A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration

BMC Clinical Pharmacology

Richard C Dart³  Becki Bucher-Bartelson⁴  Victoria Anderson¹  Jody L Green²  Kennon Heard³ 

[1] Rocky Mountain Poison and Drug Center, Denver Health, Denver, CO, USA;Vanderbilt School of Nursing, Nashville, TN, USA;University of Colorado Department of Emergency Medicine, Aurora, CO, USA;Colorado School of Public Health, Aurora, CO, USA

关键词: Hepatotoxicity;    Drug-induced liver injury;    Alanine aminotransferase;   

Others  :  1084935
DOI  :  10.1186/2050-6511-15-39

 received in 2014-03-16, accepted in 2014-07-08,  发布年份 2014

【 摘 要 】

Background

Acetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days.

Methods

A randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction.

Results

157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction.

Conclusions

A minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued.

Trials registration

Clintrials.govNCT00743093 registered August 26, 2008

【 授权许可】

   
2014 Heard et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Dart RC, Bailey E: Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 2007, 27:1219-1230.
• [2]Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, Smith PC, Tennant R, Bogue M, Paigen K, Harris C, Contractor T, Wiltshire T, Rusyn I, Threadgill DW: Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 2009, 19:1507-1515.
• [3]Heard K, Green JL, Bailey JE, Bogdan GM, Dart RC: A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol. Aliment Pharmacol Ther 2007, 26:283-290.
• [4]Heard KJ, Green JL, Dart RC: Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers. Pharmacotherapy 2010, 30:818-822.
• [5]Parra D, Beckey NP, Stevens GR: The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007, 27:675-683.
• [6]Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC: Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006, 296:87-93.
• [7]Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI: Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991, 325:87-91.
• [8]Kuffner EK, Temple AR, Cooper KM, Baggish JS, Parenti DL: Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials. Curr Med Res Opin 2006, 22:2137-2148.
• [9]Pincus T, Koch GG, Sokka T, Lefkowith J, Wolfe F, Jordan JM, Luta G, Callahan LF, Wang X, Schwartz T, Abramson SB, Caldwell JR, Harrell RA, Kremer JM, Lautzenheiser RL, Markenson JA, Schnitzer TJ, Weaver A, Cummins P, Wilson A, Morant S, Fort J: A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum 2001, 44:1587-1598.
• [10]Temple AR, Benson GD, Zinsenheim JR, Schweinle JE: Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther 2006, 28:222-235.
• [11]Altman RD, Zinsenheim JR, Temple AR, Schweinle JE: Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage 2007, 15:454-461.
• [12]Prescott LF: Therapeutic misadventure with paracetamol: fact or fiction? Am J Ther 2000, 7:99-114.
• [13]Gronbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sorensen TI: Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med 2000, 133:411-419.
• [14]Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf webcite
• [15]Singer AJ, Carracio TR, Mofenson HC: The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction. Ann Emerg Med 1995, 26:49-53.
• [16]Maheshwari A, Ray S, Thuluvath PJ: Acute hepatitis C. Lancet 2008, 372:321-332.
• [17]Kechagias S, Ernersson A, Dahlqvist O, Lundberg P, Lindstrom T, Nystrom FH: Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut 2008, 57:649-654.
• [18]Sudano I, Flammer AJ, Periat D, Enseleit F, Hermann M, Wolfrum M, Hirt A, Kaiser P, Hurlimann D, Neidhart M, Gay S, Holzmeister J, Nussberger J, Mocharla P, Landmesser U, Haile SR, Corti R, Vanhoutte PM, Lüscher TF, Noll G, Ruschitzka F: Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation 2010, 122:1789-1796.
• [19]Narjes H, Nehmiz G: Effect of hospitalisation on liver enzymes in healthy subjects. Eur J Clin Pharmacol 2000, 56:329-333.
• [20]Mitchell SJ, Hilmer SN, Murnion BP, Matthews S: Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty. J Clin Pharm Ther 2011, 36:327-335.
• [21]Lavonas EJ, Reynolds KM, Dart RC: Therapeutic acetaminophen is not associated with liver injury in children: a systematic review. Pediatrics 2010, 126:e1430-e1444.
• [22]Senior JR: Monitoring for hepatotoxicity: what is the predictive value of liver "function" tests? Clin Pharmacol Ther 2009, 85:331-334.
• [23]Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD: Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004, 126:1287-1292.
• [24]Nolan CM, Goldberg SV, Buskin SE: Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999, 281:1014-1018.
• [25]Pollak PT, Shafer SL: Use of population modeling to define rational monitoring of amiodarone hepatic effects. Clin Pharmacol Ther 2004, 75:342-351.
• [26]Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW: Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994, 271:992-998.
• [27]Olsson R, Korsan-Bengtsen BM, Korsan-Bengtsen K, Lennartsson J, Waldenstrom J: Serum aminotransferases after low-dose heparin treatment. Short communication. Acta Med Scand 1978, 204:229-230.
• [28]Tolman KG: The liver and lovastatin. Am J Cardiol 2002, 89:1374-1380.