Parasitaemia Clearance And Pharmacokinetics Of Artemether/ Lumefantrine Co-Administered With Unsweetened Natural Cocoa Powder

Abstract

Background: One major setback of the use of Artemether/Lumefantrine (A/L) is its high dependence on fatty diets for maximum gastrointestinal (GI) absorption. This is further compounded by nausea and lack of appetite by malaria-infected patients posing a risk of treatment failure and poor therapeutic outcomes. The antimalarial activity and fat content in Unsweetened Natural Cocoa Powder (UNCP) may produce synergism when taken as a dietary supplement with A/L in the efficient treatment of uncomplicated malaria. Aim: To evaluate the effect of UNCP on plasma concentration and malaria parasite clearance of A/L co-administration in murine models. Methodology: An antimalarial experimental study was carried out in A/L-sensitive Plasmodium berghei-infected male Sprague-Dawley (SD) rats to examine the effect of UNCP (300, 600, 900, 1,200 and 1,500 mg/kg), n = 5, when administered alone and in combination with A/L. Also, a pharmacokinetic study was performed on healthy non-malarious male SD rats co-administered A/L with varying doses of UNCP (300, 600, 900, 1,200 and 1,500 mg/kg), n = 3, to assess the effect of UNCP on the plasma drug concentration, bioavailability and other pharmacokinetic parameters using HPLC/UV-Vis method. This was followed by a Liver Function Test (LFT) on the serum samples of the various groups. Phytochemical screening was performed on UNCP to determine the various phytochemicals present. A total fat assay was also performed using the Soxhlet solvent extraction method to ascertain the percentage fat content of UNCP. Results : Results indicate a significant difference in parasite clearance for A/L+UNCP (1,200 and 1,500 mg/kg) groups at 36 and 48 hours of administration. A/L + UNCP (1,500 mg/kg) group recorded the most significant parasite decrease (F₆,28=1333, P < 0.0001) in comparison with Coartem® only group (positive control) with a percentage drop of 55.89% and 39.63% respectively and this was followed by A/L + UNCP (1,200 mg/kg) (F₆,28=1333, P < 0.0210) with a percentage drop of 51.98% at 36 hours. A similar trend was observed at 48 hours for A/L + UNCP (1,500 mg/kg) (F₆,28=1333, P < 0.0017) and A/L + UNCP (1,200 mg/kg) groups (F₆,28=1333, P < 0.0391) with percentage drop of 71.97% and 71.3% respectively in comparison with Coartem® only group, (percentage drop of 57.68%) at 48 hours. The UNCP only groups however did not show significant antimalarial activity, but results showed that 1,200 mg/kg and 1,500 mg/kg UNCP only groups survived 24 hours longer than the other UNCP only groups with their survival rate expressed as Mean Survival Time (MST); 2 ± 0.4 days/animals and 2 ± 0.8 days/animals respectively. On the other hand, there was no significant difference in MST for the A/L+UNCP groups (28 ± 0.6 days/animals). Pharmacokinetic studies indicated a significant difference in the area under the curve (AUC0→24) over the 24 hours post drug administration of Lumefantrine for A/L+UNCP (1,200 mg/kg) and A/L+UNCP (1,500 mg/kg) groups (**P < 0.0091) and (***P < 0.0003) in comparison with the Coartem® only group respectively. Similarly, there was a significant difference in peak serum concentration (Cmax) for A/L+UNCP (1,200 mg/kg) (**P < 0.0051) and A/L+UNCP (1,500 mg/kg) (***P < 0.0003) groups in comparison with the Coartem® only group. However, there was no significant difference for (half-life) t1/2, (elimination rate constant) Ke and (peak time) Tmax amongst the various groups. Phytochemical analysis showed the presence of alkaloids, saponins, tannins, glycosides, flavonoids, phenols and the absence of reducing sugars and terpenoids with a percentage fat content of 28.11%. Also, LFT results did not show any significant difference amongst the various groups. Conclusion Higher doses of UNCP (1,200 and 1,500 mg/kg) co-administered with A/L showed significant antimalarial activity and a higher plasma concentration of A/L with a safe hepatic profile.