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)

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 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

One thousand and eighty-one evaluable HIV-infected patients were assessed for pancreatic abnormalities in a prospective case-control study including the whole follow-up period of each patient (minimum 12 months). The 435 patients (40.2%), who experienced at least one episode of confirmed pancreatic laboratory abnormality had a longer duration of seropositivity, exposure to protease inhibitors, a more frequent immunodeficiency, AIDS, chronic liver and/or biliary disease and hypertriglyceridaemia, while no relation was found with antiretroviral administration, and the duration of type of nucleoside analogues, when compared with the 646 controls. High and prolonged laboratory alterations eventually associated with signs of organ involvement occurred in 166 cases (38.2%), and were related to the administration of didanosine, stavudine, lamivudine, pentamidine, cotrimoxazole or antitubercular/antimycobacterial therapy, cytotoxic chemotherapy, illicit substance or alcohol abuse, opportunistic infections, chronic liver and/or biliary disease, a protease inhibitor-based highly active antiretroviral therapy (HAART) and hypertriglyceridaemia (usually associated with HAART administration). No difference was noticed between the 46 patients with clinical and/or imaging evidence of pancreatic involvement and the 120 asymptomatic subjects. Although recurrences of enzyme alterations involved 69.6% of patients, only in 30.1% of cases did a change of the underlying antiretroviral or antimicrobial therapy become necessary. An acute, uncomplicated pancreatitis occurred in nine of the 46 symptomatic subjects (19.6%). A two to four week gabexate and/or octreotide administration (performed in 79 cases of 166, 47.6%), achieved a significant laboratory, clinical and imaging cure or improvement in 82.3% of cases, with a better success rate of combined (gabexate mesilate plus octreotide) vs. single (gabexate mesilate or ocreotide) therapy. Reduced disease recurrences and a better tolerability of antiretroviral regimens, were also noticed.
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PMID:HIV infection and the pancreas: risk factors and potential management guidelines. 1833 62

Human immunodeficiency virus (HIV) infection is now a chronic manageable disease due to which is it imperative for reviewing various medical emergencies which an individual case may encounter. Emergencies may occur at any stage of the disease. HIV infection is associated with several opportunistic infections/malignancies that may be life threatening and need quick intervention by health care workers. These emergencies could be related to opportunistic infections that are seen at presentation or that occur as the immune system gets weaker, or may be HIV induced diseases like enteropathy and wasting, diarrhea leading to dehydration and its sequel, neurological complication like PML etc. and from complications resulting from use of anti-HIV medication like lactic acidosis, pancreatitis, bone marrow suppression and may include the immune reconstitution syndromes.
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PMID:Emergencies in HIV medicine--part I. 1908 56

In a short span of two and a half decades, HIV/AIDS has emerged as second largest killer disease that has affected mankind. The triple drug antiretroviral therapy (ART) has ensured a reasonably good quality of life to HIV infected individuals. Human immunodeficiency virus (HIV) infection is associated with several opportunistic infections/malignancies that may be life threatening and need quick intervention by health care workers. These emergencies could be related to opportunistic infections that are seen at presentation or that occur as the immune system gets weaker, or may bedue to HIV itself per se. The emergencies could also result from use of antiretroviral drugs like lactic acidosis, pancreatitis, bone marrow suppression and may include the immune reconstitution syndromes. The emergencies due to the opportunistic conditions and HIV per se had been dealt with in detail in the part 1, and this part describes various emergencies that could be encountered due to the administration of the anti retroviral treatment. Some patients may present due to emergencies as a result of co-administration of antiretroviral drugs with drugs used for treatment of some opportunistic infections like ATT etc.
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PMID:Emergencies in HIV--part 2. 1926 5

There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase (P < 0.05). Conversely, trypsin activity, serum cytokine levels, and pancreatic and lung inflammation were unaffected. NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation.
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PMID:Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis. 1928 75

Gastrointestinal (GI) opportunistic infections (OIs) are commonly encountered at various stages of human immunodeficiency virus (HIV) disease. In view of the suppressive nature of the virus and the direct contact with the environment, the GI tract is readily accessible and is a common site for clinical expression of HIV. The subject is presented based on information obtained by electronic searches of peer-reviewed articles in medical journals, Cochrane reviews and PubMed sources. The spectrum of GI OIs ranges from oral lesions of Candidiasis, various lesions of viral infections, hepatobiliary lesions, pancreatitis and anorectal lesions. The manifestations of the disease depend on the level of immunosuppression, as determined by the CD4 counts. The advent of highly active antiretroviral therapy has altered the pattern of presentation, resorting mainly to features of antimicrobial-associated colitis and side effects of antiretroviral drugs. The diagnosis of GI OIs in HIV/acquired immunodeficiency syndrome patients is usually straightforward. However, subtle presentations require that the physicians should have a high index of suspicion when given the setting of HIV infection.
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PMID:Gastrointestinal opportunistic infections in human immunodeficiency virus disease. 1956 72

Mitochondrial toxicity is a well-recognized adverse effect of nucleoside reverse transcriptase inhibitor therapy for human immunodeficiency virus (HIV) infection. Transient lactic acidosis is often observed in children born after in utero antiretroviral prophylaxis against mother-to-child transmission of HIV. However, the extent and the mechanism of in utero adverse effects are largely unknown. We describe a 4-year-old girl who presented with manifestations of severe mitochondrial disease, specifically, developmental and growth delay, hypotonia, lactic acidosis, congenital cataracts, and pancreatitis. Her HIV-positive mother was receiving lamivudine, zidovudine, and nelfinavir mesylate during her pregnancy. The child tested HIV negative after birth. She was found to have a homoplastic T9098C sequence change in the mitochondrial gene coding for adenosine 5'-triphosphate synthase 6 (MTATP6) that was previously reported as a mitochondrial polymorphism. This polymorphism is in the MTATP6 gene-coding sequence and leads to the replacement of a nonpolar amino acid with a polar amino acid. Because of the typical clinical manifestations of mitochondrial disorder and because of the nature of the mitochondrial sequence change, the observed polymorphism likely predisposed this patient to develop severe antiretroviral-associated mitochondrial disease. Mitochondrial sequence alterations may be important factors in mitochondrial toxicity associated with antiretroviral treatment. Mitochondrial sequencing may be warranted in cases of persistent lactic acidosis after antiretroviral prophylaxis to further study this association.
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PMID:Mitochondrial T9098C sequence change in the MTATP6 gene and development of severe mitochondrial disease after in utero antiretroviral prophylaxis. 1994 8

The combination of highly active antiretroviral therapy (HAART) plus ribavirin (RBV) in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection has been reported to cause mitochondrial toxicity (MT). Sixty-four patients with HIV-HCV coinfection who were receiving antiviral therapy were evaluated for MT. Patients with concomitant HAART showed greater increases in lactate levels than did patients without HAART, and this difference was more pronounced in patients who received higher dosages of RBV. The incidence of pancreatic enzyme elevations and symptomatic pancreatitis was higher among patients who received HAART and high-dose RBV. Hepatic steatosis increased in patients who received HAART and high-dose RBV. Patients who showed signs of MT achieved higher rates of sustained virologic response than did patients without MT (73% vs 44%).
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PMID:Mitochondrial toxicity is associated with virological response in patients with HIV and hepatitis C virus coinfection treated with ribavirin and highly active antiretroviral therapy. 2048 58

The nucleoside analogues, 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxyinosine (ddI, didanosine) and 2',3'-dideoxycytidine (ddC, zalcitabine), used in the treatment of human immunodeficiency virus (HIV) infection, have been associated with a number of dose-limiting toxicities in clinical studies. These include myelotoxicity (AZT), myopathy (AZT), peripheral neuropathy (ddC, ddI) and pancreatitis (ddI). Myopathy, peripheral neuropathy and pancreatitis are also observed in HIV-infected patients who have not been treated with the nucleoside analogues. Thus, nucleoside analogue toxicity can be confused with the adverse effects of HIV infection. Animal models exist for some, but not all, aspects of nucleoside analogue-related toxicity. In vitro studies have been used extensively to elucidate the mechanisms of nucleoside analogue toxicity. Cellular purine and pyrimidine metabolizing enzymes phosphorylate the analogues, which can then interact with DNA polymerases. Inhibition of one of these, HIV reverse transcriptase, is responsible for the antiviral activity of the nucleoside analogues. Toxicity is caused by inhibition of nuclear or mitochondrial DNA polymerases (or both) and by chain termination of replicating DNA at the point of insertion of the nucleoside analogue. The different toxicities observed in the case of each nucleoside analogue are most likely explained by different affinities for each of the cellular DNA polymerases.
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PMID:In vitro studies of the toxicity of nucleoside analogues used in the treatment of HIV infection. 2069 86


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