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United States Patent (10) Patent No.: US 9.474,763 B2 Mograbi Et Al

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United States Patent (10) Patent No.: US 9.474,763 B2 Mograbi Et Al USOO9474763B2 (12) United States Patent (10) Patent No.: US 9.474,763 B2 Mograbi et al. (45) Date of Patent: Oct. 25, 2016 (54) COMPOSITIONS AND METHODS FOR 5: E: 3. Elects et al. AMELORATION AND PREVENTION OF 6.863,906 B2 3/2005 Henderson et al. DRUG-INDUCED TOXCITY 7,238,373 B2 7/2007 Meyrowitz 7,563,779 B2 7/2009 Henderson et al. (71) Applicants: Hadasit Medical Research Services E. R: 5399 Enberg et al. and Deyelopment Ltd., Jerusalem (IL). 2001/0000472J. I w A1* 4/2001 HendersonaWW ............. A61K 36,28 Josef Mograbi, Tel Aviv (IL) 424,725 2007/0021376 A1 1/2007 Giampapa (72) Inventors: Josef Mograbi, Tel Aviv (IL); Yaron 2011/O124718 A1* 5, 2011 McCain ................. A61K 36,28 Ilan, Jerusalem (IL) 514,452 2012/0022161 A1 1, 2012 Pavliv (73) Assignee: Hadasit Medical Research Services and Development Ltd., Jerusalem (IL) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this W. 29: A. 1939, patent is extended or adjusted under 35 WO 2011044230 A2 4, 2011 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 14/551,724 Lee, D., et al. “Molecular Structure and Stereochemistry of Silybin (22) Filed: Nov. 24, 2014 A. Silybin B, Isosilybin A, and Isosilybin B, Isolated from Silybum marianum (Milk Thistle).” J. Nat. Prod. (2003), vol. 66, pp. 1171 (65) Prior Publication Data 1174).* WebMD. "Acetaminophen Liver Damage Directory.' (C) Nov. 19, US 2015/OO8O348 A1 Mar. 19, 2015 2011. Available from: to Wii OSA-mannen acetaminophen-liver-damage-directory >. RxList.com. “Percocet.” (C) Jan. 14, 2012. Available from: <http:// Related U.S. Application Data web.archive.org/web/20120114190338/http://www.rxlist.com/ percocet-drug warnings-precautions.htm>. (63) Continuation of application No. McNeil-PPC. “Tylenol R. Sinus Congestion & Pain Caplets (Day PCT/IL2013/050446, filed on May 23, 2013. time).” (C) 2011. Available from: < http://www.tylenol.com/prod ucts/tylenol-sinus-congestion-pain-caplets-daytime D. (60) Provisional application No. 61/654,971, filed on Jun. McNeil-PPC. “Tylenol.R Cough and Sore Throat.” (C) 2010. Avail 4, 2012, provisional application No. 61/651,005, filed able from: < http://dailymed.nlm.nih.gov/dailymed/archives/ on May 24, 2012. fdalDrugInfo.cfm?archiveid=43326 >.* Drugs.com. "Acetaminophen/Diphenhydramine Dosage.' (c) Feb. (51) Int. Cl. 2012. Available from: < http://web.archive.org/web/ A 6LX 3L/357 (2006.01) 20120215211820/http://www.drugs.com/dosage/acetaminophen CO7D 309/36 (2006.01) diphenhydramine.html> - Drugs.com. "Acetaminophen and guaifenesin.” (C) Feb. 2009. Avail A6 IK3I/66 (2006.01) able from: < http://web.archive.org/web/20090201110251/http:// A6 IK 45/06 (2006.01) www.drugs.com/mtmfacetaminophen-and-guaifenesin.html D. A6 IK3I/It (2006.01) (Continued) A6 IK3I/I67 (2006.01) A6 IK3I/98 (2006.01) A6 IK3I/685 (2006.01) Primary Examiner — Andrew D. Kosar A6 IK3I/7056 (2006.01) Assistant Examiner — John S Kenyon A 6LX 3L/7076 (2006.01) (74) Attorney, Agent, or Firm — Vorys, Sater, Seymour A 6LX 3L/97 (2006.01) and Pease LLP (52) U.S. Cl. CPC ............. A61K3I/661 (2013.01); A61K 31/10 (57) ABSTRACT (2013.01); A61K 31/167 (2013.01); A61 K Pharmaceutical compositions including combinations of 31/197 (2013.01); A61K 31/198 (2013.01); protective agents selected from isosilybin B, methylsulfo A6 IK3I/357 (2013.01); A61 K3I/685 nylmethane (MSM), phosphatidylcholine, cysteine (Cys), (2013.01); A61 K3I/7056 (2013.01); A61 K seleno-cysteine (Se-Cys), ribose-cysteine (RibCys), N-ace 31/7076 (2013.01); A61K 45/06 (2013.01) tylcysteine (NAC), N-acetylcysteine-amide (AD4), methio (58) Field of Classification Search nine (Met) and S-adenosylmethionine (SAM) for reducing CPC ........................... A61 K 31/357; CO7D 309/36 and/or preventing drug-induced toxicity, Such as acetamino See application file for complete search history. phen-induced toxicity. The compositions may be formulated with or without acetaminophen, and accordingly may be (56) References Cited used as safe formulations of acetaminophen with reduced risk of causing liver damage, or as an antidote for the U.S. PATENT DOCUMENTS treatment of acetaminophen overdose. Methods for treating 4,868,114. A 9/1989 Nagasawa et al. acetaminophen intoxication. 6,495,170 B1 12/2002 Smit et al. 6,555,141 B1 4/2003 Corson et al. 8 Claims, 5 Drawing Sheets US 9,474,763 B2 Page 2 (56) References Cited Nourjah et al., (2006) Estimates of acetaminophen (Paracetomal)- associated overdoses in the United States. Pharmacoepidemiol Drug Saf 15(6): 398-405. OTHER PUBLICATIONS O'Riordan et al., (2011) Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced Bessems and Vermeulen (2001) Paracetamol (acetaminophen)-in hepatotoxicity. Nephrol Dial Transplant 26(11): 3501-8. duced toxicity: molecular and biochemical mechanisms, analogues Ostapowicz et al., (2002) Results of a prospective study of acute and protective approaches. Crit Rev Toxicol 31(1): 55-138. liver failure at 17 tertiary care centers in the United States. Ann Blakely and McDonald (1995) Acute renal failure due to acetamino Intern Med 137(12): 947-54. phen ingestion: a case report and review of the literature. JAm Soc Polyaket al., (2010) Identification of hepatoprotective Nephrol 6(1): 48-53. flavonolignans from silymarin. Proc Natl AcadSci U S A 107(13): Bower et al., (2007) Population-based surveillance for acute liver 5995-9. failure. Am J Gastroenterol 102(11): 2459-63. Rakela et al., (1985) Fulminant hepatitis: Mayo Clinic experience Bray et al., (1992) S-adenosylmethionine protects against acet with 34 cases. Mayo Clin Proc 60(5): 289-92. aminophen hepatotoxicity in two mouse models. Hepatology 15(2): Slitt et al., (2005) Effect of ribose cysteine pretreatment on hepatic 297-301 and renal acetaminophen metabolite formation and glutathione Chassaing et al., (1999) Determination of reduced and oxidized depletion. Basic Clin Pharmacol Toxicol 96(6): 487-94. homocysteine and related thiols in plasma by thiol-specific pre Stern et al., (2005) Contribution of acetaminophen-cysteine to column derivatization and capillary electrophoresis with laser acetaminophen nephrotoxicity II. Possible involvement of the induced fluorescence detection. J Chromatogr B Biomed Sci Appl gamma-glutamyl cycle. Toxicol Appl Pharmacol 202(2): 160-71. 735(2): 219-27. Stern et al., (2005) Contribution of acetaminophen-cysteine to Chun et al., (2009) Acetaminophen hepatotoxicity and acute liver acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of failure. J Clin Gastroenterol 43(4): 342-9. acetaminophen nephrotoxicity by acetaminophen-cysteine. Toxicol Darbar et al., (2011) Antihepatoprotective potential of Livina, a Appl Pharmacol 202(2): 151-9. polyherbal preparation on parcetamol induced hepatotoxicity: a FDA, "Acetaminophen Overdose and Liver Injury Background comparison with Silymarin. Asian Journal of Pharmaceutical and and Options for Reducing Injury'; dated May 22, 2009. Retrieved Clinical Research 4(1): 72-77. from the internet on Mar. 14, 2012. Dvorák et al., (2003) Primary cultures of human hepatocytes as a Legalon SIL Mushroom Poisoning Clinical Study. URL: https:// tool in cytotoxicity studies: cell protection against model toxins by sites.google.com/site/legalonsil?; retrieved on Dec. 28, 2011. flavonolignans obtained from Silybum marianum. Toxicol Lett Wiley Blackwell. “Milk thistle herb protects cancer patients from 137(3): 201-12. chemotherapy-associated liver toxicity.” ScienceDaily. Kaufman et al., (2002) Recent patterns of medication use in the ScienceDaily, Dec. 27, 2009. www.sciencedaily.com/releases/2009/ ambulatory adult population of the United States: the Slone survey. 12/091215172325.htm. JAMA 287(3): 337-44. Jaeschke et al., (2003) The role of oxidant stress and reactive Khashab et al., (2007) Epidemiology of acute liver failure. Curr nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett Gastroenterol Rep 9(1): 66-73. 144(3): 279-288. Lai et al., (2006) 2005 Annual Report of the American Association Nakhostin-Roohi et al., (2011) Effect of chronic supplementation of Poison Control Centers' national poisoning and exposure data with methylsulfonylmethane on oxidative stress following acute base. Clin Toxicol (Phila) 44(6-7): 803-932. exercise in untrained healthy men. J Pharm Pharmacol 63(10): Larson et al., (2005) Acetaminophen-induced acute liver failure: 1290-1294. results of a United States multicenter, prospective study. Hepatology Woodhead et al., “An analysis of N-acetylcysteine treatment for 42(6): 1364-72. acetaminophen overdose using a systems model of drug-induced Lee (2003) Acute liver failure in the United States. Semin Liver Dis liver injury”, J Pharmacol Exp Ther, vol. 342, No. 2, pp. 529-540, 23(3): 217-26. (2012). Murray et al., (2008) Drug-related hepatotoxicity and acute liver failure. J Pediatr Gastroenterol Nutr 47(4): 395-405. * cited by examiner U.S. Patent Oct. 25, 2016 Sheet 1 of 5 US 9,474,763 B2 4 mg APAP 4 mg APAP+ 4 mg APAP+ 4 mg APAP+ 3.5 mg NAC 3.5 mg NAC+ 3.5 mg NAC+ 0.4 mg IB 0.1 mg IB FIGURE 1 4 mg APAP 4 mg APAP+ 4 mg APAP+ 4 mg APAP+ 3 mg NAC 3 mg NAC+ 3 mg NAC+ 0.7 mg PC 0.7 mg PC after 1.5 h after 3 h FIGURE 2 U.S. Patent Oct. 25, 2016 Sheet 2 of 5 US 9,474,763 B2 4 mg APAP 4 mg APAP+ 4 mg APAP+ 3.5 mg NAC 3.5 mg NAC, 3h later: 0.9 mg of PC FIGURE 3 4 mg APAP 4 mg APAP+ 4 mg APAP+ 3.5 mg NAC 3.5 mg NAC, 1.5 mg MSM FIGURE 4 U.S. Patent Oct. 25, 2016 Sheet 3 of 5 US 9.474,763 B2 400 - 350 - 300 - 250 - 200 - 150 - 100 - 50 - Average SD APAP 259.98 56.39 APAP + MSM 255.30 108.78 APAP +B 229.27 119.85 APAP + MSM - B 253.39 62.78 FIGURES U.S.
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