Background & Aims N -acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non–acetaminophen-related acute liver failure. Methods In a prospective, double-blind ...trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. Results A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I–II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III–IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). Conclusions Intravenous NAC improves transplant-free survival in patients with early stage non–acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.
Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in ...the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.
Using a well characterized model of cell-cell actin-based adherens junction (AJ) disruption by suppressing the intratesticular testosterone level in adult rats with testosterone-estradiol implants, ...we have confirmed earlier findings that Sertoli-germ cell AJ dynamics are regulated by the activation of kinases via putative signaling pathways but with some unexpected findings as follows. First, the loss of germ cells from the seminiferous epithelium during androgen suppression was associated with a surge in myotubularin-related protein 2 (MTMR2, a lipid phosphatase, in which adult MTMR2−/− mice were recently shown to be azoospermic because of the loss of cell adhesion function between germ and Sertoli cells); kinases: phosphatidylinositol 3-kinase, c-Src, and C-terminal Src kinase; adaptors: α-actinin, vinculin, afadin, and p130 Crk-associated protein; and AJ-integral membrane proteins at the ectoplasmic specialization (ES, a testis-specific cell-cell actin-based AJ type) site: N-cadherin, β-catenin, integrin β1, and nectin 3. Second, MTMR2, instead of structurally interacting with phosphatidylinositol 3-kinase, a protein and lipid kinase, was shown to associate only with c-Src, a nonreceptor protein tyrosine kinase, as demonstrated by both coimmunoprecipitation and fluorescent microscopy at the site of apical ES, but none of the kinases, adaptors, and AJ-integral proteins that were examined. Collectively, these results suggest that the MTMR2/c-Src is an important phosphatase/kinase protein pair in AJ dynamics in the testis. Because c-Src is known to associate with the cadherin/catenin protein complex at the ES in the testis, we next sought to investigate any changes in the protein-protein interactions of this protein complex during androgen suppression-induced germ cell loss. Indeed, there was a loss of N-cadherin and β-catenin association, accompanied by a surge in Tyr phosphorylation of β-catenin, during germ cell loss from the epithelium. Third, and perhaps the most important of all, during natural recovery of the epithelium after removal of testosterone-estradiol implants when spermatids were reattaching to Sertoli cells, an increase in N-cadherin and β-catenin association was detected with a concomitant loss in the increased Tyr phosphorylation in β-catenin. In summary, these results illustrate that the cadherin/catenin is a crucial cell adhesion complex that regulates AJ dynamics in the testis, and its functionality is likely modulated by the MTMR2/c-Src protein complex.
Drug-Induced Hepatotoxicity Lee, William M
The New England journal of medicine,
07/2003, Letnik:
349, Številka:
5
Journal Article
Recenzirano
Drug-induced hepatic injury accounts for more than 50 percent of cases of acute liver failure in the United States. More than 75 percent of idiosyncratic drug reactions result in liver ...transplantation or death. This review discusses the pathogenesis of drug-induced liver injury, common adverse drug reactions involving the liver, and the drug-approval process. Monitoring for and recognition of drug-induced hepatotoxicity may prevent some cases of acute hepatic failure.
Drug-induced injury is a major cause of acute liver failure.
In the past five years, two drugs have been withdrawn from the market by the Food and Drug Administration (FDA) for causing severe liver injury, a potential danger that had not been fully recognized in the course of the preapproval clinical trials. Reports of adverse drug reactions of any type engender fear and skepticism in the public about the actions of the pharmaceutical industry and the FDA.
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Drug-induced hepatic injury is the most frequent reason cited for the withdrawal from the market of an approved drug, and it also accounts for more than 50 percent of the cases of acute . . .
XELOX (capecitabine + oxaliplatin) and FOLFOX 4 (5-FU + folinic acid + oxaliplatin) have shown similar improvements in survival in patients with metastatic colorectal cancer (MCRC). A US ...cost-minimization study found that the two regimens had similar costs from a healthcare provider perspective but XELOX had lower costs than FOLFOX4 from a societal perspective, while a Japanese cost-effectiveness study found XELOX had superior cost-effectiveness. This study compared the costs of XELOX and FOLFOX4 in patients with MCRC recently treated in two oncology departments in Hong Kong.
Cost data were collected from the medical records of 60 consecutive patients (30 received XELOX and 30 FOLFOX4) from two hospitals. Drug costs, outpatient visits, hospital days and investigations were recorded and expressed as cost per patient from the healthcare provider perspective. Estimated travel and time costs were included in a societal perspective analysis. All costs were classed as either scheduled (associated with planned chemotherapy and follow-up) or unscheduled (unplanned visits or admissions and associated tests and medicines). Costs were based on government and hospital sources and expressed in US dollars (US$).
XELOX patients received an average of 7.3 chemotherapy cycles (of the 8 planned cycles) and FOLFOX4 patients received 9.2 cycles (of the 12 planned cycles). The scheduled cost per patient per cycle was $2,046 for XELOX and $2,152 for FOLFOX4, while the unscheduled cost was $240 and $421, respectively. Total treatment cost per patient was $16,609 for XELOX and $23,672 for FOLFOX4; the total cost for FOLFOX4 was 37% greater than that of XELOX. The addition of the societal costs increased the total treatment cost per patient to $17,836 for XELOX and $27,455 for FOLFOX4. Sensitivity analyses showed XELOX was still less costly than FOLFOX4 when using full drug regimen costs, incorporating data from a US model with costs and adverse event data from their clinical trial and with the removal of oxaliplatin from both treatment arms. Capecitabine would have to cost around four times its present price in Hong Kong for the total resource cost of treatment with XELOX to equal that of FOLFOX4.
XELOX costs less than FOLFOX4 for this patient group with MCRC from both the healthcare provider and societal perspectives.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatotoxicity due to overdoses of acetaminophen (also known as paracetamol) has become an important problem.
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Previous reports have defined two distinct clinical syndromes. When patients ...attempting suicide ingest large amounts of acetaminophen, acute liver failure associated with multiorgan failure, nephrotoxicity, and occasionally pancreatitis may develop unless antidotes are given.
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This pattern is the most common cause of acute liver failure in the United Kingdom. A second pattern, apparently more prevalent in the United States, is observed in alcoholic or fasting patients who ingest smaller amounts of acetaminophen only to relieve pain and in whom alcohol use or starvation . . .
The aim of our study is to report upon the presentation of two patients with life-threatening acute liver failure (ALF) due to amoxicillin and amoxicillin/clavulanate. A 59-year-old, Caucasian male ...presented with ALF 34 days after receiving amoxicillin/clavulanate. Despite aggressive supportive care, he died on hospital day 10. A 42-year-old, Caucasian female presented with ALF 21 days after receiving amoxicillin. She underwent successful liver transplantation on hospital day 19. In both cases, all competing causes of ALF had been excluded, liver pathology was consistent with drug-induced hepatitis, and cases were deemed "definite/highly probable" using causality assessment. Amongst 14 prior ALF/death cases due to amoxicillin/clavulanate, the mean age (62 years), male predominance (57%), and mean delay from drug cessation to presentation (17 days) is similar to what has been reported in patients with self-limited cholestatic hepatitis. Acute liver failure is a rare manifestation of amoxicillin and amoxicillin/clavulanate hepatotoxicity with no obvious clinical features at presentation portending a poor prognosis. Early transfer of patients with severe drug-induced hepatotoxicity (i.e., encephalopathy or coagulopathy) to a transplant center is recommended due to their poor likelihood of recovery.
Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 ...deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than $1 billion dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self‐diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over‐the‐counter pain reliever? (HEPATOLOGY 2004;40:6–9.)
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