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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic steatosis together with lactic acidosis is a life threatening side effect in HIV infected patients receiving highly active antiretroviral therapy (HAART). We describe 5 patients developing hepatic drug toxicity during longterm treatment with nucleoside reverse transcriptase inhibitors. The main clinical symptoms included abdominal pain, fever, and neurological disorders. Serum lactate levels were elevated leading to severe metabolic acidosis in 3 cases. Liver biopsies revealed extensive macro- and microvesicular steatosis. Mitochondrial alterations were detected by electronmicroscopy. Microvesicular steatosis was seen in one case with elevated liver enzymes, but normal serum lactate levels, and was most extensive in a patient with a severe lactic acidotic coma. We conclude that detection of microvesicular steatosis and mitochondrial alterations in liver biopsies may help to identify the development of a nucleoside induced hepatopathy before the onset of severe lactic acidosis.
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PMID:[Nucleoside induced hepatopathy in HIV patients. Diagnostic value of liver biopsy assessment]. 1517 22

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) represent key components of the antiretroviral combinations used to manage HIV infection. A range of nucleoside analogues are currently available which differ in their convenience of administration, frequency of dosing, resistance profile and frequency and severity of adverse effects. Many of the important and treatment limiting side-effects of nucleoside analogues have been suggested to be related to the impact of these agents on mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA or impacts of these agents on mitochondrial enzymes during chronic nucleoside analogue therapy may lead to cellular respiratory dysfunction and both generalised and tissue specific toxicities. In particular, fatal lactic acidosis represents a rare but clinically important manifestation of nucleoside analogue induced mitochondrial dysfunction. Other potentially severe toxicities which are well-characterised include peripheral neuropathy (PN) and myopathy. Management of potentially mitochondrial toxicity during nucleoside analogue therapy remains a challenge. A range of nutritional supplements, both as treatments and prophylaxes have been proposed and some investigated in vitro but not as yet in vivo. At present, therefore, interruption of nucleoside analogue therapy, or substitution of the probable causative agent with nucleoside analogues which appear better tolerated represent the mainstay of management.
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PMID:Mitochondrial toxicity: myths and facts. 1523 76

The toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is linked to altered mitochondrial DNA (mtDNA) replication and subsequent disruption of cellular energetics. This manifests clinically as elevated concentrations of lactate in plasma. The mechanism(s) underlying how the changes in mtDNA replication lead to lactic acidosis remains unclear. It is hypothesized that mitochondrial oxidative stress links the changes in mtDNA replication to mitochondrial dysfunction and ensuing NRTIs toxicity. To test this hypothesis, changes in mitochondrial function, mtDNA amplification efficiency, and oxidative stress were assessed in HepG2-cultured human hepatoblasts treated with the NRTI stavudine (2',3'-didehydro-2',3'-deoxythymidine or d4T) for 48 h. d4T produced significant mitochondrial dysfunction with a 1.5-fold increase in cellular lactate to pyruvate ratios. In addition, d4T caused a dose-dependent decrease in mtDNA amplification and a correlative increase in abundance of markers of mitochondrial oxidative stress. Manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, MnTBAP, a catalytic antioxidant, ameliorated or reversed d4T-induced changes in cell injury, energetics, mtDNA amplification, and mitochondrial oxidative stress. In conclusion, d4T treatment elevates mitochondrial reactive oxygen species (ROS), enhances mitochondrial oxidative stress, and contributes mechanistically to NRTI-induced toxicity. These deleterious events may be potentiated in acquired immunodeficiency syndrome (AIDS) by human immunodeficiency virus (HIV) infection itself, coinfection (e.g., viral hepatitis), aging, substance, and alcohol use.
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PMID:Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. 1528 86

HIV-positive persons requiring a highly active antiretroviral therapy containing one or more nucleosidic reverse transcriptase inhibitors associated with or without protease inhibitors are exposed to metabolic side effects among which lipodystrophy and hyperlactemia, defined by blood lactates higher than 2,25 mmol/L. Hyperlactatemia had to be differentiated from lactic acidosis of type B (without hypoxemia, lactates higher than 5 mmol/L and arterial pH lower than 7,3), a rare but potentially fatal complication by multi-visceral failure. The accused INRT induce mitochondrial toxicity by inhibition of DNA gamma polymerase and deterioration of its DNA. Our exploratory study, troop of 282 patients, identified age and stavudine like statistically associated, which has occurred of this metabolic anomaly. The patients having profited of a therapeutic change with the profit from drugs minus hyperlactatogenic presented an obvious clinical and biological improvement; whereas similar switch of therapy occurred for the lipodystrophic patients presented any clinical improvement. Nevertheless, biological parameters (blood lactates, triglycerides, total cholesterol and LDL-cholesterol) were significantly decreased after this therapeutic switch occurred on the lipodystrophic patients. In conclusion, the measurement of the following biological parameters: glycemia, lactatemia, triglycerides, total cholesterol and LDL-cholesterol at patient VIH, in a simple and rigorous pre-analytical and analytical context, appears to us justified in the monitoring of metabolic disorders in treated HIV patients by INRT and/or IP.
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PMID:[Outcome of hyperlactatemia and lipodystrophy syndromes in patients infected with human immunodeficiency virus]. 1529 45

We conducted a retrospective study to identify prognostic factors in the lactic acidosis syndrome (LAS) caused by nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/AIDS. Fifty-eight cases of LAS were included in our analysis, 8 from our hospital spanning the years 1992-2002, and 50 reported in the English language literature from 1986 through 2002. Peak venous lactate level was the best predictor of mortality. Zidovudine was associated with higher lactate levels and higher mortality than stavudine and lamuvidine. Mortality declined progressively after 1986 when the first cases of NRTI-related LAS were described. Increased mortality with zidovudine in this study appears due in part to its greater use prior to 1990 when LAS was not widely recognized as a potential complication of NRTI therapy.
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PMID:Prognostic factors in lactic acidosis syndrome caused by nucleoside reverse transcriptase inhibitors: report of eight cases and review of the literature. 1530 26

Mitochondrial toxicity has been implicated in the development of a variety of nucleoside reverse transcriptase inhibitor-associated syndromes. Mitochondrial damage and decreases in mitochondrial DNA levels have been demonstrated in various tissues of patients treated with NRTIs, especially in conjunction with exposure to stavudine. Clinical syndromes that may be mediated by mitochondrial toxicity include hyperlactatemia and lactic acidosis, hepatic steatosis, lipoatrophy, peripheral neuropathy, HIV-associated neuromuscular weakness syndrome, pancreatitis, skeletal myopathies, and cardiomyopathy. Early recognition of these syndromes in their mild forms involves close monitoring and a high index of suspicion. This may allow prompt discontinuation of the causative agent(s) and initiation of appropriate therapeutic measures, thereby increasing the chances of reversibility of the syndrome.
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PMID:Mitochondrial dysfunction: patient monitoring and toxicity management. 1531 67

Lactic acidosis is a life-threatening complication of antiretroviral therapy with an incidence of about 1% per year. Its clinical onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. Lactic acidosis is caused by nucleoside analogue reverse transcriptase inhibitors (mainly didanosine, stavudine and zalcitabine), which are relatively strong inhibitors of gamma polymerase, the enzyme responsible for the replication of mitochondrial DNA. Zidovudine is also a mitochondrial toxin, but its toxicity probably reflects several mechanisms unrelated to mtDNA-depletion. When lactic acidosis is diagnosed, nucleoside analogues and other mitochondrial toxins, such as valproic acid and acetylsalicylic acid, must be discontinued immediately. Uridine should be supplemented, a cocktail consisting of vitamins, L-carnitine and coenzyme Q10, may be given.
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PMID:[Lactic acidosis in HIV-patients--diagnosis and treatment]. 1537 54

Carnitine and its congeners may regulate the immune networks, and their influence on functions of immune cells predominantly or exclusively relies on carnitine-dependent energy production from fatty acids. A reduced pool of carnitines has been demonstrated in either serum or tissues, or both, from patients with a wide spectrum of disorders characterized by unregulated or impaired immune responses ranging from sepsis syndrome to systemic sclerosis, infection with human immunodeficiency virus, and chronic fatigue syndrome. Furthermore, experimental studies have consistently reported that the deranged immune responses and the less efficient inflammation towards infectious organisms associated with aging may be enhanced or modulated by treatment with carnitines. There is also evidence that carnitine deprivation could adversely affect the course of the sepsis syndrome, at least in experimental models, and preliminary studies suggest that carnitine deficiency is ultimately implicated in the pathophysiology of endotoxin-mediated multiple organ failure. Several data indicate that carnitine deficiency is a contributing factor to the progression of infection with human immunodeficiency virus, and carnitine therapy in those patients could counteract the unregulated process of lymphocyte apoptosis and improve CD4 counts. Some case reports have suggested the use of carnitine for the treatment of the severe lactic acidosis that complicates in some patients the use of reverse transcriptase inhibitors.
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PMID:Carnitines and its congeners: a metabolic pathway to the regulation of immune response and inflammation. 1559 Oct 10

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

Data from 2543 HIV-infected women were analyzed to correlate antiretroviral therapy (ART) used during pregnancy with maternal and pregnancy outcomes. ART was analyzed according to class of agents used and according to monotherapy versus combination ART containing neither protease inhibitors (PIs) nor nonnucleoside reverse transcriptase inhibitors versus highly active ART. Timing of ART was classified according to early (recorded at or before 25-week gestation study visit) and late (recorded at 32-week gestation or delivery visit) use. Maternal outcomes assessed included hematologic, gastrointestinal, neurologic, renal, and dermatologic complications; gestational diabetes; lactic acidosis; and death. Adverse pregnancy outcomes assessed included hypertensive complications; pre-term labor or rupture of membranes; preterm delivery (PTD); low birth weight; and stillbirth. Logistic regression analyses controlling for multiple covariates revealed ART to be independently associated with few maternal complications: ART use was associated with anemia (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.1-2.4), and late use of ART was associated with gestational diabetes (OR = 3.5, 95% CI: 1.2-10.1). Logistic regression analyses revealed an increase in PTD at <37 weeks for 10 women with late use of ART not containing zidovudine (ZDV; OR = 7.9, 95% CI: 1.4-44.6) and a decrease in adverse pregnancy outcomes as follows: late use of ART containing ZDV was associated with decreased risk for stillbirth and PTD at <37 weeks (OR = 0.06, 95% CI: 0.02-0.18; OR = 0.5, 95% CI: 0.3-0.8, respectively), and ART containing nucleoside reverse transcriptase inhibitors but not ZDV during early and late pregnancy was associated with decreased risk for PTD at <32 weeks (OR = 0.3, 95% CI: 0.2-0.7). Benefits of ART continue to outweigh observed risks.
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PMID:Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. 1576 63


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