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In This Article
 »  Abstract
 »  Introduction
 »  Material and Methods
 »  Discussion
 »  Results
 »  References

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Year : 2004  |  Volume : 36  |  Issue : 5  |  Page : 303-305

The hepatotoxic effect of halofantrine in guinea pigs

Toxicology Unit, Department of Pharmacology, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria

Date of Submission21-Oct-2003
Date of Decision10-Feb-2004
Date of Acceptance23-Feb-2004

Correspondence Address:
Department of Anatomy, College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria
[email protected]

 » Abstract 

OBJECTIVE: To investigate the hepatotoxic effects of halofantrine in guinea pigs. MATERIAL AND METHODS: Halofantrine (30-105 mg/kg) was administered orally to three groups of guinea pigs thrice a week for 4 weeks. One group of animals which received distilled water served as control. The relative weight of the liver was measured. The biochemical parameters like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and also total and conjugated bilirubin were measured. Liver tissues were subjected to histopathological examination. RESULTS: There was a significant (P<0.05) increase in the relative weight of the liver in all the treated groups compared to control. There was also a significant (P<0.05) increase in all the liver enzymes and total and conjugated bilirubin. Histopathological examination of the liver revealed moderate portal triaditis to severe hepatic degeneration in the halofantrine-treated groups. CONCLUSION: Halofantrine exhibits hepatotoxic effect in guinea pigs.

How to cite this article:
Obi E, Orisakwe O E, Asomugha L A, Udemezue O O, Orish V N. The hepatotoxic effect of halofantrine in guinea pigs. Indian J Pharmacol 2004;36:303-5

How to cite this URL:
Obi E, Orisakwe O E, Asomugha L A, Udemezue O O, Orish V N. The hepatotoxic effect of halofantrine in guinea pigs. Indian J Pharmacol [serial online] 2004 [cited 2023 Feb 7];36:303-5. Available from: https://www.ijp-online.com/text.asp?2004/36/5/303/12650

 » Introduction Top

Halofantrine hydrochloride is a highly lipophilic phenanthrenemethanol, belonging to the aryl-amino-alcohol family. This drug is prescribed as standby treatment in travelers to the tropics who develop febrile illness and has been proposed as a radical cure to avoid the constraints of prolonged chemophylaxis.[1] Numerous studies indicate the cardiotoxicity of halofantrine.[2],[3] The observed cardiotoxicity may be due to its quinidine-like effect.[4] The effect of other antimalarials like chloroquine on biochemical liver functions and liver tissue have been studied.[5] Farver and Lavin (1999) reported an increase in alanine transaminase (ALT) and aspartate transaminase (AST) in quinine-induced hepatotoxicity.[6] The effects of older antimalarials on the liver have been appreciably studied.[5] The information is scanty on the effect of new antimalarials, especially of halofantrine on the liver.
The present study was based on biochemical parameters and pathological changes as indices for assessing liver dysfunction as a result of halofantrine toxicity.

 » Material and Methods Top

Animals: Dunkin-Hartley guinea pigs weighing 500-600 g obtained from the Veterinary Institute, Vom, Nigeria were acclimatized to housing conditions for one week prior to the commencement of the experiment. They were housed under standard housing conditions of temperature (22±3oC), and a 12 h light 12 h dark cycle. The animals were housed singly in small partitioned cubicles and provided with water and food (elephant grass) ad libitum.
Experimental design
Halofantrine (Halfan) (100 mg/5 ml suspension) was used for the experiment. Four experimental groups of ten animals each were used. The first group received 30 mg/kg of halofantrine (low dose). The second group had 50 mg/kg of halofantrine (medium dose), the third group received 105 mg/kg of halofantrine (high dose)[7] and the fourth group received only distilled water (control). The drug was administered orally thrice a week for 28 days using oral cannula. The animals were allowed free access to food and water till the end of the experiment.
Any mortality that occurred was recorded. At the end of the experiment, blood samples were collected by cardiac puncture for measurement of biochemical parameters and the animals were sacrificed under chloroform anesthesia. The liver tissue was excised and transferred into ice-cold containers for biochemical estimations.
Small pieces of liver tissues were collected in 10% formal saline for fixation. They were processed in an automatic tissue processor, and embedded in paraffin wax. Sections of 5 um were cut on a rotary microtome by serial sectioning until the entire thickness of the liver was sectioned. Staining was done by haematoxylin and eosin (H&E) staining method, and microscopy and photomicrograph carried out, using a leitz light microscope.
Determination of serum aspartate and alanine transaminases (AST, ALT), alkaline phosphatase (ALP) and bilirubin
The transaminases, alkaline phosphatase and total and conjugated bilirubin were measured using the Randox laboratories (UK) Kit procedures.
Statistical analysis
All parameters were analyzed using one-way analysis of variance (ANOVA) while the differences between treatment groups were tested using the Scheffe multiple comparison method with 0.05 representing the level of significance. Results were expressed as mean±SEM.

 » Results Top

There was a significant (P<0.05) increase in the levels of serum transaminase, alkaline phosphatase activity and total and conjugated biliburin in all the treated groups compared to control [Table - 1]. There was also a significant (P<0.05) increase in the relative weight of the liver, in all the treated groups compared to control [Table - 1]. Five animals died in the 105 mg/kg dose group and one animal died in the 50 mg/kg whereas there was no death in the 30 mg/kg dose group. Histological examination showed that the control group exhibited normal architecture of the liver [Figure - 1]a and liver cells in the treated group showed moderate portal triaditis to severe hepatic degeneration [Figure - 1]b,c,d.

 » Discussion Top

More than 1000 xenobiotic substances are potentially hepatotoxic.[8] The ability of the chemical to produce liver damage in vivo often results from the interaction of a series of complex cellular processes involved in the uptake, biotransformation and elimination of these potentially toxic compounds.
The observed increase in the relative weight of the liver in all the treated groups is in agreement with the work of Simons et al, 1995 who reported that increased organ weight (whether absolute or relative) is a sensitive indicator of organ toxicity.[9]
Bilirubin and all the enzymes measured in this study were significantly increased in all the treated groups. Liver enzymes are usually raised in acute hepatotoxicity, but tend to decrease with prolonged intoxication due to damage to the liver cells.[10] Increase in liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST) are common findings in liver toxicity[5],[11] while increased activity of these enzymes may be found in damaged tissues.[12] The present study has shown that there was a significant increase in all the measured liver enzymes indicating liver damage. Smith et al, 1998 reported an increase in ALT in oral acetaminophen-induced hepatotoxicity in rats indicating a biochemical evidence of significant liver damage.[13] Mizutani and co-workers, 1999 reported an increase in serum ALT activity in methimazole-induced hepatotoxicity in mice.[14]
Exposure to halofantrine caused pathologic changes in guinea pigs, which included moderate portal triaditis to severe hepatic degeneration. These changes were dose-dependent. Whatever the agent responsible for injury, the reaction of the liver involves a common sequence of events that can be analyzed at the tissue, cellular and molecular levels. It is however difficult in vivo to distinguish the primary effects of a compound from those induced secondarily because liver functions are under the influence of various endogenous and exogenous factors that result from complex interactions with other organs.[9] The interaction of halofantrine with biological membranes is potentially significant as membrane-related processes might be implicated in the antimalarial action and toxicity of the drug.[15]
Most of the understandings of liver injury induced by chemicals remain confined to animal models, and data obtained in animals cannot be extrapolated with certainty to the human situation. Because of the drawbacks of in vivo studies of drug and chemical induced hepatotoxicity, in vitro liver systems may be approached to investigate mechanisms by which halofantrine induces liver damage. In conclusion, we are aware that the dose used in the present study is high in comparison to the therapeutic dose levels in humans; since small laboratory animals eliminate drugs at a higher rate than humans,[16] higher doses were used in order to maintain an appreciable quantity of the drug in the system. 

 » References Top

1.Bandon D, Bernard J, Mouliat Peliat JP, Martek G, Sarrouy JE, Spiegel A, et al. Efficacy of a radical cure by halofantrine to prevent falciparium malaria on return from malarious areas. Annales de la societe Belge Medecine Tropicale 1972;72:263-70.  Back to cited text no. 1    
2.Ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, et al. Halofantrine versus mefloquine in treatment of multi drug-resistant falciparum malaria. Lancet 1993;341:1044-9.  Back to cited text no. 2    
3.Nosten F, Ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993;341:1054-6.  Back to cited text no. 3  [PUBMED]  
4.Touze JE, Fourcade L, Peyron F, Heno P, Deharo JC. Is halofantrine still advisable in malaria attack? Anna Trop Med Parasitol 1997:91:867-73.  Back to cited text no. 4    
5.Okonkwo CA, Agomo PU, Mafe AG, Akindele SK. A study of the hepatoxicity of chloroquine (SN - 7618) in mice. Nig Qt J Hosp Med 1997;7:183-7.  Back to cited text no. 5    
6.Farver DK, Lavin MN. Quinine-induced hepatotoxicity. Ann Pharmacother 1999;33:32-4.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Orisakwe OE, Obi E, Orish VN, Udemezue OO. Effect of halofantrine on testicular architecture and testosterone level in guinea pigs. Eur Bull Drug Res 2003;11:105-9.  Back to cited text no. 7    
8.Guillouzo A. Liver cell models in in vitro toxicology. Environ Health Perspect 1998;106(Suppl 2):511-32.  Back to cited text no. 8  [PUBMED]  
9.Simmons JE, Yang RS, Berman E. Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: Advantages and disadvantages of the use of real-world complex mixtures. Environ Health Perspect 1995;103(Suppl 1):67-71.  Back to cited text no. 9  [PUBMED]  
10.Cornelius CE. Biochemical evaluation of hepatic function in dogs. J Am Hosp Ass 1979;15:25-9.  Back to cited text no. 10    
11.Varley H, Gowenlock AH, Bell M. Practical Clinical Biochemistry. Vol. 1. 5th Ed. India: CBS Publishers and Distributors 1991.  Back to cited text no. 11    
12.Ferguson WW, Starling JR, Wangensteen SL. Role of lysosomal enzyme release in the pathogenesis of stress-induced gastric ulceration. Surg Forum 1997;23:380-2.  Back to cited text no. 12    
13.Smith GS, Nadig DE, Kokoska ER, Solomon H, Tiniakos DG, Miller TA. Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats. J Surg Res 1998;80:252-8.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Mizutani T, Murakami M, Shirai M, Tanaka M, Nakamishi K. Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione. J Appl Toxicol 1999;19:193-8.  Back to cited text no. 14    
15.Lim L, Go ML. The antimalarial agent halofantrine perturbs phosphatidylcholine and phosphatidylethanolamine bilayers: A differential scanning calorimetric study. Chem Pharm Bull 1999;47:732-7.  Back to cited text no. 15    
16.Laumann H, Lullmann-Rauch R, Wassermann O. Drug induced phospholipidosis. Crit Rev Toxicol 1995;4:185-218.  Back to cited text no. 16    
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