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 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

The carcasses of 25 great horned owls and 12 goshawks were investigated for West Nile virus (WNV) infection by immunohistochemistry (IHC) performed on various organs, including brain, spinal cord, heart, kidney, eye, bone marrow, spleen, liver, lungs, pancreas, intestine, and proventriculus, using a WNV-antigen-specific monoclonal antibody and by WNV-specific reverse transcriptase-polymerase chain reaction (RT-PCR), performed on fresh brain tissue only. WNV infection was diagnosed by IHC in all owls and all goshawks. WNV-specific RT-PCR amplified WNV-RNA in the brain of all goshawks but only 12 owls (48%). Cachexia was a common macroscopic finding associated with WNV infection in owls (76%). Myocarditis was occasionally macroscopically evident in goshawks (33%). Microscopically, inflammatory lesions, including lymphoplasmacytic and histiocytic encephalitis, myocarditis, endophthalmitis, and pancreatitis were present in both species but were more common and more severe in goshawks than in owls. The most characteristic brain lesion in owls was the formation of glial nodules, in particular in the molecular layer of the cerebellum, while encephalitis affecting the periventricular parenchyma of the cerebral cortex was common in the goshawks. In owls, WNV-antigen-positive cells were present usually only in very small numbers per organ. Kidney (80%), heart (39%), and cerebellum (37%) were the organs that most commonly contained WNV antigen in owls. WNV antigen was frequently widely distributed in the organs of infected goshawks, with increased amounts of WNV antigen in the heart and the cerebrum. Spleen (75%), cerebellum (66%), heart (58%), cerebrum (58%), and eye (50%) were often WNV-antigen positive in goshawks. In contrast with the goshawks, WNV antigen was not present in cerebral and retinal neurons of owls. WNV infection appears to be capable of causing fatal disease in great horned owls and goshawks. However, the distribution and severity of histologic lesions, the antigen distribution in the various organs, and the amount of antigen varied among both species. Therefore, the diagnostician may choose organs for histology and immunohistochemistry as well as RT-PCR depending on the investigated species in order to avoid false-negative results.
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PMID:Pathologic and immunohistochemical findings in goshawks (Accipiter gentilis) and great horned owls (Bubo virginianus) naturally infected with West Nile virus. 1609 31

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

Highly active antiretroviral therapy is beyond reach of most HIV-infected children in developing countries. There is paucity of data on more affordable regimens such as ones based on nevirapine and 2 nucleoside reverse transcriptase inhibitors. We report our experience with the use of antiretroviral therapy in children with HIV-1 infection at a tertiary care hospital in north India. The study subjects were HIV-1 infected children, who were receiving 3-drug antiretroviral therapy for a period of three or more months. The children were regularly followed up for any complications, changes in anthropometry, and changes in CD4 counts. The mean age of children at diagnosis (n=26; 22 boys) was 68.5 +- 33.4 months. These children were followed up for a mean of 19.7 +- 18.7 months. Twenty four children received nevirapine based regimen. There was statistically significant improvement in weight for height and body mass index on follow up. The mean CD4 count changed from baseline (n=24) of 584.3 +- 685.9 mm3 to 614.4 +- 455.7 mm3 (n=15) at last follow up. One child developed minor skin rash in the initial two weeks of starting nevirapine. One child developed pancreatitis. We conclude that administration of nevirapine based ART for HIV-1 infected children is feasible in resource poor setting. There is improvement in growth parameters with use of this therapy.
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PMID:Antiretroviral therapy in HIV-1 infected children. 1614 80

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

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

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

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

Pancreatitis-associated protein (PAP) is a secretory protein that is not only expressed during acute pancreatitis but also in pancreatic adenocarcinoma, gastric carcinoma, hepatocellular carcinoma, and colorectal carcinoma. Expression in carcinoma might be another characteristic of PAP. The aim of our study was to assess, in 27 patients undergoing surgery for colorectal carcinoma, the expression of the PAP mRNA and to evaluate its association with DNA ploidy and proliferative activity (S-phase fraction, SPF) by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometric analysis (FCM). PAP mRNA was expressed in 29.6% (8 of 27) of the patients with colorectal carcinoma. DNA aneuploid and high SPF were found in 87.5% (7 of 8) of patients with PAP mRNA positive colorectal carcinoma. The serum PAP level was significantly elevated in patients with colorectal carcinoma when compared with the healthy subjects. Twelve of the 27 patients with colorectal carcinoma had high serum PAP concentrations (>25 ng/mL) and the mean SPF was 17.82% +/- 8.02%, which was significantly higher compared with the normal colorectal tissue group (7.33% +/- 3.18%, P < 0.05). The mean serum PAP concentration of DNA aneuploidy colorectal carcinomas was 46.67 +/- 17.58 ng/mL, which was significantly different when compared with the DNA diploidy group (19.18 +/- 8.89 ng/mL, P < 0.05). PAP mRNA expression and serum PAP levels are closely related to neoplastic proliferative activity in patients with colorectal carcinoma. No significant differences are observed between PAP mRNA expression and clinicopathologic parameters (P > 0.05).
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PMID:Pancreatitis-associated protein is related closely to neoplastic proliferative activity in patients with colorectal carcinoma. 1905 Dec 57


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