Introduction

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 Plasmodium falciparium, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.

The resistance of these parasites especially Plasmodium falciparium to most antimalarial drugs is rampant and on the increase too. This is due to remarkable adaptability of the parasites to drugs and man's abuse of malaria drugs for prophylaxis and treatment of undiagnosed fever in endemic areas.

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 Plasmodium falciparium or Plasmodium vivax. It has limited effect against the exoerythrocytic or gametocyte stages of malaria parasites, (SmithKline Beecham, 1998).

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 et al, 1993, Touze and Fourcarde, 1997). This may be similar to that of chloroquine, quinine and mefloquine by forming toxic complexes with ferritoporphyrin IX that damage the membrane of the parasite or organs. Also several studies have shown that other antimalarials such as chloroquine, and quinine are hepatoxic (Okonkwo et al, 1997, Debra and Megan, 1999).

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

Animals

Drugs

Experimental designs

Blood Sample Collection

Biochemical Analysis

Result

Table 1 shows the effect of halofantrine on body weight changes of Wistar rats and mean relative liver weight. The control and 30mg/kg halofantrine groups showed slight gain in body weight whereas the 60mg/kg and 90mg/kg halofantrine groups had slight loss in body weight. There was significant increase in the relative weight of the liver in 60mg/kg and 90mg/kg halofantrine groups (p< 0.05) when compared with the control.

Figure 1

Table 1: Mean body weight changes and relative liver weight before and after treatment with halofantrine in Wistar rats.

The changes in the mean value of serum bilirubin and serum hepatospecific markers in all the groups are shown in table 2. There was a significant increase in the levels of total and conjugated bilirubin concentrations and AST, ALT and alkaline phosphatase activities in both 60mg/kg and 90mg/kg halofantrine groups (p < 0.05) when compared with control while 30mg/kg halofantrine groups showed significant increase only in serum ALT and AST activities (p <0.05) when compared with the control. Two animals died in the 90mg/kg dose group while one animal died in 60mg/kg, no death was seen in 30mg/kg halofantrine group.

Figure 2

Table 2: Mean values of activities of serum AST, ALT, ALP and levels of bilirubin in normal and experimental rats.

Discussion

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 et al, 1995).

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 et al, 1991). The increased activities of AST, ALT, ALP and the level of bilirubin in serum indicate halofantrine - induced hepatocellular damage. Liver enzymes are usually raised in acute hepatoxicity but tend to decrease with prolonged intoxication due to damage to the liver cells (Cornellius, 1979). This was confirmed by an earlier study (Obi et al, 2004), in which the marked elevations of hepatic marker molucules were reported. Other antimalarials such as chloroquine (Pari and Murugavel, 2004), amodiaquine (Farombi et al, 2000) and quinine (Debra and Megan, 1999) are also reported to induce hepatic damage.

It has been suggested that halofantrine by virtue of its lyophilic character (Hurberstone et al, 1996), can be expected to permeate biomembraneous barriers (Bloom and Fawceth, 1973). Pretreatment with halofantrine has evidently been shown to inhibit Na+-K+-ATPase and Ca2+- Mg2+-ATPase pumps. Also many of the cell proteases and phospholipase are activated in the presence of calcium ions. The activation of phospholipases has a damaging effect on the membrane, causing release of free fatty acids and phospolipids. These are toxic and can also initiate arachidonic acid production resulting in production of free radicals (Murphy et al, 1983). It has been reported that halofantrine pre-treatment enhances the levels of nicotinamide adenine diphosphate (NADPH), cytochrome C reductase and cytochrome Gs, both enzymes being involved in metabolism of endogenous and exogenous compounds (Voznessensky and schenkman, 1994). The enhancement of these two enzyme systems will obviously lead to accumulation of free radical oxygen species, since the enzymes have been shown to generate superoxide radical (Gibson and Sket, 1992). These may in part explain the level of bilirubin in serum manifested in the halofantrine induced hepatocellular damage in Wistar rats.

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 et al, 1995). From this study, however, it is found that halofantrine induced hepatocellular damage at high concentrations causes increase in serum hepatospecific markers in Wistar rats.

Correspondence to

Harrison Ugo Nwanjo,Ph.D, Department of Medical Lab. Science, Imo State University, Owerri, Nigeria. E-mail – harrisonnwanjo@yahoo.co.uk GSM-08033525389