical trials are ongoing. For replication inside the cell, Ebola virus (EBOV) must undergo the proteolytic processing of its surface glycoprotein in the endosome by proteases including cathepsin B (CatB), followed by the fusion of the viral membrane and host endosome. Thus, the proteases have been considered as potential targets for drugs against EVD. However, no protease inhibitor has been presented as effective clinical drug against it. A synthetic serine protease inhibitor, nafamostat mesilate (NM), reduced the release of CatB from the rat pancreas. Furthermore, it has anticoagulant activities, such as inhibition of the factor VIIa complex, and has been used for treating DIC in Japan. Thus, NM could be considered as a drug candidate for the treatment of DIC induced by EBOV infection, as well as for the possible CatB-related antiviral action. Moreover, the drug has a history of large-scale production and clinical use, and the issues of safety and logistics might have been cleared. We advocate in vitro and in vivo experiments using active EBOV to examine the activities of NM against the infection and the DIC induced by the infection. In addition, we suggest trials for comparison among anti-DIC drugs including the NM in EVD patients, in parallel with the experiments.
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PMID:A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease. 2634 67

This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and 'other' (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%-83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%-76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53-61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.
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PMID:HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment. 2803 May 79


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