Can herbal-paracetamol

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

Issued 24 May 2008

ABSTRACT

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.

INTRODUCTION

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

S. No.	Worker	Year	Model	Name of the herbal Compound	Hepato protective property	Nephro protective property	Parameters
S. No.	Worker	Year	Model	Name of the herbal Compound	Hepato protective property	Nephro protective property	Lethali ty test	Histo - pathology	Biochemical / clinical /other parameters
1	Akintonwa et al.	1990	Rat	Garcinia Kola	Yes	No	Yes	Yes	Glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT)
2	Handa et al.	1990	Rat	Andrographis paniculata (andrographolide)	Yes	No	No	Yes	GOT, GPT, ALP, bilirubin, triglycerides
3	Donatus et al.	1990	Rat hepatocytes	Curcuma longa (Curcumin)	Yes (cytopro tectivity)	No	No	No	lipid peroxidation, LDH - leakage, GSH - depletion
4	Ansari et al.	1991	Rat	Picrorhiza kurrooa (Picrolive)	Yes	No	No	Yes	Various biochemical parameters
5	Chattopadhyay et al.	1992	Rat	Azadirachta indica	Yes	No	No	Yes	GOT, GPT, acid phosphatase, alkaline phosphatase
6	Muriel et al.	1992	Rat	Silymarin	Yes	No	No	No	Liver glutathione,lipid peroxidation, glycogen & serum alkaline phasphotase(AP)gamma- glutamyltranspeptidase,(GGT P) glutamic pyruvic transaminase (GPT)
7	Yamada et al.	1993	Rat	Scizandra fruits(gomisin A)	Yes	No	No	Yes (degeneration and necrosis of hepatocytes)	Serum amino transferase activity and hepatic lipoperoxides content, glutathione
8	Gilani et al.	1993	Mice & Rat	Artemisia scoparia	Yes	No	Yes	No	GOT, GPT
9	Cheng et al.	1994	Mice & Rat	Hippophae rhammoides	Yes	No	No	Yes	MDA), GPT, GOT, GSH
10	Lin et al.	1994	Mice	Wedelia chinensis	Yes	No	No	Yes	GOT, GPT
11	Lin et al.	1995	Rat	'teng-khia-u' Taiwan folk medicine (Elephantopus scaber L. E.mollis H.B.K. and Pseudoelephantopus spicatus(Juss.)Rohr.)	Yes	No	No	No	GOT, GPT
12	Singh et al.	1995	Rat	Apium graveolens & Hygrophila auriculata	Yes	No	No	Yes	GOT, GPT, alkaline phosphates (ALP), sorbitol dehydrogenase (SDH), glutamate dehydrogenase, bilirubin, tryglycerides
13	Thabrew et al.	1995	Mice & cutured Rat Hepatocytes	Osbeckia octandra	Yes	No	No	Yes	Blood Normotest, glutathione level, plasma aspartate amino transferase, cell viability, lactate dehydrogenase (LDH).
14	Janbaz et al.	1995	Mice & Rat	Artemisia maritima	Yes	No	Yes	No	GOT, GPT
15	Gilani et al.	1995	Mice & Rat	Cyperus scariosus	Yes	No	Yes	No	Alkaline phosphatase (ALP), GOT, GPT
16	Rasheed et al.	1995	Mice	Teucrium stocksianum	Yes	No	Yes	No	Aspartate amino transferase, bilirubin, GSH, liver weight, pento barbitone induced sleeping time.
17	Chin et al.	1996	Rat	'Ham-hong-Chho' Taiwan folk medicine (Bidens pilosa L..var minor (Blume)Sherff, B. Pilosa L. and B. Chilensis DC)	Yes	No	No	Yes	GOT, GPT
18	Gilani et al.	1996	Mice & Rat	Fumaria parviflora	Yes	No	Yes	No	ALP, GOT, GPT
19	Wang et al.	1996	Mice	Garlic	Yes	No	No	Yes	ALT, LDH & GSH
20	Lin et al.	1997	Rat	Scutellaria rivularis (Ban- zhi-lian)	Yes	No	No	Yes	GOT, GPT
21	Subramoniam et al.	1998	Rat	Trichopus zeylanicus	Yes	No	No	Yes	Serum marker enzymes, level of lipid peroxides in liver
22	Ryu et al.	1998	Rat	Artemisia asiatica (DA - 9601)	Yes	No	No	Yes (centrilobular necrosis, vacular degeneration, inflammatory cell infitration)	ALT, AST, LDH, GSH
23	Rusu et al.	1999	Rat	Corylus avellana	Yes	No	No	Yes	GOT, GPT, SDH, GtDH, G-6 Pase and ATPase,steatosis by sudan black staining.
24	Jafri et al.	1999	Rat	Cassia occidentalis	Yes	No	No	Yes	AST, ALT, ALP, cholesterol, Total lipid
25	Karan et al.	1999	Rat	Swertia chirata	Yes	No	No	-	-
26	Lin et al.	2000	Rat	Acathopanax senticosus	Yes	No	No	Yes	AST, ALP
27	Janbaz et al.	2000	Rat	Berberis aristata (Berberine)	Yes	No	No	No	ALP, AST, ALT
28	Lin et al.	2000	Rat	Anoectochilus formosanus Gynostemma pentaphyllum	Yes	No	No	Yes (necrosis in the centrilobular area, sinosoidal congestion, infiltration of the lymphocytes and kupffer cells around the hepatic central vein, loss of cell boundaries and ballooning degeneration.	AST, ALT
29	Mandal et al.	2000	Rat	Ficus hispida	Yes	No	No	Yes	GOT, GPT, bilirubin, ALP
30	Ray et al.	2000	Mice	IH 636 Grape seed proanthocya- nidine extract	No	Yes	No	Yes (apoptosis + necrosis , DNA fragmentation)	ALT, BUN, CPK
31	Yang et al.	2000	Mice	Yang-Gan-Wan	Yes	No	No	Yes (necrosis)	ALT, SDH
32	Emmanuel et al.	2001	-	Wedelia calendulacea (Coumestans)	Yes	No	No	No	LDH, ALT, AST, ALP
33	Wang et al	2001	Mice	Astragalus (total flavonoids)	Yes	No	No	Yes (hepatocellular necrosis)	ALT paracetamol prolonged pentobarbital induced sleeping time,paracetamol and its metabolites in mice urine
34	Ali et al.	2001	Mice	Rhazya stricta	Yes	No	Yes	Yes	Pentobarbitone induced sleeping time, GSH, AST, ALT, gamma glutamyl transferase (GGT), cholesterol, liver weight
35	Datta et al.	2001	Mice	herbal protein CI-1 (from Cajanus indicus)	Yes	No	No	Yes (ultrastructure)	No
36	Bhakta et al.	2001	Rat	Cassia fistula	Yes	No	No	No	GOT, GPT, bilirubin, ALP
37	Wu et al.	2001	Rat	Legumes (Mung bean, adzuki bean, black been and rice been)	Yes	No	No	No	GOT, GPT
38	Ahmed et al.	2001	Rat	Ambrosia maritima	Yes	No	No	No	AST, ALT, ALP malondialdehyde (MDA), glutathione (GSH), glutathione reductase (GSH-R), glutathione peroxidase (GSH-Px), glutathione - S- trasferase (GST)
39	Reen et al.	2001	Cultured Rat Hepatocytes	Swertia species	Yes	No	No	No	GSH, leakage of LDH as biological end - points of toxicity
40	Ye et al.	2001	Mice and Rat	Angelica sinensis	Yes	No	No	No	ALT, hepatic nitric oxide synthase (NOS) activities, GSH, MDA
41	Lin et al.	2001	Rat	Terminilia catappa (Punicalagin and Punicalin)	Yes	No	No	Yes	AST, ALT
42	Hittori et al.	2001	Mice	Ajoene ( a garlic derived sulfur-contaning compound)	Yes	No	No	No	GSH, GPT, hepatic protein thiol content
43	Echard et al.	2001	Rat	Combination of medicinal herbs	Yes	No	No	No	AST, ALT
44	Lee et al.	2002	Rat	Chinese yam	Yes	Yes	No	Yes (renal tublar degranulation changes,necrosis,disintegration. inflammation of central vein and necrosis of liver tissue)	-
45	Bagchi et al.	2002	Mice	Grape seed proanthocyani- dine extract	Yes	Yes	No	Yes (apoptosis + necrosis + DNA damage)	Serum chemistry
46	Ko et al.	2002	Rat	Silene aprica	Yes	No	No	No	Morphological and biochemical observations.
47	Janbaz et al.	2002	Mice & Rat	Menthol	Yes	No	Yes	No	ALP, AST, ALT
48	Janbaz et al.	2002	Mice & Rat	Rutin	Yes	No	Yes	No	AST, ALT
49	Bhattacharyya et al.	2003	Rat	Himolive (a polyherbal formulation)	Yes	No	No	No	GOT, GPT, ALP, thiobarbituric acid - reacting substances (TBARS) SOD.
50	Gamal el-din et al.	2003	Mice	Arabic gum	Yes	No	No	No	ALT, AST, lipid peroxidation, nitrate + nitrities
51	Kumar et al.	2004	Rat	Trianthema portulacastrum	Yes	No	No	No	GOT, GPT, ALP, bilirubin, total Protein
52	Devi et al.	2004	Rat	Premna tomentosa	Yes	No	No	No	Cholesterol, tryglycerides, free fatty acids, phospholipids, serum lipoproteins, lipid metabolizing enzymes.
53	Tabassum et al.	2004	Mice	Eclipta alba Hassk	Yes	No	No	Yes (centrizonal and local necrosis, ballooning in liver)	ALT
54	Shon et al.	2004	Mice	Moutan Cortex	Yes	No	No	DNA fragmentation	ALT, GSH, Cyt P450 2E₁- dependent aniline and p-nitrophenol hydroxylases activities
55	Han et al.	2004	Rat	Adzuki bean hulls	Yes	No	No	No	GSH, GSH-R, GSH-Px, AST, catalase, phosphatidylcholine hydroperoxide, phosphatidyl ethanolamine hydroperoxide
56	Rao et al.	2004	Rat	Ulva reticulata	Yes	No	No	No	Aspartate transaminase, alanine transaminase, lipid peroxides, superoxide dismutase, catalase, glutathione, Vit. E and C.
57	Gupta et al.	2004	Rat	Bauhinia racemosa	Yes	No	No	No	GOT, GPT, ALP, SOD, CAT, LPO, GSH, bilirubin, total Protein
58	Kim et al.	2004	Rat & cultured rat hepatocytes	Alnus japonica	Yes	No	No	No	Lipid peroxidation, superoxide dismutase, Catase
59	Mroueh et al.	2004	Rat	Centaurium erythraea	Yes	No	No	Yes	GPT, GOT, LDH
60	Porchezhian et al.	2005	Rat	Abutilon indicum	Yes	No	No	No	Enzymatic examination
61	Murugesh et al.	2005	Rat	Berberis tinctoria	Yes	No	No	No	GOT, GPT, ALP, bilirubin, total protein, lipid peroxidation GSH, SOD, catalase activity
62	Oliveira et al.	2005	Mice	Protium heptaphyllum (alpha- and beta- amyrin)	Yes	No	Yes	Yes (centrilobular necrosis, cell infiltration)	ALT, AST, GSH, pentobarbital sleeping time
63	Raghavendran et al.	2005	Rat	Sargassum polycystum (Brown alga)	Yes	No	No	No	Lipid peroxides, SOD, CAT, GSH, GPx, GST
64	YJ et al.	2006	-	Boswellia serrata (Oleo-gum-resin)	Yes	No	No	Yes	Serum marker enzymes and liver weight
65	Kim et al.	2006	Rat	Glycyrrhizae radix (liquiritigenin)	Yes	No	No	Yes (hepatic necrosis,inflammation)	ALT , LDH
66	Baheti et al.	2006	Rat	Hemidesmus indicus	Yes	No	No	No	GPT, GOT, ALP, Bilirubin
67	Iwalokun et al.	2006	Mice	Vernonia amygdalina	Yes	No	No	No	GPT, GOT, LDH, ALP, bilirubin, catalase , iron & total protein concentrations, lipid peroxidation products thibarbituric acid- reactive substances (TBARS)
68	Sadasivan et al.	2006	Rat & In vitro	Hedyotis corymbosa	Yes	No	No	Yes	SGPT,SGOT, SAKP, bilirubin, hexobarbitone- induced sleeping time, antilipid peroxidant effect in vitro.
69	Shyamal et al.	2006	Rat	Pittosporum neelgherrens wight & Arn.	Yes	No	No	Yes	GOT, GPT
70	Pandey et al.	2006	Rabbit	Livol, Eclipta alba and Silybum marianum	Yes	No	No	Yes (varying degree of congestion, degeneration and necrosis, areas of focal mononuclear cell infiltration enlarged biliary ducts and periportal oedema)	-
71	Yemitan et al.	2006	Rat	Zingiber officinale	Yes	No	No	Yes	ALT, AST, ALP, LDH, SDH, glutamate dehydrogenase.
72	Parial et al.	2006	Rat	Carica papaya	Yes	No	No	No	GOT, GPT, ALP, Total biliribun,
73	Sener et al.	2006	Mice	Ginkgo biloba	Yes	No	No	Yes	ALT, AST, tumor necrosis factor apha (TNF-alpha) in blood, GSH, MDA, myeloperoxidase (MPO) activity, collagen content in liver tissues,luminol and lusigenin CL levels.
74	Roy et al.	2006	-	Psidium guajava	Yes	No	No	Yes	AST, ALT, ALP, bilirubin, liver weight.
75	Yen et al.	2007	Rat	Cuscuta chinensis	Yes	No	No	Yes	GOT, GPT, ALP, SOD, catalase glutathione peroxidase (GPx) and malondialdehyde (MDA)
76	Lin et al.	2007	Rat	Chai-Hu-Ching-Kan-Tang	Yes	No	No	Yes (central necrosis,fatty changes)	GOT, GPT, lipid peroxides, SOD, GPx
77	Setty et al.	2007	Rat	Calotropis procera	Yes	No	No	No	GPT, GOT, ALP, biliribuin, cholesterol, HDL, tissue GSH.
78	Chaturvedi et al.	2007	Rat	Raphanus sativus	Yes	No	No	No	Thiobarbituric acid reactive substances (TBARS), GOT, GPT, GSH, catalase.
79	BR et al	2008	Rat	Phyllanthus polyphyllus	Yes	No	No	Yes	AST, ALT, ALP,total bilirubin, gamma glutamate transpeptidase (GGPT), lipid peroxidase (LPO), total protein, SOD, catalase, GPx, glutathione S- transferase (GST)

DISCUSSION

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.

CONCLUSION

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.

ACKNOWLEDGEMENTS

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.

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