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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly active antiretroviral therapy (HAART) has significantly reduced mortality, and prolonged life expectancy of human immunodeficiency virus (HIV)-positive patients. Such improvements have led to increasing numbers of HIV-infected patients with end-stage organ disease as potential candidates for transplantation. A HAART regimen usually consists of a combination of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and/or protease inhibitors (PI). PI are known to strongly inhibit the cytochrome P450 3A (CYP3A) enzyme system that is responsible for the metabolism of immunosuppressive drugs, such as tacrolimus, sirolimus, and cyclosporine. Besides these pharmacokinetic drug-drug interactions, potential pharmacodynamic drug-drug interactions may also occur with concomitant HAART and antimetabolites, such as mycophenolate mofetil. An approach to immunosuppressive management in HIV-infected organ transplant recipients requires attention to such complexities as unique drug-drug interactions and increased drug-related toxicities.
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PMID:Antiretroviral and immunosuppressive drug-drug interactions in human immunodeficiency virus-infected liver and kidney transplant recipients. 1991 90

Interactions between combination antiretroviral therapy (CART) and lung cancer treatment are emerging clinical concerns. Among the reasons for that, one can observe the longer survival of human immunodeficiency virus (HIV)-infected patients since introduction of CART and the epidemiologic rising of lung cancer, mainly adenocarcinomas, in this population. In addition, the higher relative risk of lung cancer in HIV-infected patients compared with general population has been recently demonstrated. Patients' demography and disease characteristics differ from the general lung cancer population, although most cases occur in patients with a smoking history: HIV-infected subjects are generally younger and diagnosis frequently made at locally advanced or metastatic stages. The choice of cytotoxic chemotherapy and antiretroviral therapy is essential in the context of lung cancer (1) to minimize potential interactions and life-threatening toxicities particularly through cytochrome P450 interaction, (2) to implement adequate prevention of foreseeable toxicity, and (3) to fully reinforce antineoplastic and antiretroviral efficacy. Pharmacokinetics data and clinical cases pinpoint to potential life-threatening interactions between protease inhibitors/ritonavir and taxanes, vinca alkaloids, as well as the anilinoquinazolines erlotinib and gefitinib and irinotecan. Optimal choice of chemotherapy and CART in HIV-infected patients with lung cancer is an individualized multidisciplinary decision, involving clinical and antiretroviral history, and predicting potential adverse events and interactions.
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PMID:Interactions between cytotoxic chemotherapy and antiretroviral treatment in human immunodeficiency virus-infected patients with lung cancer. 2019 69

Etravirine (TMC-125, ETV) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that demonstrates potent activity against NNRTI-resistant strains of human immunodeficiency virus type-1 (HIV-1). Thus, ETV has been used in combination with ritonavir-boosted protease inhibitor (PI) and integrase inhibitor for therapy-experienced HIV-1-infected patients. On the other hand, as ETV is a substrate and inducer of cytochrome P450 3A4 (CYP3A4), ETV may induce metabolism of PI and alter the concentrations of co-administered PIs. In order to ensure optimal drug efficacy and prevention of resistance, it is essential to monitor plasma concentrations of ETV and PIs. Here we describe the application of HPLC with UV detection for the simulataneous assay of ETV and 4 PIs, darunavir (DRV), atazanavir (ATV), ritonavir (RTV) and lopinavir (LPV). In this study, the calibration curve of each drug was linear with the average accuracy ranging from 93.6 to 110.9%. Both intra- and interday coefficients of variation for each drug were less than 11.6%. The mean recovery of all drugs ranged from 88.0 to 97.5%. The limit of quantification was 0.04, 0.04, 0.04, 0.05 and 0.07 microg/ml for ETV, DRV, ATV, RTV and LPV, respectively. These results demonstrate that our HPLC-UV method can be used for routine determination of plasma concentrations of ETV and 4 PIs in clinical settings.
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PMID:High performance liquid chromatography using UV detection for the simultaneous quantification of the new non-nucleoside reverse transcriptase inhibitor etravirine (TMC-125), and 4 protease inhibitors in human plasma. 2068 42

Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase.
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PMID:Implications of efavirenz for neuropsychiatry: a review. 2096 56

Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
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PMID:An integrated pharmacokinetic model for the influence of CYP3A4 expression on the in vivo disposition of lopinavir and its modulation by ritonavir. 2149 55

Family physicians are treating patients infected with human immunodeficiency virus in their practices more often. Long-term complications of this disease are multifactorial and can be related to the virus itself or to adverse effects of antiretroviral therapy. Each drug class has side effects: nucleoside/nucleotide reverse transcriptase inhibitors are associated with lactic acidosis, lipodystrophy, and hyperlipidemia; non-nucleoside reverse transcriptase inhibitors are associated with neuropsychiatric symptoms, rash, liver toxicity, and lipid abnormalities; and protease inhibitors are associated with gastrointestinal intolerance and glucose and lipid abnormalities. The entry inhibitor maraviroc and the integrase inhibitor raltegravir have been approved for treatment-naive and treatment-experienced patients. Maraviroc is associated with bronchitis, nasopharyngitis, and esophageal candidiasis. Adverse effects of raltegravir are comparable to those experienced with placebo, with the exception of increased risk of myopathy and rhabdomyolysis. Information about drug interactions for both of these medications is limited. Non-nucleoside reverse transcriptase inhibitors and protease inhibitors are primarily metabolized through the cytochrome P450 system, and as a result have numerous drug-drug interactions. Monitoring for adverse effects of antiretroviral therapy includes a complete blood count and comprehensive metabolic profile every three to six months. A lipid profile and urinalysis for proteinuria should be per- formed annually. Dual energy x-ray absorptiometry should be considered in patients older than 50 years. Long-term morbidity related to antiretroviral therapy includes liver, renal, glucose, and lipid abnormalities, and cardiovascular and bone disease. With some exceptions for lipid management, these morbidities can be managed as in the general population.
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PMID:Common adverse effects of antiretroviral therapy for HIV disease. 2167 46

Lersivirine (UK-453,061) is a new nonnucleoside reverse transcriptase inhibitor currently being developed as a treatment for human immunodeficiency virus type 1 infection. Lersivirine shows potent activity against wild-type and clinically relevant drug-resistant strains. Previous studies have demonstrated that lersivirine is metabolized by glucuronidation via UGT2B7 and by cytochrome P450 3A4 (CYP3A4). Lersivirine is also a weak inducer of the CYP3A4 enzyme. Therefore, coadministered lersivirine could potentially affect the pharmacokinetics of maraviroc, a CCR5 antagonist metabolized by CYP3A4, and raltegravir, an integrase inhibitor metabolized by glucuronidation. Two open-label studies assessed the pharmacokinetics of raltegravir and of maraviroc when they were coadministered with lersivirine and the pharmacokinetics of lersivirine when it was coadministered with raltegravir. Minor, clinically nonsignificant effects on the pharmacokinetics of raltegravir coadministered with lersivirine were observed at steady state for raltegravir, with estimated mean changes of -15%, -29%, and +25% in the area under the concentration-time profile from time zero to the end of the dosing interval (AUC(tau)), maximum plasma concentration (C(max)), and concentration observed 12 h postdose (C(12)), respectively. There were no clinically relevant effects of steady-state raltegravir on lersivirine AUC(tau), C(max), or concentration observed 24 h postdose (C(24)) (estimated mean changes of -2 to +5%). Coadministration of lersivirine at steady state with maraviroc resulted in no clinically relevant effects on maraviroc AUC(tau), C(max), or C(12) (estimated mean changes of +3.4 to +8.6%). Lersivirine appeared to be generally well tolerated in these studies and appears to be suitable for coadministration with raltegravir or maraviroc without the need for dose modification.
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PMID:Pharmacokinetic effects of coadministration of lersivirine with raltegravir or maraviroc in healthy subjects. 2212 5

This report concerns a case of torsades de pointes (TdP) associated with the concomitant administration of methadone and voriconazole in a patient with comorbid medical conditions. A 57-year-old man, with a medical history of human immunodeficiency virus, infective endocarditis, hepatitis C and orbital Aspergillus infection, was admitted to the intensive care unit following several episodes of TdP. The patient was being treated with methadone for opioid addiction and had started taking voriconazole 2 weeks prior for orbital Aspergillosis. He experienced multiple episodes of TdP with a prolonged QTc interval (>600 ms). The pronounced inhibitory impact of voriconazole on methadone metabolism via the cytochrome P450 (CYP)2B6 isoenzyme was identified as a probable cause of the arrhythmia. Voriconazole was subsequently temporarily withheld and the methadone dose was significantly reduced. The patient received an implantable cardioverter-defibrillator, did not experience additional episodes of TdP during hospitalisation, and was discharged from the hospital on day 13.
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PMID:Torsades de pointes associated with methadone and voriconazole. 2219 Sep 85

11-Ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy] ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355) is an inhibitor of the human immunodeficiency virus-1. BILR 355 exhibited a nonlinear pharmacokinetic profile and low exposure after oral administration to humans. This article describes the in vitro metabolism of BILR 355, which is correlated with the in vivo nonlinearity findings. Our in vitro studies had demonstrated that BILR 355 was extensively metabolized by cytochrome P450 3A. Thus, BILR 355 was concomitantly administered with ritonavir (RTV) in an attempt to boost systemic exposure, which did occur in humans. In addition, the expectation was that the overall metabolism of BILR 355 would be decreased with concomitant administration of RTV. Subsequent metabolite profiling was performed using human plasma samples obtained from clinical phase Ib studies with concomitant administration of BILR 355 and RTV. A total of 18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development.
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PMID:Metabolic switching of BILR 355 in the presence of ritonavir. I. Identifying an unexpected disproportionate human metabolite. 2239 20

With the licensing of the first hepatitis C (HCV) protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC), cure rates for chronic HCV infection will substantially improve. Human immunodeficiency virus- chronic hepatitis C (HIV-HCV) co-infected patients are in urgent need for these new drugs, because they are facing both severe liver disease and lower response rates than HCV monoinfected patients. The currently available efficacy data are however, limited to two phase II trials. Fortunately, TVR and BOC appear to be able to improve cure rates in co-infected patients. A major challenge for clinicians will be the management of drug-drug interactions of antiretroviral drugs and new PI. As HCV PI are also metabolized by the cytochrome P450 3A4 system interactions are probable as well with non-nucleoside reverse transcriptase inhibitors as with HIV PI. To our knowledge, TVR can only be safely used with one protease inhibitor, boosted atazanavir, and also with efavirenz (EFV), although this combination requires TVR dose adjustments. Boceprevir should not be combined with HIV PI and should not be combined with EFV. The approval of TVR and BOC will create new chances of cure also for HIV-HCV co-infected patients. However, the decision who to treat or not has to be taken carefully on the basis of fibrosis stage and previous treatment outcomes. In addition, HIV therapy needs to be optimized according to the available drug-drug interaction data.
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PMID:HIV-HCV co-infection facing HCV protease inhibitor licensing: implications for clinicians. 2251 96


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