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)

Peripheral neuropathy (PN) is among the most frequent side effects described with nucleoside reverse transcriptase inhibitors (NRTIs). We investigated the incidence, evolution and predictive factors of PN during stavudine (d4T)-didanosine (ddI) combination therapy in 65 HIV infected patients, previously treated with zidovudine and/or zalcitabine (ddC) for at least 3 months. A subset of 16 patients was referred for systematic electromyographic examination at weeks 0 and 24: six among the 16 exhibited nerve conduction abnormalities at day 0, probably related to previous ddC treatment in four of those and to HIV infection in the other two, with worsening of abnormalities in one patient at week 24. In total, seven of the 59 assessable patients (11.8%) exhibited grade 2-3 neuropathy, with a median time of occurrence of 17 weeks. Distal, symmetrical paraesthesias of the extremities were the first symptoms in all the patients; none had motor symptoms. In all the patients, PN resolved rapidly after stopping d4T. There were no statistically different parameters between the seven cases and the other 52 patients according to CD4 T cells, HIV RNA, Centers for Disease Control and Prevention (CDC) stage C or d4T daily dose. In our study, the d4T-ddI combination did not seem to increase the incidence of PN; risk factors for PN could not be identified, probably in part because of the low number of patients with PN.
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PMID:Peripheral neuropathy during stavudine-didanosine antiretroviral therapy. 1173 85

For the last several years, the combination of ddI (didanosine, Videx) and d4T (stavudine, Zerit) as a backbone of three-drug therapy has been popular both in treatment and in research. Together, the two nucleoside analog reverse transcriptase inhibitor (NARTI) drugs offered relatively high strength and fairly simple use. Despite this, some researchers have long questioned the wisdom of the combination as it violates one of the key rules of combining drugs: combine only drugs with different side effect profiles. Both drugs are associated with the development of peripheral neuropathy and pancreatitis. Pancreatitis is more commonly seen with ddI and neuropathy with d4T, but both occur to a significant degree with each drug and to a higher degree than was seen with other drugs of their class. However, few if any studies were run comparing the ddI/d4T combination to alternatives such as AZT/3TC (Combivir) or even 3TC/d4T. Both ddI and d4T come from the same company, Bristol Myers Squibb.
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PMID:New questions about an old combination--ddI + d4T. 1264 75

HAART has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. Increased experience with HAART has led to the detection of drug related toxicities that may compromise adherence and necessitate discontinuation of treatment and alteration of otherwise effective regimens. This article considers the major long-term complications associated with nucleoside reverse transcriptase inhibitor (NRTI) use--hyperlactatemia and lactic acidosis/hepatic steatosis, other hepatotoxicities, pancreatitis, lipodystrophy, lipoatrophy, neuropathy, and hematologic toxicities. Mechanisms by which NRTIs may produce these effects are discussed, as are differential effects of agents in this class and management options.
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PMID:Long-term complications of nucleoside reverse transcriptase inhibitor therapy. 1274 68

Data from basic science and clinical studies suggest that hydroxyurea (hydroxycarbamide)-based regimens are effective treatment options for patients with HIV at various stages of disease. In vitro studies of HIV-infected lymphocytes have shown that hydroxyurea: (i) inhibits viral DNA synthesis; (ii) synergistically interacts with nucleoside reverse transcriptase inhibitors (NRTI); and (iii) increases the antiviral activity of didanosine. Clinical studies have confirmed that hydroxyurea in combination with didanosine produces potent and sustained viral suppression in patients with HIV infection. However, some concerns have been recently raised on the use of hydroxyurea in association with NRTI. Hydroxyurea can cause myelosuppression, skin toxicities, mild gastrointestinal toxicity, and abnormalities of renal and liver functions. In addition, hydroxyurea may accentuate the toxic effects of nucleoside analogues. In fact, some clinical data seem to indicate an increased risk of pancreatitis and neuropathy when hydroxyurea is combined with didanosine and stavudine. Since hydroxyurea-related toxicity is dose dependent, a systematic study of hydroxyurea optimal dosage and schedule was initiated to monitor patients for possible nucleoside toxicity. In the Research Institute for Genetic and Human Therapy (RIGHT) 702 study it was shown that a low, well-tolerated hydroxyurea dose (600 mg daily) achieved better antiretroviral activity than higher doses, together with better CD4+ cell count increase and fewer adverse effects. In this paper the effects of hydroxyurea as salvage therapy for heavily pretreated patients with advanced HIV disease are presented. These studies have shown that some patients with extensive pretreatment experience and advanced disease can respond substantially to the addition of hydroxyurea. The addition of hydroxyurea to didanosine does not prevent the emergence of resistance to didanosine; nonetheless, the efficacy of this therapeutic regimen may not be attenuated by the presence of didanosine-resistant HIV mutants. Since CD4 T lymphocyte activation is essential for virus replication and CD8 T lymphocyte activation may contribute to pathogenesis, the combination of hydroxyurea with other drugs may lead to the inhibition of HIV, by blocking the 'cell activation-virus production-pathogenesis' cycle. Clinical data indicate that hydroxyurea may play a role in attenuation of viral rebound and immune reconstitution by decreasing CD4 T cell proliferation, as well as preventing the exhaustion of CD8 T cell populations that may result from excessive activation during HIV infection. While the combination of hydroxyurea with didanosine has provided hope, future studies including those that evaluate optimal dosing and long-term toxicity are needed to define the role for this agent in the treatment of HIV infection.
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PMID:Hydroxyurea in the treatment of HIV infection: clinical efficacy and safety concerns. 1281 30

An HIV-infected man taking long-term zidovudine and didanosine presented with a polyphenotypic expression of nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity. Clinical features included lactic acidosis, myopathy, Fanconi-type proximal tubulopathy, pancreatic dysfunction, pseudo-obstruction, mega-oesophagus, peripheral sensory neuropathy and osteoporosis. A muscle biopsy showed morphologically abnormal mitochondria and respiratory chain biochemistry revealed marked reductions in the activity of respiratory chain enzymes containing mitochondrial DNA-encoded subunits. Southern blotting showed no mitochondrial DNA depletion and long PCR revealed only minor deletions. Following withdrawal of NRTI therapy, the lactic acidosis, pancreatic dysfunction and Fanconi's tubulopathy rapidly improved. Over the next 6 months there was marked improvement in osteoporosis, myopathy and neuropathy. At this stage, dual protease inhibitors and nevirapine were started. A repeat muscle biopsy 14 months after presentation showed normal morphology and respiratory chain biochemistry was almost normal.
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PMID:Polyphenotypic expression of mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors. 1292 44

The objective of this study is to examine the risk factors associated with the development of sensory neuropathy in human immunodeficiency virus (HIV)-infected patients in 292 HIV+ patients recruited through a community-based sentinel survey. We determined the clinical and treatment factors associated with the presence of peripheral sensory neuropathy in HIV+ subjects at baseline examination, and at 1-year follow-up. Baseline examination was assessed with a logistic regression analysis controlling for age, education level, history of drug/alcohol use, and anti-retroviral treatment. The risk of developing new peripheral neuropathy at follow-up was determined using a Cox proportional hazard model analysis. At study entry, neuropathy (n=64) was associated with acquired immunodeficiency syndrome (AIDS), nucleoside analogue reverse transcriptase inhibitors (NRTI) (i.e. ddC), and history of alcohol abuse. After 1-year follow-up, the development of neuropathy was predicted by AIDS, age (older subjects), and NRTI use. These findings indicated that AIDS, age, alcohol abuse/dependence, and anti-retroviral medication use are important predictors of motor/sensory peripheral neuropathy in the HIV infection. The peripheral neurotoxic effect of anti-retroviral medication should be taken into account in the design of long-term therapies.
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PMID:Risk modifiers for peripheral sensory neuropathy in HIV infection/AIDS. 1474 69

Peripheral neuropathy is a common neurotoxic effect of medications. Antineoplastic agents and antiretroviral medications are most often involved: platinum compounds, vinca alkaloids, taxols and nucleoside reverse transcriptase inhibitors. These agents cause a dose-related axonal polyneuropathy. Symptoms are indicative of a predominantly sensory or sensory-motor neuropathy which in some cases is accompanied by dysfunction of autonomic nervous system. Depending on dosage and agent used symptoms resolve completely or not. Neurotoxic effect can appear immediately during or shortly after administration of the drug but sometimes after cessation of chemotherapy. In all cases the neuropathy alters the quality of life. A general predisposition for developing a neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or in inherited neuropathy. Within the past five years, some cases of neuropathy caused by alpha-interferon, statins or tacrolimus have been reported. Although rare, these aetiologies should be considered by physicians and the drugs removed when others causes of neuropathy have been excluded. Few cases of peripheral neuropathy have been recently reported with metronidazole, dapsone, nitrofurantoin or colchicin. Thalidomide induces a dose-dependant sensori-motor length-dependent axonal neuropathy. It should be judiciously used with close neurologic monitorin. Little is known about the mechanisms responsible for the development of neuropathy. Up to now, no drug is available to prevent or cure drug-induced neuropathies.
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PMID:[Neurotoxic effects of medications: an update]. 1524 67

The orphan hepatic nuclear factor (HNF) HNF4alpha is of pivotal importance for liver development and hepatocellular differentiation and plays an essential role in a regulatory circuitry to control a wide range of metabolic processes. It also targets genes in other organs, including pancreas, kidney, intestine, and colon; promotes expression of an epithelial phenotype; triggers de novo formation of functional tight junctions; and contributes to epithelial cell polarity. In particular, HNF4alpha dysfunction leads to metabolic disorders, including diabetes. We used the chromatin immunoprecipitation (ChIP) cloning procedure and a bioinformatic approach to search for candidate genes associated with impaired liver, pancreas, and kidney function. We identified two novel targets regulated by HNF4alpha, which participate in the control, at least in part, in cell-cycle regulation and are members of the mitogen-activated kinase pathway. In multiple ChIP assays, ribosomal S6 kinase 4 (RSK4) and p21-activated kinase 5 (PAK5) were confirmed, and in vitro binding of HNF4alpha was evidenced by electrophoretic mobility shift assays (EMSA) using oligonucleotides, which harbor novel binding sites. We also used EMSA to probe for binding sites in promoters of HNF1alpha, apolipoprotein B, alpha1-antitrypsin, and angiotensinogen. We further studied RSK4 and PAK5 kinase expression in streptozotocin-induced diabetic rat kidney and brain and observed significant repression of HNF4alpha, RSK4, and PAK5 as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. RSK4 and PAK5 may provide a molecular rationale for late-stage complications in disease, and further studies are warranted to explore these targets for the treatment of diabetic nephro- and neuropathy, frequently seen in patients with HNF4alpha dysfunction.
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PMID:RSK4 and PAK5 are novel candidate genes in diabetic rat kidney and brain. 1561 95

The availability of durable, effective antiretroviral therapy for HIV-infected patients has fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic acidosis, neuropathy, pancreatitis and, more recently, a syndrome of pathological loss of subcutaneous fat tissue (lipoatrophy). Importantly, the toxicity profile of each NRTI drug within this class is unique in terms of the overall risk of long-term complications, as well as the tissue specificity of its toxic effects. In this review, the clinical manifestations, risk factors and pathological basis for NRTI-associated toxicity syndromes are explored, with an emphasis on clinical assessment and management.
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PMID:Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. 1565 44

Advances in anti-retroviral therapy (ART) has led to improved survival of patients infected with the human immunodeficiency virus (HIV). ART for HIV patients is composed of a combination of nucleoside reverse transcriptase inhibitors (NRTI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and/or a protease inhibitor (PI). The long-term exposure to ART and HIV are causing mitochondrial toxicities, such as myopathies, neuropathy, myelopoiesis, pancreatitis, lactic acidosis, hepatic steatosis, and lipodystrophy. The mitochondrial pathogenesis has been believed to be due exclusively to NRTI-induced inhibition of DNA polymerase-gamma; it is now apparent that the etiology is far more complex, involving multiple mechanisms as well as an effect by HIV per se. Current therapy for patients includes interruption or change in medications and mitochondrial co-factors.
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PMID:Mitochondrial dysfunction in AIDS and its treatment. 1612 Apr 31


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