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The myth of statin-induced hepatotoxicity

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The Myth of Statin-Induced Hepatotoxicity
Am J Gastroenterol 2010;105:978–980; doi:10.1038/ajg.2010.102 Statin-induced hepatotoxicity is a myth. cebo trial with a median follow-up of 5 years have a 1.13% incidence of liver test abnor- “Myth” is used here to mean a false collec- randomized 6,500 subjects to drug and pla- malities vs. 0.29% with placebo (P = 0.04) tive belief that, despite factual contradiction, cebo. The number of patients who developed (9). However, the incidence of changes in endures as suspicion. The legend asserts that ALT elevations greater than three times the the placebo groups was exceedingly low, isolated alanine aminotransferase (ALT) ULN did not differ between lovastatin and whereas the observed incidence with fluvas- elevations associated with statin therapy are placebo (18 (0.6%) vs. 11 (0.3%)) (3).
tatin was similar to that with other statins.
harmful and must be avoided. How did this Elevation of serum ALT is not a disease. Study enrolled more than 2,200 placebo At worst, the ephemeral out-of-range ALT posed in 1978 that an ALT value more than recipients. Patients developing an ALT values represent adaptation to exposure to three times the upper level of normal (ULN) level greater than three times the ULN statins by the different organs involved in was “markedly abnormal” and should be did not differ between the simvastatin and ALT regulation. In the liver this is done by used as an indicator for drug-induced liver placebo groups (14 (0.7%) vs. 12 (0.6%)). alteration of metabolic enzyme and trans- injury. Not a shred of proof was offered for In two other controlled studies of simvas- porter systems to process the drug. When tatin, no patient emerged with persistent a statin is continued, despite elevations of sure became a standard for monitoring liver test abnormalities following the ini- ALT, the ALT eventual y returns to normal drugs in clinical trials (1). In the 1980s, tri- tial 6 months of treatment at a given dose unless some other cause for liver disease als of hydroxy-3-methylglutaryl coenzyme (4). Another placebo-controlled trial, exists (4,10,11).
A reductase inhibitors, known as statins, with 20,536 participants over 5 years with were just getting started. Since then, statins 40 mg simvastatin, found no hepatitis in may be merely the result of lowering choles- have been observed to cause mild ALT ele- either group. The latter investigators con- terol and not a sign of tissue effect. Indeed, vations in 10% of recipients, and in 1–3% of cluded that “routine monitoring of liver there is up to a 3% incidence of transient, patients the elevations are more than three function tests during treatment with sim- reversible elevations of ALT that are char- vastatin 40 mg is not useful” (5).
acteristic of all the lipid-lowering agents, ALT testing is not specific to the liver; it For pravastatin, more than 19,000 including bile acid sequestrants, fibric acid was first discovered as a marker for acute patients were randomized to drug or derivatives, and nicotinic acid (11).
myocardial infarction in 1955 by Arthur placebo in three trials. Again, marked Karmen. Many organs, such as the heart, abnormalities of ALT or aspartate amino- tions, the development of a chronic liver muscle, and kidney, need to transfer amino transferase (AST) occurred with similar disease, such as that seen with isoniazid, acids to link protein and carbohydrate low frequency with pravastatin or placebo has not been seen. Moreover, no consistent metabolism. The liver is not responsible (≤1.2%) (6).
liver biopsy picture has arisen to represent for regulating the plasma activity of ami- A 2.5-year database survey in the United potential statin-induced hepatotoxicity (2).
notransferases, whose levels are the net Kingdom did not show any cases of acute result of release and degradation of enzyme hepatitis in 10,289 users of rosuvastatin. overall incidence of acute liver failure The definition of acute, not infectious or (ALF) in the United States. One estimate Is an isolated ALT elevation greater than alcoholic, hepatitis in this latter study was determined the idiopathic ALF rate to be three times the ULN a marker of statin-in- from 0.5 to 1.0 cases per million, and the duced liver injury? No. A lovastatin vs. pla- ogy guideline stated as “a clinical diagnosis incidence of possible statin-induced ALF of hepatitis requiring hospitalization, with to be 0.2 cases per million (11). Thus, one levels of serum ALT elevated to >three cannot tell whether statins are involved in 1Gastroenterology Section, Department of Medicine, VA Medical Center, University of Oklahoma Health Sciences Center, Oklahoma Atorvastatin is also without significant is especial y true when 10% of the adult City, Oklahoma, USA. Correspondence: Ted
population is taking statins, since, when a Bader, MD, FACG, VA Medical Center, University of Oklahoma Health Sciences Center, 921 NE Final y, in two placebo-controlled trials case of idiopathic ALF arises, 1 in 10 will 13th Street, Oklahoma City, Oklahoma 73104, with 2,106 patients, fluvastatin was found to be taking a statin by chance alone.
The American Journal of GastroenteroloGy
Volume 105 | may 2010 www.amjgastro.com
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Table 1. Summary of changes in liver-test recommendations on US Food and Drug Administration package inserts
Older package insert
Current package insert
(2001) LFTs before and at 6 and 12 weeks after start or elevation of (2009) LFTs before initiation of therapy in those with a history of liver disease or when otherwise clinically indicated (2000) LFTs before treatment and semiannually for first year or until 1 (2008) LFTs before treatment and then when clinically indicated (2001) LFTs before initiation of therapy, before elevation of dose, and (2007) LFTs before initiation of therapy and when otherwise (2001) LFTs before and at 12 weeks after the initiation of therapy and (2001) LFTs before initiation of therapy, after elevation of dose, and (2003) LFTs before and at 12 weeks after the initiation of therapy and any elevation of dose and periodically (e.g., semiannually) thereafter labels available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. lFT, liver-function test.
Simvastatin may become useful in the language about ALT monitoring for the consider statins to have any significant treatment of portal hypertension. Abraldes generic statins lovastatin, simvastatin, and hepatotoxicity. A national panel of liver and colleagues have extensively investi- pravastatin (Table 1). The most dramatic
experts concluded that aminotransferase gated simvastatin as an agent to treat portal change has occurred with lovastatin, for elevations associated with statin therapy hypertension (21). They recently reported which liver-function monitoring is no lon- are not evidence for liver damage or dys- trolled trial using 20–40 mg/d of simvasta- What about giving statins to patients with tin in 59 patients with advanced cirrhosis liver disease? Hyman Zimmerman, author and portal hypertension (wedged hepatic be better to continue ALT monitoring in of the first book on drug-induced hepato- venous pressure ≥12 mm Hg). A significant order to detect any possible damage that toxicity, stated, “A stubborn misconception lowering of portal hypertension (–8.3%) as might exist. However, the continued myth regarding susceptibility to hepatic injury has measured by hepatic venous pressure gra- of statin hepatotoxicity causes real harm been the view that patients with preexisting dient was noted (22).
on individual, group, and financial levels.
liver disease are more likely than others to I am not suggesting that statins are ready experience hepatic injury on exposure to to be recommended for treatment of liver asked me, a board-certified transplant drugs that cause liver damage” (13).
diseases but raise the topic to help turn the hepatologist, to see a 47-year-old man with tables about the suspicion of harm. Most familial hypercholesterolemia. The patient tain liver diseases. Randomized controlled physicians “know” statins cause hepatotox- had recently suffered a myocardial infarc- trials of statins have been started in non- icity because the package inserts contain tion, and his low-density lipoprotein (LDL) alcoholic steatohepatitis (NASH) after warnings about this problem. When I dis- two case series with NASH patients have cussed the lack of evidence of hepatotoxic- apy that lowered this patient’s LDL below shown histological and liver test improve- ity of statins with a high-ranking US Food 200 mg/dl (5.18 IU) was statin treatment. and Drug Administration (FDA) official Yet the cardiologist was adamant that the (who asked not to be quoted), the official statin be stopped for fear of hepatotoxic- ment of abnormal ALT levels in patients replied that the FDA is no longer con- ity because the ALT was minimally out of infected with hepatitis C virus (HCV) who cerned about statins causing hepatotoxic- range at 61 IU/l. It took some persuasion by have elevated ALT when the statin is started ity. When I asked why the package inserts the endocrinologist and me to convince the (16). We have also shown anti-HCV activity still contained the language, I learned that cardiologist that the benefit/risk ratio for of fluvastatin in chronic carriers of HCV in only the manufacturer can request a label the statin was greatly in favor of continuing change and the FDA can then consent to the statin.
virin had failed (17). Three retrospective the change; the agency cannot unilateral y studies have shown an increased sustained delete language on a package insert.
viral remission rate of HCV when statins Nonetheless, the FDA has responded is discontinued permanently because of were taken during peginterferon/ribavirin positively to manufacturers by agreeing elevated ALT, it is a practice that I com- to the omission and watering down of the monly encounter. One could estimate that 2010 by the american College of Gastroenterology The American Journal of GastroenteroloGy
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8. Arca M. Atorvastatin: a safety and tolerability Table 2. Cost assumptions for liver-function testing during statin use
profile. Drugs 2007;67(Suppl 1):63–9.
9. de Denus S, Spinler SA, Miller K et al. Statins Number of people in the United States taking statins in 2005a: 30 million and liver toxicity: a meta-analysis. Pharmaco- 10. Navarro VJ, Senior JR. Drug-related hepatotoxic- Cost per year of semiannual testsc: 30,000,000 × $50 × 2 = $3,000,000,000 11. Tolman K. Defining patient risks from expanded preventive therapies. Am J Cardiol 2000;85:15E– From 2000 to 2005, statin use doubled. The number of persons taking statins in 2010 is probably far greater. bCosts vary from $12 to $99; $50 was chosen as average. caccording to package inserts (see 12. Cohen DE, Anania FA, Chalasani N. An as- Table 1). This does not include tests performed before initiation of statin use and at 12 weeks after start
sessment of statin safety by hepatologists. Am J as recommended in several package inserts.
13. Zimmerman H. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the 1–10% of those taking statins (i.e., 300,000 with literal y billions of pil s taken. If there Liver, 2nd edn. Lippincott Williams & Wilkins: to 3,000,000) have been denied the benefit were patterns of liver damage caused by 14. Rallidis LS, Drakoulis CK, Parasi AS. Pravas- of statins as a result of unwarranted con- statins, these would surely have been seen tatin in patients with nonalcoholic steato- hepatitis: results of a pilot study. Atherosclerosis 15. Hyogo H, Tazuma S, Arihiro K et al. Efficacy of liver disease are denied statins. This is CONFLICT OF INTEREST
atorvastatin for the treatment of nonalcoholic il ustrated by the recent report that only Guarantor of the article: Ted Bader, MD,
steatohepatitis with dyslipidemia. Metabolism 2% of HCV patients in the Individualized FACG.
16. Madhoun MF, Bader T. Statins improve ALT Dosing Efficacy vs. Flat Dosing to Assess Financial support: None, and no editorial
values in chronic hepatitis C patients with abnor- Optimal Pegylated Interferon Therapy help.
mal values. Dig Di Sci 2010;55:870-1.
17. Bader T, Fazili J, Madhoun M et al. Fluvastatin (IDEAL) trial (n = 3,070) received sta- Potential competing interests: Dr Bader
inhibits hepatitis C replication in humans. Am J tins, when by current LDL guidelines 38% does not have financial connections with should have been on statins (S. Harrison, any pharmaceutical company, including 18. Bader T, Madhoun M, Rizvi S. Retrospective analysis of the effect of taking a statin along with peginterferon and ribavirin (PI plus R) on SVR. In 2005, 30 million people in the United support. Dr Bader and the University of Gastroenterology 2007;132:A788-A (abs).
States were taking statins—double the Oklahoma share a utility patent for the 19. Singh V, Carey E, Rudraraju M. Role of HMG- CoA reductase therapy in hepatitis C treatment number in 2000. The cost of semiannual possible use of statins in hepatitis B and C.
outcomes. Gastroenterology 2007;132(Suppl estimated to be $3 billion a year (Table 2) REFERENCES
20. Harrison SA, Rossaro L, Ke-Qin H et al. 1. Davidson C, Leevy C, Chamberlayne E (eds). Relationship of the use of statins and elevated (23,24). Although it is likely that physi- Guidelines for Detection of Hepatotoxicity Due low-density lipoprotein or total cholesterol cians do not comply well with these pack- to Drugs and Chemicals. NIH publication no. to virologic response in patients treated for age insert guidelines, whatever fraction of 79-313. National Institutes of Health: Bethesda, hepatitis C virus in the IDEAL study. Hepatology this number is chosen by the reader still 2. Tolman KG. The liver and lovastatin. ACC Curr 21. Zafra C, Abraldes J, Turne J et al. Simvastatin enhances hepatic nitric oxide production and de- the current medico-political climate, sav- 3. Mevacor [package insert]. Merck, 2009 <http:// creases the hepatic vascular tone in patients with www.accessdata.fda.gov/scripts/cder/drug- cirrhosis. Gastroenterology 2004;126:749–55.
ings by eliminating unnecessary tests are a 22. Abraldes JG, Albillos A, Bañares R et al. 4. Zocor [package insert]. Merck, 2008 <http:// Simvastatin lowers portal pressure in patients The most effective way to dispel the myth www.accessdata.fda.gov/scripts/cder/drug- with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology would be to allow the FDA a regulatory 5. MRC/BHF Heart Protection Study Col abora- tive Group, Armitage J, Bowman L, Collins R et 23. Stagnitti MN. Trends in Statins Utilization and language—a sort of “black box” in reverse. al. Effects of simvastatin 40 mg daily on muscle Expenditures for the U.S. Civilian Noninstitu- and liver adverse effects in a 5-year randomized tionalized Population, 2000 and 2005. Statistical placebo-controlled trial in 20,536 high-risk Brief #205. Agency for Healthcare Research lines could promulgate freedom from liver people. BMC Clin Pharmacol 2009;9:6.
and Quality: Rockville, MD, 2008 <http://www.
6. Pravachol [package insert]. Bristol–Myers meps.ahrq.gov/mepsweb/data_files/publications/ Squibb, 2007 <http://www.accessdata.fda.gov/ It is much more difficult to prove safety 24. Making More Cost-Effective Health Care than efficacy. The passage of time and the 7. Garcia-Rodriguez LA, Masso-Gonzalez EL, Choices Starts Here. Fallon Community Health Wal ander MA et al. The safety of rosuvasta- Plan: Worcester, MA, 2009 <http://www.fchp.
tin in comparison with other statins in over resent the best test of safety. Statins have 100,000 statin users in UK primary care. Phar- been on the market for more than 22 years, macoepidemiol Drug Saf 2008;17:943–52.
The American Journal of GastroenteroloGy
Volume 105 | may 2010 www.amjgastro.com

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Contents

The Water Economics in the Middle East Main Problems and Possible Solutions Contents 4. Water situation in each of the area’s countries. 6 5. Understandings and Treaties regarding water in the Middle East. 22 6. Means of improving the water situation in the Middle East . 26 a) Methods of increasing the quantity of water that do not require cooperation between the sides. 27 b)

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