H Nwanjo, G Oze, M Okafor
halofantrine, hepatic dysfunction, toxicity
H Nwanjo, G Oze, M Okafor. Biochemical Evaluation Of Hepatic Dysfunction As A Result Of Halofantrine Toxicity In Wistar Rats. The Internet Journal of Third World Medicine. 2006 Volume 4 Number 2.
Halofantrine is a phenanthrene methanol, belonging to the aryl-amino alcohol family, which is widely prescribed for the treatment of infections with chloroquine-resistant strains of Plasmodium falciparium. This study examined biochemical evaluation of hepatic dysfunction as a result of halofantrine toxicity in Wistar rats. Various concentrations of halofantrine (30mg/kg, 60mg/kg and 90mg/kg were administered to the three groups of Wistar rats. The fourth group of animals received distilled water (control). The body weight changes and the relative weight of the liver were measured. The serum hepatospecific markers such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) activities and serum total bilirubin level were also estimated. The halofantrine treated groups had a significant increase in the relative weight of their livers (0<0.05) when compared with control. There was also significant increase in all the enzymes and total bilirubin (p<0.05) when compared with control. The results indicated that halofantrine might have hepatotoxic effect in Wistar rats.
Malaria is an infectious diseased that continues to be associated with considerable morbidity and mortality and significant social and economic impact in developing countries. According to the World Health Organisation (WHO) Malaria is endemic in 91 countries, predominantly in Africa, Asia and Latin America with about 40% of the world's population at risk (WHO, 1996). It is caused by parasites that belong to the genius plasmodium with four different species namely
The resistance of these parasites especially
Halofantrine, a lipophilic phenanthrenemethanol belonging to the aryl amino alcohol is used for the treatment of acute uncomplicated multi-drug resistant malaria (Philips-Howard and Wood, 1996). It is schizonticidal with high degrees of activity against the asexual erythrocytic stage of malarial infections caused by single or mixed infections of
Clinical treatment with halofantrine is often accompanied by serious side effects such as abdominal pain, diarrhoea, prolongation of QTc interval and arrythmias that could be fatal. However, an increasing number of reports describing serious complications in the last few years have raised some doubt about the safety of halofantrine (Touze and Fourcarde, 1997) Halofantrine has been reported to be cardiotoxic (Nosten
Self-medication is especially common in developing countries like Nigeria and sometimes at dosages above the therapeutic dose. It has been shown that drugs that are effective in malaria treatment may cause damage to certain organs of the body, it is therefore important for drugs to be avoided and only to be safely administered when necessary. This study was therefore, carried out on the biochemical parameters as indices for assessing halofantrine-induced hepatotoxicity.
Materials And Methods
Twenty four Wistar rats bred in the Central Animal House of College of Medicine and Health Sciences, Imo State University, Owerri, Nigeria were used in the present study. They were maintained at a temperature range of 25oC to 30oC and a 12h light 12h dark cycle. They were fed with commercial growers mash, product of Tops Feeds Ltd, Sapele, Nigeria. Water and feed were provided
Halofantrine (HAL FAN) (20 mg/ml suspension) used in this study was the product of Smith Kline and French Laboratories, Nanterre, Cedar, France and was purchased from a standard pharmacy shop in Owerri, Nigeria. The drugs suspension was administered to the animals on the basis of their body weight. The suspension of halofantrine was administered orally using cannula.
Animals were randomly assigned to 4 experimental groups (n = 6x4 groups) each having similar body weights.
The drugs were administered orally for a period of 14 days. All the animals were allowed free access to food and water till the end of the experiment.
Blood Sample Collection
Twenty four hours after the last doses were administered, the animals were weighed and then anaesthetized with chloroform vapour, quickly brought out of the jar and sacrificed. Whole blood was collected by cardiac puncture from each animal into clean dry centrifuge tubes. The blood were allowed to stand for about 30 minutes to clot, and further centrifuged at 10,000 rpm for 5 minutes using Wisperfuge model 1384 centrifuge (Samson, Holland). Serum was separated from clot with Pasteur pipette into sterile serum sample tubes for the measurement of biochemical parameters. The liver from both control and test animals were removed and immediately washed with physiological saline and weighed.
Serum total bilirubin level was estimated based on Van den Berg reaction (Malloy and Everlyn, 1937). Diazotised sulphonilic acid (0.5ml) reacts with bilirubin in diluted serum (0.2ml serum + 1.8ml distilled water) and forms purple coloured azobilirubin, which was measured at 540 nm. Activities of serum aspartate transaminase (AST) and Alanine transaminase (ALT) were assayed by the method of Reitman and Frankel (1957). 0.2 ml of serum with 1ml of substrate (asparatate and ?-ketoglutarate) for AST, alanine and ?-ketoglutarate for ALT, in phosphate buffer pH 7.4) was incubated for an hour in case of AST and 30 minutes for ALT. 1ml of DNPH solution was added to arrest the reaction and kept for 20 minutes in room temperature. After incubation 1ml of 0.4N NaOH was added and absorbance was read at 540 nm. Activities expressed as IU/L.
Based on the method of King and Armstrong (1934) alkaline phosphates activities was assayed using disodium phenylphosphate as substrate. The colour developed was read at 680nm after 10 minutes and activities of ALP expressed as IU/L.
The changes in the mean value of serum bilirubin and serum hepatospecific markers in all the groups are shown in
The observed increase in the relative weight of the liver in this study indicates that the drug might have toxic effect on this organ. It has been reported that increase or decrease in either absolute or relative weight of an organ after administering a chemical or drugs is an indication of the toxic effect of that chemical (Simons
The results of this study revealed that halofantrine might have deleterious effects on the liver of Wistar rats. Serum AST, ALT, ALP and bilirubin are the most sensitive markers employed in the diagnosis of hepatic damage because they are cytoplasmic enzymes released into circulation after cellular damage (Sallie
It has been suggested that halofantrine by virtue of its lyophilic character (Hurberstone
This study has established the hepatoxic potential of high doses of halofantrine in Wistar rats. The dose used in this work is high in comparison with the therapeutic dose levels in humans because small laboratory animals eliminate drugs faster than humans (Laumann
Harrison Ugo Nwanjo,Ph.D, Department of Medical Lab. Science, Imo State University, Owerri, Nigeria. E-mail – firstname.lastname@example.org GSM-08033525389