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UNLABELLED: BACKGROUND Bloating is common, but its significance as a marker of underlying disease has not been defined. AND AIMS: We report on risk factors for bloating, its relationship to physical activity and quality of life (QOL), and its predictive value for functional bowel disorders. METHODS: This is a cross-sectional population-based study of 1,069 employees of the Veterans Affairs Black Hills Health Care System. The validated Bowel Disease Questionnaire was used to identify subjects with abdominal bloating and other bowel disorders. The association of bloating with QOL was assessed using the SF36 (Short-Form 36) questionnaire. Physical activity was assessed using the modified Baecke questionnaire. RESULTS: The response rate was 72% (723 of 1,069). Bloating was reported by 21% of all subjects (95% confidence interval [CI] 17.7-23.7), 64% with irritable bowel syndrome (IBS), 35% with non-IBS constipation, 23% with non-IBS diarrhea, and 42% with dyspepsia. Functional bloating (i.e., bloating in the absence of other bowel disorders) was reported by 7% of subjects (95% CI 5.2-9.0). Of those with bloating, 28% had IBS, 25% non-IBS constipation, 8% non-IBS diarrhea, and 30% dyspepsia. The positive and negative predictive values of bloating in the diagnosis of functional bowel disorder were 66% and 87%, respectively. The only risk factors were smoking and high-dose aspirin. Bloating was not associated with physical activity. QOL on all subscales of SF36 was lower in subjects with bloating than those without bloating. CONCLUSIONS: Bloating is a common symptom in otherwise healthy adults, and is often associated with but not predictive of functional bowel disorders. Smoking and high-dose aspirin are associated with bloating while physical activity is not.
Assuntos
Doenças Funcionais do Colo/epidemiologia , Doenças Profissionais/epidemiologia , Adulto , Idoso , Aspirina/efeitos adversos , Doenças Funcionais do Colo/diagnóstico , Comorbidade , Constipação Intestinal/epidemiologia , Estudos Transversais , Diarreia/epidemiologia , Relação Dose-Resposta a Droga , Dispepsia/epidemiologia , Exercício Físico , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/diagnóstico , Qualidade de Vida , Fatores de Risco , Fumar/efeitos adversos , South DakotaRESUMO
BACKGROUND: As the comparative pharmacokinetics and pharmacodynamics of lansoprazole and rabeprazole have not previously been studied, we set out in this study to compare the pharmacokinetics and pharmacodynamics of single and repeated daily doses of lansoprazole 15 mg and 30 mg with those of rabeprazole 10 mg and 20 mg. METHODS: This was an open-label, randomised, crossover, two-centre study in 72 healthy volunteers. Each subject received each of the four treatments for 5 days, with 2-week washout periods. Continuous 24-hour intragastric pH and pharmacokinetics were studied on days 1 and 5. RESULTS: Mean 24-hour pH and percentage time for pH > 4 were not significantly different between lansoprazole 30 mg and rabeprazole 20 mg. Mean 24-hour pH and percentage time for pH > 4 were significantly greater after lansoprazole 30 mg and rabeprazole 20 mg than after lansoprazole 15 mg and rabeprazole 10 mg, respectively. Lansoprazole resulted in greater acid suppression during hours 0-5 on days 1 and 5, whereas rabeprazole had greater suppression during hours 11-24 on day 5. Time to maximum plasma concentration was significantly shorter for lansoprazole on both days. CONCLUSION: Lansoprazole had a consistently faster onset of action, whereas rabeprazole had a greater effect during the evening hours after 5 days of administration.
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2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Antiulcerosos/farmacologia , Inibidores Enzimáticos/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Feminino , Determinação da Acidez Gástrica , Humanos , Lansoprazol , Masculino , RabeprazolRESUMO
Diabetes mellitus is the fifth leading cause of death in the United States; 17 million people are affected. Liver disease is one of the leading causes of death in persons with type 2 diabetes. The standardized mortality rate for death from liver disease is greater than that for cardiovascular disease. The spectrum of liver disease in type 2 diabetes ranges from nonalcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma. The incidence of hepatitis C and acute liver failure is also increased. Nonalcoholic fatty liver disease is now considered part of the metabolic syndrome, and, with alcohol and hepatitis C, is the most common cause of chronic liver disease in the United States. Weight reduction and exercise are the mainstays of treatment for nonalcoholic fatty liver disease, but there are promising results with the new thiazolidinediones (pioglitazone and rosiglitazone) as well as metformin and 3-hydroxy-3-methylglutaryl coenzyme A inhibitors.
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Diabetes Mellitus Tipo 2/complicações , Hepatopatias/complicações , Colelitíase/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Humanos , Fígado/metabolismoRESUMO
The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 x the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.
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Anticolesterolemiantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Fígado/efeitos dos fármacos , Lovastatina/efeitos adversos , Animais , Anticolesterolemiantes/farmacologia , Ensaios Clínicos como Assunto , Humanos , Fígado/enzimologia , Testes de Função Hepática , Lovastatina/farmacologia , Vigilância de Produtos Comercializados , Fatores de RiscoRESUMO
Troglitazone, the first of the thiazolidinediones, caused severe hepatotoxicity including liver failure in several patients. It appears, however, that the thiazolidinediones as a class are not as hepatotoxic as troglitazone. Comparative data at comparable dates of usage indicate that pioglitazone and rosiglitazone are not significant hepatotoxins. This is further supported by experimental data that demonstrate that troglitazone, alone among the thiazolidinediones, is toxic in hepatocyte cell culture. All of the thiazolidinediones cause ALT elevations; however, ALT monitoring for hepatotoxicity does not appear to prevent serious liver disease nor reduce patient risk.
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Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hipoglicemiantes/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Tiazóis/efeitos adversos , Tiazolidinedionas , Cromanos/efeitos adversos , Humanos , Pioglitazona , Rosiglitazona , Troglitazona , Estados Unidos , United States Food and Drug AdministrationRESUMO
INTRODUCTION: The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions. Many new therapies have emerged, including thiazolidinediones (TZDs), selective agonists of PPAR-γ, now used as both primary and add-on therapies. Given that T2DM is a lifetime disease, there is a need for assurance that new drugs are both safe and effective. Recent concern about the cardiovascular safety of one of the new drugs, rosiglitazone, is the stimulus for this review. AREAS COVERED: The safety of pioglitazone and rosiglitazone under the headings of liver safety, cardiovascular safety, fluid retention, weight gain and bone fractures is reviewed based on a PubMed search of the years 1997 through June 2010. This review also describes the magnitude of the risks of the TZDs and provides a recommendation on the use of TZDs. EXPERT OPINION: Liver safety is no longer an issue with the TZDs. There are no significant differences between rosiglitazone and pioglitazone in fluid retention, weight gain and bone fractures. However, pioglitazone tends to be cardioprotective while rosiglitazone is cardiotoxic. There is no current justification for prescribing rosiglitazone.
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Hipoglicemiantes/efeitos adversos , Tiazolidinedionas/efeitos adversos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Pioglitazona , Rosiglitazona , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêuticoRESUMO
BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide). METHODS: Patients were randomized to receive either pioglitazone (15-45 mg once daily) or glibenclamide (5-15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 x ULN) with a secondary endpoint of 8 x ULN. MAIN RESULTS: The intent-to-treat population included 1051 pioglitazone-treated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 x ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 x ULN + total bilirubin 2 x ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 x ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p < or = 0.05) fewer cases of ALT >1.5 x ULN, aspartate aminotransferase >1.5 x ULN and gamma-glutamyl transpeptidase >1.5 x ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported. CONCLUSION: This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes. Trial registration number (clinicaltrials.gov): NCT00494312.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Método Duplo-Cego , Aprovação de Drogas , Determinação de Ponto Final , Feminino , Glibureto/uso terapêutico , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Pioglitazona , Estados Unidos , United States Food and Drug Administration , Adulto JovemRESUMO
Non-alcoholic fatty liver disease, defined as the presence of macrovascular steatosis in the presence of less than 20 gm of alcohol ingestion per day, is the most common liver disease in the USA. It is most commonly associated with insulin resistance/type 2 diabetes mellitus and obesity. It is manifested by steatosis, steatohepatitis, cirrhosis, and, rarely, hepatocellular carcinoma.Hepatic steatosis results from an imbalance between the uptake of fat and its oxidation and export. Insulin resistance, predisposing to lipolysis of peripheral fat with mobilization to and uptake of fatty acids by the liver, is the most consistent underlying pathogenic factor. It is not known why some patients progress to cirrhosis; however, the induction of CYP 2E1 with generation of reactive oxygen species appears to be important.Treatment is directed at weight loss plus pharmacologic therapy targeted toward insulin resistance or dyslipidemia. Bariatric surgery has proved effective. While no pharmacologic therapy has been approved, emerging data on thiazolidinediones have demonstrated improvement in both liver enzymes and histology. There are fewer, but promising data, with statins which have been shown to be hepatoprotective in other liver diseases. The initial enthusiasm for ursodeoxycholic acid has not been supported by histologic studies.
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Acetaminophen has been used safely and effectively for many years to manage pain and/or fever in patients of all ages. It is commonly recommended as first-line therapy for a variety of patients and conditions, including the elderly, children with viral illnesses, and patients with osteoarthritis, gastrointestinal conditions, bleeding disorders, cardiovascular disease, or renal disease. However, its use is often avoided in patients with chronic liver disease. The perception that acetaminophen should be avoided in such patients arose from awareness of the association between massive acetaminophen overdose and hepatotoxicity, combined with a lack of understanding of the metabolism of acetaminophen in patients with liver disease. There are various theoretical mechanisms of acetaminophen hepatotoxicity in chronic liver disease including: altered metabolism and depleted glutathione stores that would be expected to increase accumulation of the hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Available studies in patients with chronic liver disease, however, have shown that although the half-life of acetaminophen may be prolonged, cytochrome P-450 activity is not increased and glutathione stores are not depleted to critical levels in those taking recommended doses. Furthermore, acetaminophen has been studied in a variety of liver diseases without evidence of increased risk of hepatotoxicity at currently recommended doses. Therefore, acetaminophen can be used safely in patients with liver disease and is a preferred analgesic/antipyretic because of the absence of the platelet impairment, gastrointestinal toxicity, and nephrotoxicity associated with nonsteroidal antiinflammatory drugs.