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) as standard of care has changed the natural history of HIV infection into a manageable chronic disease requiring long-term antiretroviral (ARV) treatment. However, response to HAART is often limited by the occurrence of toxicity or by the emergence of drug resistance. Antiretroviral treatment is characterized by differing rates of adverse events and responses. Genetic variations between human beings account for a relevant proportion of this variability. A relevant number of associations between human genetic variants and predisposition to adverse events have been described and for some antiretroviral drugs a clear and casual genotype-phenotype correlation has already been established. The strong association between abacavir hypersensitivity reaction and HLA-B*5701 has been demonstrated in both observational and blinded randomized clinical trials in racially diverse populations and represents the best example of the clinical utility of pharmacogenetic screening in HIV medicine. Genotyping for HLA-B*5701 before prescribing an abacavir containing regimen has been introduced into routine clinical practice as the standard of care for all patients. Other well-established associations include CYP2B6 alleles and efavirenz central nervous system side effects, UGT1A1 alleles and atazanavir-associated hyperbilirubinemia and HLA class II allele HLA-DRB*0101 and nevirapine-associated hypersensitivity. Despite genetic associations having been described for peripheral neuropathy, lipodystrophy, hyperlipidaemia, pancreatitis and renal proximal tubulopathy, numerous barriers exist to the successful introduction of widespread genetic testing to the clinic. Future prospects point in the direction of individualization of antiretroviral therapy through insights from host genetics. The present paper is aimed to provide a comprehensive review of the published literature and to summarize the state of research in this area. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
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PMID:Pharmacogenetics of antiretrovirals. 1974 23

Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumour and haematological malignancies, including cancers of the testes, ovary, bladder, head and neck, oesophagus, stomach and lung, as well as lymphoma and osteosarcoma. Its non-specific targeting commonly results in adverse effects and toxicities affecting the gastrointestinal, renal, neurological and haematological systems even when administered at standard doses. Since cisplatin-related toxicities are dose-dependent, these may be more pronounced in the setting of a cisplatin overdose, resulting in significant morbidity and/or mortality. The incidence of cisplatin overdoses is unknown; however, early-phase clinical trials utilizing high-dose cisplatin, and case reports in the overdose setting have characterized the clinical features associated with cisplatin overdoses, highlighting some therapeutic strategies for consideration. To date, no published guidelines exist for managing a cisplatin overdose. The major toxicities of a cisplatin overdose include nausea and vomiting, renal insufficiency, electrolyte abnormalities, myelosuppression, ototoxicity, peripheral neuropathy, hepatotoxicity and retinopathy. Diarrhoea, pancreatitis, seizures and respiratory failure have also been reported. No specific antidote for cisplatin exists. Key management principles and strategies to lessen toxicities include renoprotection and enhancing drug elimination with aggressive intravenous hydration with or without the use of an osmotic diuretic, and avoidance of nephrotoxic medications. Sodium thiosulfate and plasmapheresis, with or without haemodialysis support, should be strongly considered. Close monitoring of clinical and laboratory parameters, and institution of supportive therapies, including antiemetics and haematopoietic colony stimulating factor support, are warranted. Based on the current literature, experimental therapies such as amifostine, ditiocarb sodium (diethyldithiocarbamate), acetylcysteine, fosfomycin and colestipol are of limited clinical effectiveness and remain investigational. This review serves to highlight the clinical spectrum of toxicities resulting from a cisplatin overdose, to critically appraise the available literature and to present a suggested algorithmic approach for the initial management of a cisplatin overdose.
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PMID:Cisplatin overdose: toxicities and management. 1991 78

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

The most important factor limiting the success of an antiretroviral therapy regimes is toxicity. Toxicity can depend on a number of factors; some of these are intrinsic to the host and may not only affect the latter's outward appearance, but also determine the intensity these toxic effects may reach. The former is exemplified by idiosyncratic or hypersensitivity reactions, whereas the latter is usually appreciated in metabolic disturbances or fat redistribution syndromes. Some of the determinants of antiretroviral toxicity are genetic in origin and have been the subject of intense study in recent years. Some of these are linked to a single nucleotide polymorphism (SNP), whereas others depend on a complex interaction between multiple genes variations. One of these tests (HLA B*5701) is now being applied in clinical practice and widely used to prevent the risk of hypersensitivity reactions to abacavir. Many other genetic determinants of antiretroviral drug toxicity have been suggested as an explanation for nucleoside analogue toxicity; these include lactic acidosis, peripheral neuropathy and pancreatitis, and have also been suggested as a potential basis for the non-nucleoside toxicity derived from immunogenetic factors involved in nevirapine hypersensitivity to SNPs in efavirenz enzyme metabolism, amongst other things. Metabolic toxicity, mainly due to protease inhibitors (PIs) is far more complex and depends on the interaction of various genes. The same seems to be true for fat redistribution syndromes and atherosclerosis, although a clear picture of the genetic factors operating in these syndromes is yet to emerge. The ultimate goal of pharmacogenetics is to customize antiretroviral therapy by identifying the genes that can maximize efficacy whilst helping avoid known side effects of antiretroviral drugs.
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PMID:The toxicogenetics of antiretroviral therapy: the evil inside. 2111 Aug 5

Different types of alcoholic beverages such as wine and beer were used in ancient times for various medicinal purposes. Being the oldest and probably the most widely used drugs, they were known to have some therapeutic value, in addition to the vital part they played in the daily life of people. Ethanol is produced by fermentation of a variety of plants and consumed either in a diluted form or concentrated by distillation to concoct alcoholic beverages. Beer made of fermented barley is an alcoholic drink that was believed to contain a spirit or a god. It is a drink of relatively low alcohol content with supernatural properties. The same was believed for wine. Considered to be divine, these beverages were the long sought elixirs of life and appeared in religious ceremonies, in mythology, and in social meals, such as the Greek symposia. In addition, these alcoholic drinks were considered to be a remedy for practically every disease and, therefore, were a common ingredient in ancient prescriptions. They were used as anaesthetics that dull the pain, as stimulants, as analgesics, as antiseptics to cleanse wounds and relieve pain, as emetics, as digestives, as antidotes for plant poisoning, for bites and stings, and as purifiers. However, we should not overlook the harmful effects of alcohol abuse such as drunkenness, chronic liver disease and, in modern terminology, infirmities that included pancreatitis, cardiomyopathy, peripheral neuropathy, dementia, and central nervous system disorders.
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PMID:Beer and wine in antiquity: beneficial remedy or punishment imposed by the Gods? 2356 Jul 53

Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients' derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn's disease. About 5% of Crohn's disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.
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PMID:Patients' Induced Pluripotent Stem Cells to Model Drug Induced Adverse Events: A Role in Predicting Thiopurine Induced Pancreatitis? 2652 32

A 46-year-old female was treated with a regimen of paclitaxel and carboplatin (TC therapy) as adjuvant chemotherapy for Stage IC ovarian adenocarcinoma. There was no severe toxicity except for grade 3 neutropenia during the first four cycles of TC therapy. However, she developed acute pancreatitis at 14 days after fifth cycle. TC therapy is commonly associated with adverse effects such as myelosuppression, hypersensitivity, alopecia, and peripheral neuropathy, but acute pancreatitis has rarely been reported. Ovarian cancer patients often present with nausea and abdominal pain, which are the same symptoms of pancreatitis. It is very important to keep in mind that acute pancreatitis may be concealed in these common symptoms of ovarian cancer during and after TC therapy. Because acute pancreatitis is fatal complication and quitting the drug usually leads to complete cure. The authors report an uncommon case in which TC therapy may have caused acute pancreatitis.
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PMID:Acute pancreatitis induced by paclitaxel and carboplatin therapy in an ovarian cancer patient. 2717 65

Twenty-six haemophilic patients with advanced HIV infection who had developed resistance or intolerance to zidovudine were treated with didanosine (ddI). 11 patients continue to take ddI at a median time of 14 months from commencement (range 7-18 months). Five of these patients showed an increase in CD4 lymphocyte count, reaching a maximum at a median time of 4 months. Four patients with HIV-related symptoms improved clinically. In general, the CD4 count and clinical improvements were not sustained. 11 patients discontinued ddI after a median of 3 months (range 3 days to 10 months), most commonly due to gastrointestinal side-effects. No case of pancreatitis or peripheral neuropathy was seen. Six patients, all with very advanced HIV disease, died. HIV-infected haemophilic patients who become resistant or intolerant to zidovudine may derive benefit from ddI, although this is usually transient.
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PMID:Didanosine treatment of haemophilic patients infected with HIV. 2721 21

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.
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PMID:Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. 2729 79

Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug's multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency's thinking. In 1994, the FDA proposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when "there is a reasonable suspected causal relationship between the investigational product and the adverse event (i.e., the causal relationship cannot be ruled out)." This last clause was codified into the suspected adverse drug reaction definition in the FDA's 2003 safety reporting requirements for drugs and biologics proposed rule. The negatively received suspected adverse drug reaction and proposed causality standard were not adopted in the FDA's 2010 finalized investigational new drug safety reporting regulations, the agency stating that "'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event." However, such new requirements as aggregate analysis of specific events and expedited reporting of animal or in vitro data suggesting significant harm to humans, and subsequent guidance that sponsors develop "a systematic approach" to premarketing safety assessment, are among the components of the FDA's efforts to enhance determination of a "reasonable possibility" of causality. They are also philosophically consistent with the 1993 task force recommendations, and a reminder of the inherent hazards associated with the use of investigational drugs, particularly in the early stages of human study.
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PMID:Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns. 2747 17


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