Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.
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PMID:Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. 207 27

Nucleoside reverse transcriptase inhibitors result in a wide range of toxic side effects. These include lactic acidosis syndrome, myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, and possibly lipodystrophy. Despite the seemingly diverse nature of these side effects, all of these toxicities may be mediated by a common pathophysiologic mechanism, namely, mitochondrial toxicity resulting from nucleoside reverse transcriptase inhibitor-induced inhibition of DNA polymerase g. This article reviews the relevant mitochondrial biology and mechanism underlying nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical manifestations of this toxicity are reviewed followed by a discussion of clinical management.
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PMID:Mitochondrial Toxicity Associated with Nucleoside Reverse Transcriptase Inhibitor Therapy. 1172 14

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

The tremendous progress achieved during the last few years with the use of highly active antiretroviral therapy in suppressing HIV replication together with improvements in immunity have been tempered by a growing number of new adverse effects. Mitochondrial toxicity is one aspect of these long-term toxicities of antiretroviral drugs, with the role of nucleoside analogs particularly underlined. Some cases of impaired mitochondrial function have been clearly identified, such as pancreatitis due to didanosine, neuropathy due to zalcitabine, myopathy due to zidovudine, and lactic acidosis due to stavudine. These mitochondrial toxicities can affect several organs, presenting different patterns of symptoms: from asymptomatic to states with few symptoms despite huge metabolic abnormalities whose prognosis is immediately life-threatening. Beyond the inhibition of DNA polymerase gamma using nucleoside analogs, responsible for decreasing mitochondrial DNA in certain targeted organs, it appears that several physiopathologic mechanisms interact to explain this observed toxicity, HIV itself plays a role, and the underlying genetic pool needs to be better identified. Such cases mean that, it is imperative to avoid cumulated toxicities caused by associated treatments. With serious cases, or persistent symptoms despite discontinuing the nucleoside analogs responsible for such toxicity, one must propose vitamins, mitochondrial co-factors, or anti-oxidants. However, the future lies in the use of potent, less toxic nucleoside analogs, and in developing compounds belonging to other classes of antiretrovirals.
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PMID:[Mitochondrial cytopathies associated with HIV infection]. 1644 24

The introduction of highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. This progress has been tempered by a growing number of new adverse effects. Mitochondrial toxicity is one aspect of these long-term toxicities of antiretroviral drugs, with the role of nucleoside analogs being particularly underlined. Some cases of impaired mitochondrial function have been clearly identified, such as pancreatitis, neuropathy, miopathy and lactic acidosis. Beyond the inhibition of DNA polymerase-g using nucleoside analogs, it appears that several physiopathologic mechanisms interact to explain the observed toxicity. At present there is no reliable method to detect subclinical mitochondrial toxicity. There is no proven effective therapy for antiretroviral therapy-associated mitochondrial toxicity other than ceasing the implicated agent, and even with this strategy, resolution of symptoms may be incomplete. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents.
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PMID:[Antiretroviral therapy and mitochondrial toxicity]. 1733 66

A hematopoietic stem cell transplant recipient developed abdominal pain, pneumatosis intestinalis, hepatitis, pancreatitis, and inappropriate antidiuretic hormone secretion. Blood for varicella-zoster virus (VZV) DNA polymerase chain reaction was positive. She was treated with acyclovir and subsequently developed VZV antigen-positive zoster. Detection of VZV DNA in blood may be useful for early diagnosis in immunocompromised hosts who present with zoster without skin lesions.
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PMID:Triad of severe abdominal pain, inappropriate antidiuretic hormone secretion, and disseminated varicella-zoster virus infection preceding cutaneous manifestations after hematopoietic stem cell transplantation: utility of PCR for early recognition and therapy. 1827 22

The combined antiretroviral therapeutic approach currently employed for the treatment of HIV infection, known as Higly Active Antiretroviral Therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, the adverse reactions associated with the long term use of this therapy have now become a major issue and researchers have focused on understanding the cellular mechanisms underlying these drug-induced detrimental effects which englobe a large list of different events including rash and hypersensibility reactions, hepatotoxicity, metabolic disturbances including lipodystrophy, and other metabolic syndrome-like disturbances such as hyperlactatemia, hyperlipedimia, insulin resistance and pancreatitis. Other events include CNS toxic effects, peripheral neuropathies as well as nephrotoxicity and increased risk of cardiovascular diseases. Many of these reactions have been shown to develop as e result of mitochondrial dysfunction. The mitochondrial effect of N(t)RTI (Nucleos(t)ide Reverse Transcriptase Inhibitors) class of drugs, which has been widely studied, is believed to originate from the inhibitory action of these drugs on DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA. However, additional mitochondrial targets have also been described and need to be considered. As to NNRTI (Non-Nucleoside-Transcriptase Inhibitor) or PI (Protease Inhibitors), evidence of the implication of mitochondria has also been reported, however the details of the mechanisms underlying these actions are still not fully known. This review covers the current knowledge of mitochondrial toxicities, particularly the available in vitro evidence, regarding the most commonly used groups of HIV drugs. Novel findings of mtDNA-independent mitochondrial dysfunction have received special attention.
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PMID:Mitochondrial toxicity in HAART: an overview of in vitro evidence. 2171 49