Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Chronic use of antiretrovirals (ARVs) to treat HIV infection, along with more prolonged patient survival, has been associated with an increase in adverse drug effects in HIV-infected patients on treatment. It has been proposed that some of these adverse effects (including myopathy, cardiomyopathy, anaemia, hyperlactataemia/ lactic acidosis, pancreatitis, polyneuritis and lipodystrophy) could be mediated by mitochondrial (mt) toxicity. From the experimental data, it has been proposed that nucleoside analogue reverse transcriptase inhibitors (NRTIs) also inhibit gamma-polymerase, the enzyme devoted to replicate (and, to a lesser extent, repair) mtDNA. It is now widely accepted that the use of most NRTIs in HIV-infected patients is associated with mtDNA depletion. Although cross-sectional studies suggest that certain ARVs, especially stavudine, are more toxic to mitochondria, the differences among different highly active ARV therapy (HAART) schedules detected in the analysis of longitudinal studies are not so clear. These types of study in previously untreated individuals suggest that the greatest mtDNA loss appears at the beginning of the treatment. Conversely, in ARV-experienced patients, the potential beneficial effects of HAART changes in terms of mtDNA content remain controversial and must be further investigated. Functional studies accompanying genetic investigations are needed for the correct pathogenic interpretation of the mtDNA abnormalities.
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PMID:Mitochondrial studies in HAART-related lipodystrophy: from experimental hypothesis to clinical findings. 1615 8

In critically ill patients, adequate sedation increases comfort, minimizes stress response and facilitates diagnostic and therapeutic procedures. Propofol (2-, 6-diisopropylphenol) is an intravenous sedative-hypnotic agent popular for sedation in the Intensive Care Unit. The favorable propofol pharmacokinetic, characterized by a three compartment linear model, allows rapid onset and short duration of action. The emergence time from sedation with propofol varies with the depth and the duration of sedation and the patient's bodyweight. Propofol causes hypotension, particularly in volume depleted patients, decreases cerebral oxygen consumption, reduces intracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties, propofol is being increasingly used in the management of traumatic head injury, status epilepticus, delirium tremens, status asthmaticus and in septic patients. Prolonged use (>48 h) of high doses of propofol (>66 mcg/Kg/min) has been associated with lactic acidosis, bradycardia, and lipidemia in pediatric patients. A rare complication firstly reported in pediatrics patients and also observed in adults is known as "propofol syndrome" characterized by myocardial failure, metabolic acidosis and rhabdomiolysis. Hyperkalemia and renal failure have also been associated with this syndrome. Hypertriglyceridemia and pancreatitis are uncommon complications. A large number of trials have compared the use of propofol with midazolam. Sedation with propofol is associated with adequate sedation in ICU patients, shorter weaning time and earlier tracheal extubation compared to midazolam, but not before ICU discharge.
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PMID:Sedation in PACU: the role of propofol. 1630 51

HIV-infected patients are living longer since the introduction of highly active antiretroviral therapy. However, coinfection with the hepatitis C virus (HCV) leads to increased morbidity from liver disease and higher overall mortality. The prevalence of chronic hepatitis C among patients with HIV/AIDS ranges from 7% (sexual transmission of HIV) to >90% (injection drug use). Uncontrolled HIV infection seems to accelerate the progression of HCV-induced liver fibrosis. Forty-eight weeks of combination therapy with pegylated interferon alpha (2a or 2b) plus ribavirin achieves a sustained viral response in coinfected individuals in up to 38% with HCV genotype 1 and up to 73% with genotypes 2 or 3. The safety profile of this treatment is similar to therapy in HCV-monoinfected patients with influenza-like symptoms, cytopenia and neuropsychiatric symptoms dominating. However, HIV/HCV-coinfected patients who also take zidovudine develop more profound anaemia than those on other HIV nucleoside analogue therapy. Didanosine and stavudine are associated with rare but serious mitochondrial toxicity, such as pancreatitis or lactic acidosis. It does not appear that the addition of ribavirin increases that risk. There is currently no evidence that in HIV/HCV coinfection one pegylated interferon product is superior to the other. Contrary to common perception, it is also unproven that HIV/HCV-coinfected patients respond less well to therapy with peginterferon alpha plus ribavirin than HCV-monoinfected patients. Given the safety and efficacy of combination therapy with peginterferon plus ribavirin and the deleterious effects of chronic hepatitis C, all HIV/HCV-coinfected patients should be evaluated for therapy.
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PMID:Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy. 1630 19

The efficacy of antiretroviral drugs has improved the prognosis for infection by human immunodeficiency virus (HIV); it is nonetheless accompanied by toxicity specific to these agents. Adverse effects of these treatments are a major cause of poor compliance as well as of the cessation or change of treatment. Knowledge of these effects allows physicians to choose an individualized and effective treatment for each patient, one that is well tolerated and appropriate to the patient's sometimes complex medical history. Although some of these adverse effects can be life-threatening (drug eruptions with nevirapine and abacavir, pancreatitis with didanosine, or lactic acidosis with nucleoside analogs), most are reversible. Lipodystrophies, sometimes combining morphologic and metabolic disorders, are observed in some patients after several years of treatment and appear to increase cardiovascular risk. They are one of the major disadvantages of combined treatments.
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PMID:[Adverse effects of antiretroviral treatments]. 1631 16

More and more HIV-infected patients are treated for viral hepatitis, increasing interactions. HEPATITIS C: The concomitant use of didanosine and ribavirin increases the risk of mitochondrial toxicity, responsible for pancreatitis and/or lactic acidosis. Lactic acidosis is characterized by a high mortality rate. Thus, didanosine, but also stavudine, should not be co-administered with ribavirin. Cases of hepatic decompensation have been reported in cirrhotics concomitantly receiving ribavirin and didanosine. Thus, this co-admininistration should be contraindicated in patients with advanced liver fibrosis. Anemia is a frequent side effect of ribavirin. In patients with zidovudine-related anemia, this drug should be discontinued before prescribing ribavirin. Erythropoietin may help to improve the haemoglobin level. HEPATITIS B: Adefovir significantly decreases the plasma levels of saquinavir. Pancreatitis may occur with the co-administration of didanosine and tenofovir. Thus this co-administration should be avoided. Atazanavir concentrations are decreased when tenofovir is co-administered. Thus, atazanavir should be boosted with ritonavir, when combined with tenofovir. Atazanavir increases the concentrations of tenofovir, with the potential risk of increasing the adverse events of tenofovir, including renal disorders. Tenofovir area under the curve is increased if lopinavir-ritonavir are co-administered. The main interactions, with a fatal risk, are observed with didanosine, when co-administered with ribavirin (hepatitis C) or with tenofovir (hepatitis B). Anemia is frequent, but usually moderate, when zidovudine is co-administered with ribavirin. Other interactions are usually easy to manage.
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PMID:Antiviral hepatitis and antiretroviral drug interactions. 1636 Feb 31

The introduction of highly active antiretroviral therapy (HAART) for treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. But since HAART is unlikely to eradicate HIV-1, antiviral therapy may be required a lifelong, leading to an increase in attention on the long-term safety of HAART. A major toxicity of HAART is the mitochondrial toxicity. Mitochondrial toxicity becomes apparent particularly over the medium-term to long-term therapy and is attributed to treatment with nucleoside reverse transcriptase inhibitors (NRTIs), leading to a wide range of severe adverse events in HIV-infected patients. These include lactic acidosis, hepatic steatosis, neuropathy, (cardio-) myopathy, pancreatitis, and probably lipodystrophy. Furthermore, lactic acidosis and encephalopathy have been reported in children exposed in-utero and/or postnatally to NRTIs. Mitochondrial toxicity could pose a major threat to long-term success of HIV-therapy, and is of great concern for children exposed in-utero and/or postnatally to NRTIs. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents. However, at present no standardized and validated screening model system exists for the investigation of NRTI-induced mitochondrial toxicity. There is a need for the generation of a relevant in vitro assay system that can assess the mitochondrial toxicity in early preclinical development. This paper gives an overview of cell culture models currently used for the investigation of NRTI-induced mitochondrial toxicity and discusses the relevance and suitability of these models for prediction of clinical toxicity.
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PMID:Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. 1640 76

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


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