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: hrvuz2000@yahoo.co.in

 

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

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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