Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial. At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for patients taking racemic methadone (37%; n = 11) and (R)-methadone (44%; n = 9). AUC changes ranged from mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine. Due to extensive variability, the adjustments must be tailored to the individual patient's needs.
 ...
PMID:Nevirapine significantly reduces the levels of racemic methadone and (R)-methadone in human immunodeficiency virus-infected patients. 1550 34

In acquired human immunodeficiency virus (HIV) infection, a long depolarization period at ECG may be the consequence of cardiac complications due to viral myocarditis or cardiomyopathy or indirectly due to autonomic neuropathy, or sometimes resulting from pharmacological treatments. Several drugs administered for direct treatment of HIV disease or its complications, such as antiretrovirus, fluconazole, and antibiotics, may induce ventricular arrhythmias due to long QT prolonged depolarization period. Also methadone, frequently associated with HIV therapy to treat patients with opiate addiction, is described in the literature to have cardiac inotropic effects. It has also the potential to increase the QT period and to develop ventricular torsade de pointes, primarily through interference with the rapid component of the delayed rectifier potassium ion current. Moreover, the use of methadone associated with other inhibitors of cytochrome P450 might increase plasma concentrations and contribute to methadone cardiac toxicity. We report the case of an HIV patient receiving antiretroviral treatment, fluconazole and high-dose methadone, who suddenly complained of vertigo, dizziness, pre-syncope and syncope due to severe ventricular arrhythmias that disappeared after discontinuation of all treatments.
 ...
PMID:[Long QT and torsade de pointes in a patient with acquired human immunodeficiency virus infection in multitherapy with drugs affecting cytochrome P450]. 1556 12

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.
 ...
PMID:Atazanavir for the treatment of human immunodeficiency virus infection. 1558 41

We describe a patient with human immunodeficiency virus type-1 (HIV) infection and alveolar echinococcosis (AE) with a focus on two messages. Despite being severely immunocompromised over years the patient exhibited a long-term asymptomatic course of AE. This is in clear contrast to reports describing accelerated courses of AE in immunocompromised patients. The patient had therapeutic mebendazole drug levels with only 1/10 of the normal drug dose. He was co-treated with protease inhibitors for his HIV infection. These drugs are known as strong inhibitors of cytochrome P450 3A4 (CYP3A4)-dependent metabolism. We speculate that benzimidazoles and protease inhibitors interfere at the CYP3A4-level. The first report of co-infection of HIV and accelerated AE was in a young girl with an extremely low CD4 cell count and an abrogated lymphoproliferative responsiveness to parasite antigen stimulation. Since the CD4 cell count in our patient remained in the range of 27-150 cells/microl, we speculate that there was a critical threshold of immunosupression for constraining AE. Initial treatment with albendazole for AE added to the current highly active antiretroviral treatment (HAART), and suppressive toxoplasmosis therapy became complicated by pancytopenia. After full recovery of the bone marrow, mebendazole was introduced with a new HAART and the previously prescribed toxoplasmosis maintenance therapy. Surprisingly, efficient mebendazole levels were achieved with an uncommonly low dose. These observations suggest that the benzimidazoles, albendazole and mebendazole, may interact with protease inhibitors, which are known for their strong inhibition of the CYP3A4.
 ...
PMID:Alveolar echinococcosis of the liver in an adult with human immunodeficiency virus type-1 infection. 1562 96

Hypericin is a naturally occurring substance found in the common St. John's Wort (Hypericum species) and can also be synthesized from the anthraquinone derivative emodin. As the main component of Hypericum perforatum, it has traditionally been used throughout the history of folk medicine. In the last three decades, hypericin has also become the subject of intensive biochemical research and is proving to be a multifunctional agent in drug and medicinal applications. Recent studies report antidepressive, antineoplastic, antitumor and antiviral (human immunodeficiency and hepatitis C virus) activities of hypericin; intriguing information even if confirmation of data is incomplete and mechanisms of these activities still remain largely unexplained. In other contemporary studies, screening hypericin for inhibitory effects on various pharmaceutically important enzymes such as MAO (monoaminoxidase), PKC (protein kinase C), dopamine-beta-hydroxylase, reverse transcriptase, telomerase and CYP (cytochrome P450), has yielded results supporting therapeutic potential. Research of hypericin and its effect on GABA-activated (gamma amino butyric acid) currents and NMDA (N-methyl-D-aspartat) receptors also indicate the therapeutic potential of this substance whereby new insights in stroke research (apoplexy) are expected. Also in the relatively newly established fields of medical photochemistry and photobiology, intensive research reveals hypericin to be a promising novel therapeutic and diagnostic agent in treatment and detection of cancer (photodynamic activation of free radical production). Hypericin is not new to the research community, but it is achieving a new and promising status as an effective agent in medical diagnostic and therapeutic applications. New, although controversial data, over the recent years dictate further research, re-evaluation and discussion of this substance. Our up-to-date summary of hypericin, its activities and potentials, is aimed to contribute to this process.
 ...
PMID:Hypericin--the facts about a controversial agent. 1563 60

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.
 ...
PMID:AIRE deficiency in thymus of 2 patients with Omenn syndrome. 1569 98

We examined 516G>T polymorphisms at the gene encoding the cytochrome P450 in 100 human immunodeficiency virus-positive subjects who were receiving efavirenz (EFV). Elevated plasma EFV concentrations were found in 40% of subjects with the polymorphic homozygous genotype and 19% of subjects with the heterozygous genotype. Conversely, 20% of subjects with the wild-type genotype had subtherapeutic concentrations of EFV. CYP2B6-516 genotyping may help to identify subjects who have plasma EFV concentrations that are outside of the therapeutic range.
 ...
PMID:Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. 1582 40

Itraconazole is a synthetic triazole antifungal agent that is commonly used in the prophylaxis and treatment of fungal infection. A role for itraconazole drug monitoring has been suggested previously; however, the advent of new formulations and increased clinical evidence may aid in further defining this role. Consequently, we have used a previously published decision-making algorithm to determine whether clinical pharmacokinetic monitoring of itraconazole is warranted. First, itraconazole has proven efficacy for the prophylaxis and treatment of fungal infection in immunocompromised individuals such as neutropenic cancer, human immunodeficiency virus (HIV), and solid organ transplant patients. Several assays have been developed to quantify itraconazole and its main metabolite in patient plasma. Measurement of these plasma drug levels in many clinical studies has resulted in no clear definition of a relationship between concentration and efficacy. However, limited evidence suggests a correlation between itraconazole levels greater than 250 or 500 ng/mL and increased efficacy. Clinical monitoring of efficacy is difficult because of the challenges in diagnosis of fungal infections and nonspecific clinical symptoms associated with fungal infections. Pharmacokinetic studies of itraconazole indicate that significant inter- and intrapatient variability exists in both healthy and immunocompromised patient populations, although subpopulations such as neutropenic cancer and HIV patients appear to require more drug than their healthy counterparts to attain similar drug levels. A therapeutic range has not been defined for itraconazole, but because of its relatively minimal side effects, a narrow range is unlikely. Drug interactions can occur with itraconazole because it is both an inhibitor and substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein transporter systems. Protein binding alterations could also lead to differences in drug effect. Last, the duration of treatment of prophylaxis is significantly long to propose a potential benefit from drug monitoring. From weighing the available evidence, it appears that itraconazole drug level monitoring would provide more information on efficacy than clinical judgment alone in a subset of patients. Immunosuppressed patients requiring preventative therapy who have suspected poor absorption, are on concomitant enzyme inducers, or are suspected to be noncompliant would have the greatest benefit from itraconazole drug monitoring.
 ...
PMID:Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. 1590 3

Amphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects that can be moderated by liposomal formulation or structural alteration. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group of amphotericin B substantially reduces toxicity. We report targeted deletions of the amphN cytochrome P450 gene from the chromosome of the amphotericin-producing bacterium Streptomyces nodosus. The mutant strains produced amphotericin analogues in which methyl groups replace the exocyclic carboxyl groups. These compounds retained antifungal activity and had reduced hemolytic activity.
 ...
PMID:Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups. 1607 35

Drug-drug interactions are a major practical concern for physicians treating human immunodeficiency virus (HIV) because of the many medications that HIV-positive patients must take. Pharmacokinetic drug interactions can occur at different levels (absorption, distribution, metabolism, excretion) and are difficult to predict. Of all the processes that give rise to drug interactions, metabolism by cytochrome P450 (CYP3A) is the most frequent. Moreover, medications prescribed to HIV-positive patients may also be CYP3A inhibitors and inducers: Tipranavir, in the absence of ritonavir, is a CYP3A inducer, and ritonavir is a CYP3A inhibitor. Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized. This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral-treatment-related conditions such as hyperlipidemia, and side effects such as diarrhea.
 ...
PMID:Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies. 1643 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>