Ethnobotanical Leaflets 12: 286-298. 2008.
Will Herbal-Paracetamol Combination Drug Prevent both Liver and Kidney Disease? - Results and Possibilities
Anjali Sharma, Mukesh Makwana and H.S. Rathore*
Cell Biology Unit, School of Studies in Zoology and Biotechnology
Vikram University, Ujjain 456010. India
*Contact: [email protected]
Issued 24 May 2008
An attempt has been made to briefly review the existing information on herbal compounds which could combat acetaminophen (paracetamol) toxicity. A careful perusal of literature revealed that acetaminophen overdose not only damages liver but also the kidney. Nevertheless, the kidney was badly ignored in studies aimed at preventing paracetamol toxicity with herbal drugs. On account of such major neglect, so far no herbal-paracetamol combination could be made. Milk thistly is only well researched drug which appears as a suitable future candidate, but its action towards the kidney must be studied. The importance of such studies in the future is discussed.
Key words: Acetaminophen/paracetamol, hepatoxicity, Nephrotoxicity, Herbal Drugs/combination.
Acetaminophen (Paracetamol: N-acetyl-p-aminophen) is an effective analgesic - antipyretic drug which is often used to treat pain and fever. Acetaminophen is available without prescription in many parts of the world (Goodman and Gilman 1996).
The most serious adverse effect of acute overdose of acetaminophen is dose-dependent, potentially fatal hepatic necrosis (Thomas 1993) which may be associated with renal tubular necrosis (Goodman and Gilman 1996). The number of self poisoning suicides with acetaminophen has grown alarming in recent years (Goodman and Gilman 1996; Gyamlani and Parikh 2002). According to a study in USA paracetamol was found to be associated with more than 10, 00, 00 cases of poisoning, 56000 visits to emergency departments, 26000 hospitalization and 450 deaths a year (BMJ 2002). Also acetaminophen was the drug most commonly taken in United Kingdom (Howton et al 1997) causing substantial number of deaths (Bray 1993). Cases of overdoses of acetaminophen in India are also not uncommon (Sharka et al. 1999).
The principal antidotal treatment is the administration of sulphydryl compound like N-acetyl-cysteine which act by replenishing hepatic stores of glutathione. This drug is effective only if given orally or intravenously within less than 10 hours after ingestion (Smilkstein et al 1988).
BRIEF REVIEW OF EXISTING REPORTS
In the past, several herbal compounds have also been screened to test their ability to reduce and / or nullify acetaminophen induced hepatotoxicity. These reports are given subsequently. It is of interest to mention here that only in two studies both liver and kidney were taken into consideration (Lee et al. 2002 and Bagchi et al. 2002) otherwise the kidney is badly ignored. However, quite earlier it was suggested that special caution should be taken in patients with liver and kidney disease while using paracetamol (Brzeznicka and Piotrowsi 1989).
BRIEF REVIEW OF EXISTING REPORTS
Only for brevity and convenience current status of knowledge on herbal drugs versus paracetamol poisoning is discussed under following separate headings:
1. Many factors enhance paracetamol toxicity:
Alcohol, many drugs rifampicin, phenobarbital, isoniazid, phenytoin and carbamazepin increase paracetamol toxicity (Whitecomb and Block, 1994: Willacy, 2007). Even fasting greatly increases the chances of liver damage by paracetamol (White comb and Block, 1994). Tobacco is found as an independent risk factor in paracetamol poisoning (Schmidt and Dalhoff, 2003).
2. Some herbal drugs can reduce paracetamol toxicity
Chinese medicine Artemisia asiatica. & A. Maritima (DA-9601) has been reported to reduce liver damage induced by paracetamol (Ryu et al., 1998, Janbaz and Gilani, 1995). Another chinese herbal medicine 'gomsin-A', a lignan component of Schisandra chinesis has also been reported to be hepatoprotective against paracetamol. It must be noted that inadequate clinical research with human subjects has been conducted on these herbal drugs to confirm the value of these herbal therapies against the toxic side effects of paracetamol (IBIS medical com., 2000). A literature review on herb-drug interaction also mentions that reported herb-drug interactions were based on case reports and were of limited clinical observations (Hu et al., 2005). On account of such badly ignored limited clinical observations on herb-drug interaction so far no herbal paracetamol combination drug could be made. On the contrary recently nitroparacetamol (NCX-701) has been introduced as a novel analgesic drug (Sandoval et al., 2007). Silybum marianum (milk thistle) reduces paracetamol induced hepatotoxiciy in animals. This is a well research herbal drug in animals and humans and has good future (Pradhan and Girish, 2006) but its preventive action towards kidney needs detail studies.
3. Problem in developing country like India:
In developing country like India where self medication with herbal and other drugs without prescription is a common practice hence chances of accidental or intentional overdose always exists. Moreover general public is not aware of drug abuse and its antidotal management under such circumstances paracetamol induced liver and kidney damage may go unnoticed and affected individual may die. Citizen and villagers know use paracetamol but none of them know about its hepatonephrotoxicity and about its principal antidotal drug N-acetylcysteine.Liver transplantation is also out of reach of general public. This drug is effective only when administrated within 10 hours of paracetamol poisoning and this drug is not available every where in India.
It is needless to say that paracetamol induced hepatonephrotoxicity and its management with herbal drugs also deserves serious attention, no matter, renal insufficiency occurs in about 1-2 percent cases of paracetamol overdose.
Authors respectfully thank Council of Scientific and Industrial Research, New Delhi for providing fellowship and grants to Miss Anjali Sharma and to University Grants Commission, New Delhi for providing Rajiv Gandhi National Fellowship and grants to Mr. Mukesh Makwana. Departmental Facilities are also acknowledged.
<![if !supportLists]>1. Acetaminophen, 2000 IBIS: Integrative Body Mind Information System IBIS Medical.com.
<![if !supportLists]>2. Ahmed, MB, Khater, MR 2001. Evaluation of the protective potential of Ambrosia maritima extract on acetaminophen- induced liver damage. J Ethnopharmacol. 75 (2-3): 169-74.
<![if !supportLists]>3. Akintonwa, A, Essien, AR. 1990. Protective effects of Garcinia Kola seed extract against paracetamol - induced hepatotoxicity in rats. J Ethnopharmacol 29(2): 207-11.
<![if !supportLists]>4. Ali, BH, Bashir, AK, Rasheed, RA. 2001. Effect of the traditional medical plants Rhazya stricta, Balanitis aegyptiaca and Haplophylum tuberculatum on paracetamol induced hepatotoxicity in mice. Phytother Res. 15(7): 598-603.
<![if !supportLists]>5. Ansari, RA, Tripathi, SC, Patnaik, GK, Dhawan, BN. 1991. Antihepatotoxic properties of picroliv: an active fraction from rhizomes of Picrorhiza kurrooa. J Ethnopharmacol. 34(1): 61-68.
<![if !supportLists]>6. Bagchi, D, Bagchi, M, Stohs, S, Ray, SD, Sen, CK, Preuss, HG. 2002. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci. 957: 260-70.
<![if !supportLists]>7. Baheti, JR, Goyal, RK, Shah, GB. 2006. Hepatoprotective activity of Hemidesmus indicus in rats. Indian J Exp Biol. 44(5): 399-402.
<![if !supportLists]>8. Bhakta, T, Banerjee, S, Mandal, SC, Maity, TK, Saha, BP, Pal, M. 2001. Hepatoprotective activity of Cassia fistula leaf extract. Phytomedicine 8(3): 220-4.
<![if !supportLists]>9. Bhattacharyya, D, Pandit, S, Mukherjee, R, Das, N, Sur, TK. 2003. Hepatoprotective effect of Himoliv, a polyherbal formulation in rats. Indian J Physiol & Pharmacol. 47 (4): 435-40.
<![if !supportLists]>10. BR, YV, JA, NH, MG, VR 2008. Protective effect of Phyllanthus polyphyllus on acetaminophen induced hepatotoxicity in rats. Pak J Pharm Sci. 21(1): 57-62.
<![if !supportLists]>11. Brey, G. 1993. Liver failure induced by paracetamol. BMJ. 306: 157-158.
<![if !supportLists]>12. Chattopadhyay, RR, Sarkar, SK, Ganguly, S, Banerjee, RN, Basu, TK, Mukherjee, A. 1992. Hepatoprotective activity of Azadirachta indica leaves on paracetamol induced hepatic damage in rats. Indian J Exp Biol 30(8): 738-40.
<![if !supportLists]>13. Chaturvedi, P, George, S, Machacha, CN. 2007. Protective role of Raphanus sativus root extract on paracetamol induced hepatotoxicity in albino rats. Int J Vitam Nutr Res.77(1):41-5
<![if !supportLists]>14. Cheng, TJ, Pu, JK, Wu, LW, Ma, ZR, Cao, Z, Li, TJ. 1994. A preliminary study on hepato-protective action of seed oil of Hippophae rhamnoides L. (HR) and mechanism of the action. Zhongguo Zhong Yao Za Zhi. 19(6): 367-70.
<![if !supportLists]>15. Chin, HW, Lin, CC, Tang, KS. 1996. The hepatoprotective effects of Taiwan folk medicine ham-hong-chho in rats. Am J Chin med 24(3-4) : 231-40.
<![if !supportLists]>16. Datta, S, Bhattacharyya, P. 2001. Effect of a herbal protein CI-1, purified from Cajanus indicus on the ultrastructural study of hepatocytes, in models of liver failure in mice. J Ethnopharmacol. 77(1): 11-8.
<![if !supportLists]>17. Devi, KP, Sreepriya, M, Balakrishna, K, Veluchamy, G, Devaki, T. 2004. Assessment of the protective potential of Premna tomentosa (L. Verbenaceae) extract on lipid profile and lipid-metabolizing enzymes in acetaminophen intoxicated rats. J Altern Complement Med. 10(3) : 540-6.
<![if !supportLists]>18. Donatus, IA, Sardjoko, Vermeulen NP. 1990. Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes.Biochem Pharmacol.39(12):1869-75
<![if !supportLists]>19. Echard, BW, Talpur, NA, Fan, AY, Bagchi, D, Preuss, HG. 2001. Hepato protective ability of a novel botanical formulation on mild liver injury in rats produced by acute acetaminophen and / or alcohol ingestion. Res Commun Mol Pathol Pharmacol. 110(1-2): 73-85.
<![if !supportLists]>20. Emmanuel, S, Amalraj, T, Ignacimuthu, S. 2001. Hepatoprotective effect of coumestans isolated from the leaves of Wedelia calendulacea Linn. in paracetamol induced liver damage. Indian J Exp Biol.39(12):1305-7
<![if !supportLists]>21. FAD. 2002. Effects of legislation restricting pack sizes of paracetamol and poisoning in the United Kingdom: before and after study. British Medical Journal. 28: 325(7366), 678.
<![if !supportLists]>22. Gamal el-din, AM, Mostafa, AM, Al-Shabanah, OA, Al-Bekairi, AM, Nagi, MN. 2003. Protective effect of arabic gum against acetaminophen- induced hepatotoxicity in mice. Pharmacol Res. 48 (6): 631-5.
<![if !supportLists]>23. Gilani, AH, Janbaz, KH, Akhatar, MS. 1996. Selective protective effect of an extract from Fumaria parviflora on paracetamol- induced hepatotoxicity. Gen Pharmacol 27(6): 979-83.
<![if !supportLists]>24. Gilani, AH, Janbaz, KH. 1993. Protective effect of Artemisia scoparia extract against acetaminophen induced hepatotoxicity. Gen Pharmacol. 24(6) : 1455-8.
<![if !supportLists]>25. Gilani, AU, Janbaz, KH. 1995. Studies on protective effect of Cyperus scariosus extract on acetaminophen and CCl4 - induced hepatotoxicity. Gen Pharmacol 26 (3) : 627-31.
<![if !supportLists]>26. Gupta, Malaya, Mazumder, Upal Kanti, Kumar, Thangavel Siva, Gomathi, Periyasamy, Kumar, Ramnathan Sambath. 2004. Antioxidant and Hepatoprotective Effects of Bauhinia racemosa against Paracetamol and Carbon tetra-chloride Induced Liver Damage in Rats. Iranian Journal of Pharmacology and Therapeutics 3(1): 12-20.
<![if !supportLists]>27. Gyamlani, G.G. and Parikh, C.R. 2002. Acetaminophen toxicity: Suicidal vs accidental. Crit care. 6(2): 155-159.
<![if !supportLists]>28. Han, KH, Fukushima, M, Ohba, K, Shimada, K, Sekikawa, M, Chiji, H, Lee, CH, Nakano, M. 2004. Hepatoprotective effects of the water extract from adzuki bean hulls on acetaminophen induced damage in rat liver. J Nutr Sci Vitaminol . 50(5): 380-3.
<![if !supportLists]>29. Handa, SS, Sharma, A. 1990. Hepatoprotective activity of andrographolide against galactosamine & paracetamol intoxication in rats. Indian J Med Res. 92: 284-92.
<![if !supportLists]>30. Hawton, K., Fagg, J., Simikin, S., Bale, E. and Bond, A. 1997. Trends in deliberate self harm in Oxford 1985-95. Br. J. Psychiatry. 171: 556-560.
<![if !supportLists]>31. Hittori, A, Yamada, N, Nishikawa, T, Fukuda, H, Fujino, T. 2001. Protective effect of ajoene on acetaminophen - induced hepatic injury in mice. Biosci Biotechnol Biochem. 65(11): 2555-7.
<![if !supportLists]>32. Hu,Z,Yang,X,Ho,PC,Chan,SY,Heng,PW,Chan,E,Duan,W, Koh,HL,Zhou, S.2005 Herb-drug interactions-a literature review.Drugs.65(9):1239- 82
<![if !supportLists]>33. Insel, A. Paul. 1996. Analgesic and antipyretic and anti-inflammatory agents and drug employed in the treatment of Govt. In: Goodman and Gilman's The Pharmacological basis of therapeutics 9th edition McGraw-Hill, USA. pp. 631-633.
<![if !supportLists]>34. Iwalokun, BA, Efedede, BU, Alabi-Sofunde JA, Oduala, T, Magbagbeola, OA, Akinwande, AI. 2006. Hepatoprotective and antioxidant activities of Vernonia amygdalina on acetaminophen induced hepatic damage in mice. Med Food. 9(4):524-30
<![if !supportLists]>35. Jafri, MA, Jalis, Subhani, M, Javed, K, Singh, S. 1999. Hepatoprotective activity of leaves of Cassia occidentalis against paracetamol and ethyl alcohol intoxication in rats. J Ethnopharmacol 66(3) : 355-61.
<![if !supportLists]>36. Janbaz, KH, Gilani, AH. 1995. Evaluation of the protective potential of Artemisia maritima extract on acetaminophen- and CCl4- induced liver damage. J Ethanopharmacol. 47(1): 43-7.
<![if !supportLists]>37. Janbaz, KH, Gilani, AH. 2000. Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents. Fitoterapia. 71(1): 25-33.
<![if !supportLists]>38. Janbaz, KH, Gilani, AH. 2002. Menthol prevents liver damage induced by paracetamol and CCl4. Pakistan Journal of Biological Sciences 5(10): 1101-1103.
<![if !supportLists]>39. Janbaz, Khalid H., Saeed, Sheikh A., Gilani, Anwar H. 2002. Protective effect of rutin on paracetamol and CCl4 induced hepatotoxicity in rodents. Fitoterapia 73:557-563.
<![if !supportLists]>40. Karan, M, Vasisht, K, Handa, SS. 1999. Antihepatotoxic activity of Swertia chirata on paracetamol and galactosamine induced hepatotoxicity in rats. Phytother Res. 13(2): 95-101.
<![if !supportLists]>41. Kim, ST, Kim, JD, Ahn, SH, Ahn, GS, Lee, YI, Jeong, YS 2004. Hepatoprotective and antioxidant effects of Alnus Japonica extracts on acetaminophen induced hepatotoxicity in rats. Phytother Res. 18(12): 971-5.
<![if !supportLists]>42. Kim, YW, Ki, SH, Lee, JR, Lee, SJ, Kim, CW, Kim, SC, Kim, SG. 2006. Liquiritigenin, an aglycone of liquiritin in Glycyrrhizae radix, prevents acute liver injuries in rats induced by acetaminophen with or without buthionine sulfoximine. Chem Biol Interact. 161(2): 125-38.
<![if !supportLists]>43. Ko, YJ, Hsieh, WT, Wu, YW, Lin, and WC. 2002. Ameliorative effect of Silene aprica on liver injuries induced by carbon tetrachloride and acetaminophen. Am J Chin Med. 30 (2-3): 235-43.
<![if !supportLists]>44. Kumar, G, Banu, GS, Pappa, PV, Sundararajan, M, Pandian, MR. 2004. Hepatoprotective activity of Trianthema portulacastrum L. against paracetamol and thioacetamide intoxication in albino rats. J Ethnopharmacol 92(1): 37-40.
<![if !supportLists]>45. Lee, SC, Tsai, CC, Chen, JC, Lin, JG, Lin, CC, Hu, ML, Lu, S. 2002. Effects of "Chinese Yam" on hepato-nephrotoxicity of acetaminophen in rats. Acta pharmacol Sin. 23(6): 503-8.
<![if !supportLists]>46. Lin, CC, Hsu, YF, Lin, TC, Hsu, HY. 2001. Antioxidant and hepatoprotective effects of punicalagin and punicalin on acetaminophen- induced liver damage in rats. Phytother Res. 15(3): 206-12.
<![if !supportLists]>47. Lin, CC, Huang, PC, Lin, JM. 2000. Antioxidant and hepatoprotective effects of Anoectochilus formosanus and Gynostemma pentaphyllum, Am J Chin Med. 28(1) : 87-96.
<![if !supportLists]>48. Lin, CC, Huang, PC. 2000. Antioxidant and hepatoprotective effects of Acathopanax senticosus. Phytother Res. 14(7): 489-94.
<![if !supportLists]>49. Lin, CC, Shieh, DE, Yen, MH, 1997. Hepatoprotective effect of the fractions of Ban-zhi-lian on experimental liver injuries in rats. J Ethnopharmacol. 56(3) : 193-200.
<![if !supportLists]>50. Lin, CC, Tsai, CC, Yen, MH 1995. The evaluation of hepatoprotective effects of Taiwan folk medicine 'teng-khia-u'. J Ethnopharmacol. 45(2): 113-23.
<![if !supportLists]>51. Lin, SC, Lin, CC, Lin, YH, Shyuu, SJ. 1994. Hepatoprotective effects of Taiwan folk medicine : wedelia chinensis on three hepatotoxin induced hepatotoxicity. Am J Chin Med. 22(2): 155-68.
<![if !supportLists]>52. Lin, TH, Ng, LT, Yen, FL, Lin, CC. 2007. Hepatoprotective effects of Chai-Hu-Ching-Kan-Tang an acetaminophen- induced acute liver injury in rats. Am J Chin Med. 35(1): 69-79.
<![if !supportLists]>53. Mandal, SC, Saraswathi, B, Kumar, CK, Mohana Lakshmi, S. Maiti, BC. 2000. Protective effect of leaf extract of Ficus hispida Linn. against paracetamol induced hepatotoxicity in rats. Phytother Res. 14(6): 457-9.
<![if !supportLists]>54. Mroueh, Mohamad, Saab, Yolande and Rizkallah, Raed. 2004. Hepatoprotective Activity of Centaurium erythraea on Acetaminophen- induced Hepatotoxicity in Rats. Phytotherapy Research. 18:431-433.
<![if !supportLists]>55. Muriel, P, Garciapina, T, Perez-Alvarez, V,Mourelle,M.1992.Silymarin protects against paracetamol-induced lipid peroxidation and liver damage.J.Appl Toxicol.12 (6):439-442.
<![if !supportLists]>56. Murugesh, Kanda Samy, Yeligar, Veerendra, Channabasappa, Maiti, Bhim Charan and Maity, Tapan Kumar. 2005. Hepatoprotective and Antioxidant role of Berberis tinctoria Lesch leaves on paracetamol induced hepatic damage in rats. Iranian Journal of Pharmacology and therapeutics 4:64-69.
<![if !supportLists]>57. Oliveira, FA, Chaves, MH, Almeida, FR, Lima, RC Jr. Silva, RM, Maia, JL,Brito, GA, Santos, FA, Rao, VS. 2005. Protective effect of alpha-and beta-amyrin, a triterpene mixture from Protium heptaphyllum (Aubl.) March. trunk wood resin, against acetaminophen induced liver injury in mice. J Ethnopharmacol, 98(1-2): 103-8.
<![if !supportLists]>58. Pandey, Govind, Srivastava, DN, Sharma, Madhuri. 2006. Hepatogenic effect of Livol, Eclipta alba and Silybum marianum on paracetamol induced liver damage in rabbits. International Journal of Green Pharmacy 1(1): 35-38.
<![if !supportLists]>59. Parial, Swapnadeep, Goel, RK, Jain, Amit K. 2006. Hepatoprotective activity of latex of Carica papaya L. on drug induced hepatotoxicity. International journal of Green Pharmacy 1(1) : 43-45.
<![if !supportLists]>60. Porchezhian, E, Ansari, SH. 2005. Hepatoprotective activity of Abutilon indicum on experimental liver damage in rats. Phytomedicine 12(1-2): 62-4.
<![if !supportLists]>61. Pradhan, SC, Girish, C.2006.Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res 124:491-504
<![if !supportLists]>62. Raghavendran, HR, Sathivel, A, Devaki, T. 2005. Protective effect of Sargassum polycystum (brown alga) against acetaminophen induced lipid peroxidation in rats. Phytother Res. 19(2) : 113-5.
<![if !supportLists]>63. Rao, H Balaji Raghavendra, Sathivel, A, Devaki, T. 2004. Antihepatotoxic nature of Ulva reticulata (Chlorophyceae) on acetaminophen- induced hepatotoxicity in experimental rats. J Med Food 7(4): 495-7.
<![if !supportLists]>64. Rasheed, RA, Ali, BH, Bashir, AK. 1995. Effect of Teucrium stocksianum on paracetamol induced hepatotoxicity in mice. Gen Pharmacol 26(2): 297-301.
<![if !supportLists]>65. Ray, SD, Patel, D, Wong, V, Bagchi, D. 2000. In vivo protection of DNA damage associated apoptotic and necrotic cell deaths during acetaminophen induced nephrotoxicity, amiodarone induced lung toxicity and dexorubicin induced cardiotoxicity by a novel IH 636 grape seed proanthocyanidin extract. Res Commun Mol Pathol Pharmacol. 107(1-2): 137-66.
<![if !supportLists]>66. Reen, RK, Karan, M, Singh, K, Karan, V, Johri, RK, Singh, J. 2001. Screening of various Swertia species extracts in primary monolayer cultures of rat hepatocytes against carbon tetrachloride and paracetamol- induced toxicity. J Ethnopharmacol. 75 (2-3) : 239-47.
<![if !supportLists]>67. Romero-Sandoval,EA,Curros-Criado,MM,Gaitan,G,Molina,C,Herrero,JF.2007 Nitroparacetamol(NCX-701) and pain:first in a series of novel analgesics.CNS Drug Rev.13(3):279-95.
<![if !supportLists]>68. Roy, CK, Kamath, JV. Asad, M. 2006: Hepatoprotective activity of Psidium guajava Linn. leaf extract. Indian J Exp Biol. 44(4): 305-11.
<![if !supportLists]>69. Rusu, MA, Bucur, N, Puica, C, Tamas, M. 1999. Effect of Corylus avellana in acetaminophen and CCl4 induced toxicosis. Phytother Res. 13(2): 120-3.
<![if !supportLists]>70. Ryu, BK, Ahn, BO, Oh, TY, Kim, SH, Kim, WB, Lee, EB. 1998. Studies on protective effect of DA-9601, Artemisia asiatica extract, on acetaminophen and CCl4 induced liver damage in rats. Arch Pharm Res. 21(5): 508-513.
<![if !supportLists]>71. Sadasivan, S, Latha, PG, Sasikumar, JM, Rajashekaran, S. Shyamal, S. Shine, VJ. 2006. Hepatoprotective studies on Hedyotis corymbosa (L) Lam. J Ethnopharmacol. 106(2) : 245-9.
<![if !supportLists]>72. Schmidt,L.E. and Delhoff,K 2003.The impact of current tobacco use on the outcome of paracetamol poisoning. Aliment Pharmacol Ther.18:979-985
<![if !supportLists]>73. Sener, G, Omurtag, GZ, Sehirli, O, Tozan, A, Yuksel, M, Ercan, F, Gedik, N. 2006. Protective effects of Ginkgo biloba against acetaminophen- induced toxicity in mice. Mol Cell Biochem. 283 (1-2): 39-45.
<![if !supportLists]>74. Setty, S. Ramachandra, Quereshi, Absar Ahmed, Swamy, A.H.M. Viswanath, Patil, Tushar, Prakash, T., Prabhu, K., Gouda, A. Veeran, 2007. Hepatoprotective activity of Calotropis procera flowers against paracetamol- induced hepatic injury in rats. Fitoterapia 78:451-454.
<![if !supportLists]>75. Sharka, S.K., Shrivastava, V., Pruthi,H.S. and Kasturi, A.S. 1999. Paracetamol poisoning - the emerging threat. J. Assoc. Physician India. 47(10): 1036.
<![if !supportLists]>76. Shon, YH, Nam, KS. 2004. Protective effect of Moutan Cortex extract on acetaminophen- induced hepatotoxicity in mice. J Ethnopharmacol. 90(2-3): 415-9.
<![if !supportLists]>77. Shyamal, S, Latha, PG, Shine, VJ, Suja, SR, Rajasekharan, S, Ganga, Devi T. 2006. Hepatoprotective effects of Pittosporum neelgherrense wight & Arn. a popular Indian ethnomedicine. J Ethnopharmacol. 107 (1) 151-5.
<![if !supportLists]>78. Singh, A, Handa, SS. 1995. Hepatoprotective activity of Apium graveolens and Hygrophila auriculata against paracetamol and thioacetamide intoxication in rats. J Ethnopharmacol, 49(3): 119-26.
<![if !supportLists]>79. Smilkestein, M.J., Knapp, G.L., Kulig, K.W. and Rumack, B.H.. 1988. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N. Engl. J. Med. 319: 1557-1562.
<![if !supportLists]>80. Subramoniam, A, Evans, DA, Rajasekharan, S, Pushpangadan, P. 1998. Hepatoprotective activity of Trichopus zeylanicus extract against paracetamol induced hepatic damage in rats. Indian J Exp Biol. 36(4) : 385-9.
<![if !supportLists]>81. Tabassum, Nahid, Agrawal, Shyam, S. 2004. Hepatoprotective activity of Eclipta alba Hassk. against paracetamol induced hepatocellular damage in mice.Experimental Medicine.11 (4):278-280.
<![if !supportLists]>82. Thabrew, MI, Hughes, RD, Gove, CD, Portmann, B, Williams, R, McFarlane, IG. 1995. Protective effects of Osbeckia octandra against paracetamol induced liver injury. Xenobiotica 25(9): 1009-17.
<![if !supportLists]>83. Thomas, S.H. 1993. Paracetamol (acetaminophen) poisoning. Pharmacol.Ther.60:91-120
<![if !supportLists]>84. Wang, DQ, Critchley, JA, Ding, BG, Ma, YQ, Zhao, HL, Thomas, GN, Tian, YP, Tomlinson, B, Critchley, LA, Edward, JA.2001. Protection against paracetamol induced hepatic damage using total flavonoids of Astragalus. Zhongguo Zhong Yao Za Zhi. 26(9): 617-20.
<![if !supportLists]>85. Wang, EJ, Li, Y, Lin, M, Chen, L, Stein, AP, Reuhl, KR, Yang, CS. 1996. Protective effects of garlic and related organosulfur compounds on acetaminophen - induced hepatotoxicity in mice. Toxicol Appl Pharmacol 136(1): 146-54.
<![if !supportLists]>86. Whitcomb,DC,Block,GD.1994.Association of acetaminophen hepatotoxicity with fasting and ethanol use .JAMA 272 (23):1845-1850
<![if !supportLists]>87. Willacy Hayley, 2007. Paracetamol Poisoning. EMIS.
<![if !supportLists]>88. Wu, SJ, Wang, JS, Lin, CC, Chang, CH. 2001. Evaluation of hepatoprotective activity of legumes. Phytomedicine 8(3): 213-9.
<![if !supportLists]>89. Yamada, S, Murawaki, Y, Kawasaki, H.1993. Preventive effect of gomisin A, a lignan component of schizandra fruits, on acetaminophen-induced hepatotoxicity in rats.Biochem Pharmacol.46 (6):1081-1085.
<![if !supportLists]>90. Yang, M, Chen, K, Shih, JC. 2000. Yang-Gan-Wan protects mice against experimental liver damage. Am J. Chin med. 28(2): 155-62.
<![if !supportLists]>91. Ye, YN, Liu, ES, Li, Y, So, HL, Cho, CC, Shoeing, HP, Lee, SS, Cho, CH. 2001. Protective effect of polysaccharides- enriched fraction from Angelica sinensis on hepatic injury. Life Sci. 69(6): 637-46.
<![if !supportLists]>92. Yemitan, OK, Izegbu, MC. 2006. Protective effects of Zingiber officinale (Zingiberaceae) against carbon tetrachloride and acetaminophen- induced hepatotoxicity in rats. Phototherapy Res. 20(11): 997-1002.
<![if !supportLists]>93. Yen, FL, Wu, TH, Lin, LT, Lin, CC. 2007. Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen- induced hepatotoxicity in rats. J Ethnopharmacol. 111(1):123-8.
<![if !supportLists]>94. YJ, Kamath, JV, Asad, M. 2006. Effect of hexane extract of Boswellia serrata oleo-gum resin on chemically induced liver damage. Pak J Pharm Sci. 19(2): 129-33.