Egyptian Journal of Basic and Clinical Pharmacology

1. Introduction

Drug interaction may result when two or more drugs are concurrently administered [1]. Interactions could also result between drugs and foods (drug-food interactions), as well as between drugs and herbal medicines, also known as drug-herb interactions [2]. This may affect pharmacokinetic and pharmacodynamic outcomes of medications leading to either therapeutic failure or toxicity [3]. In West Africa, co-administration of orthodox drugs and herbal medications is common and could be before, during or after treatment of malaria [4]. Malaria is a serious public health problem with increasing morbidity and mortality especially among developing countries. In 2017, about 219 million cases of malaria were reported with about 435,000 related deaths. Report suggested that Africa accounted for 92% and 93% of the prevalence and mortality respectively [5]. Effective therapy is therefore required to reduce the morbidity and mortality as well as improve quality of life.

Artesunate, a derivative of artemisinin, has remained one of the drugs of choice used in the treatment of especially chloroquine and quinine resistant malaria and is highly effective against multidrug-resistant falciparum. It also provides an advantage over artemisinin combination due to a better absorption profile [6]. It is used for treatment of severe malaria and has proven effective with much faster fever resolution than occur with quinine [7,8]. Medicinal plants have received wide acceptability especially in low and middle income countries especially in Africa due to poor accessibility to orthodox drugs [9]. At the global stage also, majority of the world population still depends on traditional medicine such as herbs for treatment of various ailments [10]. Ficus platyphylla Del. Holl. (Moraceae) is a deciduous medicinal plant that is widely distributed throughout West Africa. It is widely distributed in Northern Nigeria and locally known as “gamji“. It has gained a profound usage among native dwellers in Hausa communities and is used traditionally with widely acclaimed efficacy for the management of epilepsy, insomnia, psychosis, depression, pain and inflammation [11]. In addition, Ficus platyphylla has been scientifically validated to possess antimalarial activity [12] and a more recent study has established its safety in rats following 28 days oral administration [13]. This suggests the possibility of concurrent administration of artesunate and Ficus platyphylla for synergistic or additive effect in the treatment of malaria thus necessitating an investigation on the hepato-renal consequence of the combination.

2. Materials and Methods

3. Results

4. Discussion

Severe malaria poses a serious health challenge in developing countries especially in the tropics [15]. With the short fall of health care facilities and poor standard of living in these countries, especially in the rural areas, traditional herbal medicine offers an affordable alternative. However, the concurrent use of herbal remedies with orthodox medications may increase the tendency for drug-herb interactions. This may enhance efficacy and/or predispose to toxicity. Hence, the study investigates the possible hepato-renal effects of concurrent administration of Ficus platyphylla and artesunate in rats.

In this study, the oral median lethal dose value for the methanol stem bark extract of Ficus platyphylla obtained in rats following oral administration was greater than 5000 mg/kg. This may suggest that the plant extract is non-toxic as no death nor sign of toxicity was recorded. This is consistent with previous findings [13], who reported that the methanol stem bark extract of Ficus platyphylla is practically non-toxic following acute toxicity studies. A substance is said to be very toxic if the value is less than or equal to 5 mg/kg, and toxic if the value is greater than 5 mg/kg but less 50 mg/kg. Furthermore, it is said to be harmful if the value is greater than 50 mg/kg but less 500 mg/kg, and non-toxic if the value is greater than 500 mg/kg or less than 2000 mg/kg [16]. Acute toxicity studies give an insight as to what dose of a substance or drug will cause deleterious effects and/or death. This helps in dose determination especially for an unknown substance in basic medical research [17].

Generally, weight loss associated with exposure to a potential toxicant serves as an index for toxicity. [18]. There was no significant change in body weights of all groups of animals throughout the duration of the study. This could be of clinical importance, as changes in body weight can have an effect on energy expenditure and has also been reported to be related to catecholamine and thyroid hormone levels [19]. This may suggest that overweight and/or insulin resistant patients can take this drug-herb combination without risk of weight associated complications.

The liver and kidneys are the most important organs for both metabolism and excretion of xenobiotics, hence, they are predisposed to toxicity. Elevated levels of alanine transferase, aspartate, and alkaline phosphatase are indicative of abnormalities in liver function [20]. In this study, administration of Ficus platyphylla and artesunate either in combination or singly did not affect serum liver function markers. This data corroborates earlier findings [13] that reported no change in serum liver markers after 28 days of continuous oral administration. In addition, at low therapeutic doses, artesunate has been found not to interfere with liver functions in rats, however, prolonged administration for four weeks at 76 mg/kg has been found to produce hepatotoxicity [21].

Increased levels of serum creatinine, blood urea nitrogen and uric acid, and reduced levels of serum albumin and protein are common markers for renal toxicity [22,23]. This present study suggests that both Ficus platyphylla and artesunate as single agents or combined have no adverse effect on renal function. This is because the renal function markers for all the groups did not differ significantly from the values of the normal control group. This is in agreement with a recent study where kidney function was left unaltered in rats after 28 days of treatment with methanol stem bark extract of Ficus platyphylla [13]. In addition, at therapeutic dose and duration, artesunate does not produce renal toxicity, as the serum levels of creatinine and urea were not affected after five days of oral administration [24], however, at higher doses and with prolonged duration of treatment, toxicity may occur.

5. Conclusion

Concurrent short term administration of the methanol stem bark extract of Ficus platyphylla and artesunate does not affect body weight as well as liver and kidney functions in rats. These may indicate safety of this drug-herb combination. Thus, there is possibility of concurrent use of both agents in practice for the purpose of treating especially complicated and chloroquine resistant malaria without affecting body weight and producing adverse effects on the liver and kidney. Further studies should however be carried out on concurrent administration of both agents to determine both the safety profile and efficacy of the combination in parasitized rats.

Competing Interests

The authors declare no competing interests.