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)

HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8+ T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.
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PMID:HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo. 1745 62

Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate. Currently, didanosine is mainly provided as an enteric-coated capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages. Didanosine may select for resistance mutations that may render the drug inactive against the virus; L74V and K65R remain as the main didanosine-related mutations. In vitro, phenotypic susceptibility to didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that didanosine retains significant antiviral activity in patients who have up to five nucleoside analogue mutations at baseline. Didanosine is useful in patients with no previous therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with lamivudine (or emtricitabine), it can be considered a good alternative for use in the nucleoside analogue backbone included in combination therapies for antiretroviral-naive patients. Didanosine could be used in initial treatments for patients intolerant of zidovudine, abacavir or tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of didanosine plus lamivudine (or emtricitabine) plus efavirenz (or nevirapine) in previously untreated HIV-1-infected patients. The administration of didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous therapies have failed (rescue therapy) and those with controlled viraemia who are switched to a didanosine-containing regimen for simplification.Adverse events associated with the administration of didanosine have been well known since the initial clinical trials with the drug. Gastrointestinal intolerance, peripheral neuropathy and hyperamylasaemia/pancreatitis were the most frequently reported. In the highly active antiretroviral therapy (HAART) era, the rate of adverse events has decreased. The tolerability of didanosine has been clearly improved with the development of the enteric-coated capsule. Severe manifestations of mitochondrial toxicity, including lactic acidosis and abnormal fat distribution, are rare complications, and occur most frequently when didanosine is used in combination with stavudine.
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PMID:Didanosine enteric-coated capsule: current role in patients with HIV-1 infection. 1760 Mar 92

In the last 10 years, the enormous impact of combination antiretroviral (ARV) therapy on paediatric HIV-associated mortality and morbidity in well-resourced settings and its role in the prevention of mother-to-child transmission (MTCT) of HIV cannot be underestimated. However, it is thus inevitable that children with HIV-1 infection will be exposed to ARVs for an ever-increasing length of time throughout post-natal growth and development, and the cumulative toxicities are becoming progressively apparent. Evidence for nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial toxicity is seen in vitro, in animal models and in NRTI-exposed adults and children. Proposed mechanisms of NRTI mitochondrial toxicity include, among others, impairment of mitochondrial DNA (mtDNA) replication and acquisition of mtDNA point mutations. Alterations in the mtDNA synthesis potentially reduce the production of mtDNA-encoded respiratory chain subunits, resulting in impaired oxidative phosphorylation and mitochondrial dysfunction. NRTI-associated mitochondrial toxicity in children has varied presentations including lactic acidosis, pancreatitis, cardiomyopathy and neuropathy, which are comparable to NRTI-exposed adults and children with congenital mitochondrial disorders. In the prevention of MTCT, uninfected infants are exposed to an ever-widening range of ARVs, often from conception and throughout fetal life. Animal models demonstrate evidence of mitochondrial toxicity from perinatal NRTI exposure, but controversy continues as to the extent of mitochondrial effects in NRTI-exposed children. Paediatric studies assessing the impact of reduced exposure to NRTIs or the use of NRTIs with lower mitochondrial toxicity are urgently required. In an era of expanding treatment options, minimizing toxicities becomes an increasing possibility, indeed a necessity.
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PMID:HIV and mitochondrial toxicity in children. 1799 78

Toxicities related to antiretroviral therapy make long-term adherence to therapy difficult for patients and present challenges to providers, especially those in the resource-poor world who work with a limited formulary. In resource-poor settings, where limited drug options are the rule, when and how to change therapy are especially difficult problems. Drugs such as stavudine and didanosine are associated with serious metabolic complications, such as lactic acidosis, pancreatitis, and peripheral neuropathy. Antiretroviral agents associated with fewer metabolic effects, such as tenofovir and abacavir, remain widely unavailable. Because the current formulary restrictions appear to be unlikely to change quickly, providers in resource-poor countries must be familiar with the common adverse events-including metabolic complications, hypersensitivity reactions, anemia, and liver enzyme abnormalities-and must understand how to manage them with what is locally available. Most importantly, to avoid drug toxicities, a larger formulary is needed in resource-poor settings, and this must be a high priority for policy makers and health care professionals involved in treating human immunodeficiency virus infection globally.
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PMID:Antiretroviral therapy-associated toxicities in the resource-poor world: the challenge of a limited formulary. 1818 93

To assess the incidence of and risk factors for acute pancreatitis in HIV-infected patients in the contemporary highly active antiretroviral therapy (HAART) era, we evaluated all cases of acute pancreatitis requiring hospitalization between 1996 and 2006 in patients followed at Johns Hopkins Hospital's HIV clinic. A nested, case-control analysis was employed for initial episodes of acute pancreatitis, and conditional logistic regression was used to assess risk factors. Of 5970 patients followed for 23,460 person-years (PYs), there were 85 episodes of acute pancreatitis (incidence: 3.6 events/1000 PYs). The incidence of pancreatitis from 1996 to 2000 was 2.6 events/1000 PYs; the incidence from 2001 to 2006 was 5.1 events/1000 PYs (p = 0.0014, comparing rates in two time periods). In multivariate regression, factors associated with pancreatitis included female gender (adjusted odds ratio [AOR] 2.96 [1.69, 5.19]; p < 0.001); stavudine use (AOR 2.19 [1.16, 4.15]; p = 0.016); aerosolized pentamidine use (OR 6.27; [1.42, 27.63]; p = 0.015); and CD4 count less than 50 cells/mm(3) (AOR 10.47 [3.33, 32.90]; p < 0.001). Race/ethnicity, HIV risk factor, HIV-1 RNA, and newer non-nucleoside reverse transcriptase inhibitors (NNRTI)- and protease inhibitor (PI)-based HAART regimens were not associated with an increased risk of pancreatitis after adjustment for the above factors. Pancreatitis remains a significant cause of morbidity in the HIV population in the HAART era. Acute pancreatitis is associated with female gender, severe immunosuppression, and stavudine and aerosolized pentamidine usage. Of note, newer antiretrovirals, particularly atazanavir, lopinivir/ritonavir, tenofovir, abacavir, and efavirenz, were not associated with an increased risk of pancreatitis.
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PMID:A ten-year analysis of the incidence and risk factors for acute pancreatitis requiring hospitalization in an urban HIV clinical cohort. 1826 Aug 2

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

Pancreatic elastase-1 is a proteolytic enzyme exclusively produced in the pancreas, is stable when passing through the bowel, and its determination is associated with chronic pancreatitis. The clinical diagnosis of pancreatitis is based on anamnesis, physical examination, radiological, sonographic, endoscopic, and laboratory findings. Nowadays, there is a test for the determination of fecal elastase-1, by enzymatic reaction (enzyme-linked immunosorbent assay, ELISA), which specifically determines human elastase-1, promoting the pancreatic function evaluation. Parameters such as linearity, calibration curve, sensitivity, specificity, precision, accuracy, recovery, and receiver operator characteristic (ROC) curve are used to evaluate the test. The aim of this study was the validation of the immunoenzymatic assay (ELISA) and the use of its results in patients with HIV, alcoholics, and under antiretroviral therapy. The study involved 157 patients, 95 of them were HIV-infected, and 62 were completely healthy. The elastase-1 ELISA kit from Bioserv was used, and we noted that the obtained results were linear, sensitive, precise, and accurate. Moreover, our results suggest that this test can be a laboratory evaluation to determine the relationship of pancreatitis with alcohol use, but not its association with antiretroviral use in HIV patients (P=0.424). This test is useful to diagnose pathologies related to pancreatic insufficiency.
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PMID:Validation of fecal elastase-1 determination using immunoenzymatic assay in HIV-infected patients. 1862 2

Drugs are a relatively rare cause of acute pancreatitis, with an estimated incidence of 0.1-2%. Many drugs have been suspected of causing pancreatitis, but the true incidence is not known as the evidence is derived mainly from random case reports. Case reports with the strongest evidence are those that clearly diagnose pancreatitis and exclude common aetiologies, provide the dose and time interval between the start of treatment with the suspected drug and the development of pancreatitis, document response to withdrawal of the drug, and demonstrate recurrent pancreatitis upon rechallenge with the drug. Few data exist on the mechanisms of drug-induced pancreatitis. Certain subpopulations such as children, women, the elderly and patients with advanced HIV infection or inflammatory bowel disease may be at higher risk. The diagnosis of drug-induced pancreatitis is often challenging because there are no unique clinical characteristics to distinguish drugs from other causes of pancreatitis. The majority of cases are mild, but severe and even fatal cases may occur, thus making identification of the offending agent critical. Management of drug-induced acute pancreatitis requires withdrawal of the offending agent and supportive care. Prevention of drug-induced pancreatitis requires an up-to-date knowledge of drugs that have the strongest evidence linking their use to the development of pancreatitis as well as the proposed mechanisms through which they may cause the reaction. In this paper, the epidemiology, diagnosis, management and prevention of drug-induced pancreatitis is reviewed. Drugs and classes of drugs strongly implicated as causing acute pancreatitis, based on well documented case reports, are discussed in detail.
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PMID:Drug-induced pancreatitis : incidence, management and prevention. 1875 7

It has long been recognized that drug metabolism and drug toxicity may vary greatly between individuals, affecting both efficacy and toxicity. Pharmacogenetics could benefit HIV therapeutics because of the high prevalence of drug-related adverse events and the long term nature and complexity of combination therapy. In recent years a number of associations between human genetic variants and predisposition to drug toxicity and risk of virologic failure have been described. This review summarizes the existing literature on pharmacogenetic determinants of antiretroviral drug exposure, toxicity, and activity. Studies across the world have consistently demonstrated that HLA-B*5701 predicts the likelihood of hypersensitivity reactions to abacavir. As a consequence, pharmacogenetic screening for HLA-B*5701 has entered routine clinical practice and is recommended in most guidelines before starting an abacavir containing regimen. Moreover, prospective clinical trials and cohort studies have identified a number of associations between human genetic variants, drug metabolism and toxicity. These include nevirapine hypersensitivity and hepatotoxicity, efavirenz plasma levels and central nervous system side effects, indinavir- and atazanavir-associated hyperbilirubinemia, antiretroviral drug-associated peripheral neuropathy, lipodystrophy and hyperlipidaemia, NRTI-related pancreatitis, and tenofovir-associated renal proximal tubulopathy. Thus, pharmacogenetics is expected to play an important role in HIV treatment in the near future. The aim of the present paper is to provide HIV clinicians with a comprehensive review of recent achievements and future prospects for HIV pharmacogenetics.
Curr HIV Res 2008 Nov
PMID:HIV pharmacogenetics in clinical practice: recent achievements and future challenges. 1899 20

Establishing a diagnosis of primary HIV infection (PHI) is important for both the affected individual and public health, because the newly infected individual might readily transmit HIV to others. Unfortunately, diagnosing PHI is hindered by its non-specific presentation, among other factors. We report the case of a patient with extensive multiple organ involvement (fever, rhabdomyolysis, myocarditis, pancreatitis, bilateral renal infarcts, acute renal failure and anemia) in the setting of documented HIV seroconversion as an unusual form of PHI.
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PMID:Primary HIV infection with multisystemic presentation. 1902 26


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