|dc.description.abstract||Malaria remains a leading cause of morbidity and mortality in tropical regions of the world despite the numerous global efforts to control and manage the disease through prevention and drug intervention. An estimated 300–500 million people are affected by malaria each year, resulting in 1.5–2.7 million mortalities annually. Recent reports indicate that 90% of malaria-related deaths occur in the Sub-Saharan Africa, where a child under five years of age dies every 30 seconds. The development of immunity and increasing resistance to affordable antimalarial drugs is believed to be one of the factors that have led to the increasing number of malaria cases. As a result, the WHO has recommended the use of artemisinin combination therapies (ACTs) for management of malaria. However, these have proven to be very costly and inaccessible in many low-income countries. Therefore, CHQ has remained the mainstay therapy for malaria prophylaxis and treatment despite development of Plasmodium falciparum resistance to this drug. The decrease in CHQ efficacy is attributed to a number of factors which are associated with the conventional oral route of administration. CHQ has a bitter, unpalatable taste when administered orally which, more often than not lead to patient’s non-compliance. This is thought to be one of the factors that have led to the increasing number of CHQ resistant strains of P. falciparum. Moreover, when administered orally, CHQ is reported to deposit in epithelial cells of many vital organs including the liver, heart and kidneys where the drug elicits adverse effects on physiological functions. Hypoglycaemia and impaired renal fluid and electrolyte handling are some of the adverse effects associated with oral administration of CHQ. The present study was designed to develop a novel CHQ-formulation that delivers sustained slow CHQ release into the systemic circulation. We also investigated the ability of this CHQ formulation to clear the malaria parasites in Plasmodium berghei-infected male Sprague-Dawley rats. The other objective of the study was to investigate and distinguish between the patho-physiological effects of malaria parasites and CHQ treatment on blood glucose homeostasis and renal fluid and electrolyte handling in rats.
The studies were carried out over a period of 3 weeks, divided into pre-treatment (days 0-7), treatment (days 8-12) and post treatment (days 13-21) periods. To distinguish between the effects of CHQ treatment and malaria infection on blood glucose homeostasis and renal function, separate groups of non-infected and P. berghei-infected male Sprague Dawley rats (90g-150g) were used. The animals were housed individually in Makrolon polycarbonate metabolic cages. During the 5-day treatment period, the animal were treated with either oral
CHQ (30 mg), twice daily, 8 hours apart or a once off topical application of the pectin-CHQ matrix patch (56 mg). To evaluate the ability of our novel CHQ-formulation to clear the malaria parasites, pectin-CHQ matrix patches containing 28 and 56 mg of CHQ were used. These doses were calculated based on current clinical doses for the treatment of malaria. However, to assess the short-term effects of our CHQ formulation, a pectin-CHQ patch containing 56 mg CHQ was used. This dose was chosen based on preliminary studies. Percentage parasitaemia, mean body weight changes, food and water intake, mean arterial pressure (MAP), blood glucose concentration, , haematocrit, and 24 hour urine volume voided, Na+, K+ and Cl- were monitored every third day during the pre-treatment and post-treatment periods. However, during the treatment period, all these parameters were monitored daily. To assess the effects of CHQ treatments on some biochemical parameters such as plasma CHQ profiles, electrolytes, AVP and insulin concentrations, separate groups of animals (n=6) were sacrificed during pre-treatment at days 0 and 7, treatment period at days 8, 9, 11, 12 and post-treatment period at day 21.
The results indicate that we were able develop a novel CHQ-formulation and achieved drug percentage incorporations ranging between 52-74%. Furthermore, the amounts of CHQ obtained in the patch compare to clinical doses. We have also demonstrated the ability of the pectin-CHQ matrix patch formulation to deliver sustained controlled therapeutic doses of CHQ which cleared the malaria parasites within a period of 5 days. Oral administration of CHQ significantly decreased blood glucose concentrations of non-infected and P. berghei infected rats with a concomitant increase in plasma insulin concentration. Animals treated with a once off- topical application of the pectin-CHQ matrix patch presented with blood glucose concentrations which were comparable to those of untreated non-infected control animals. Both malaria infection and oral CHQ treatment significantly reduced food intake, water intake and % body weight changes by comparison with untreated non-infected control animals. In addition, oral CHQ was associated with increased urinary Na+ and K+ outputs, which were mediated through increased plasma AVP concentrations and red blood cells haemolysis respectively. The P. berghei parasites and oral CHQ treatment demonstrated blood pressure lowering effects without any change in GFR. On the other hand the once off transdermal application of the pectin-CHQ matrix patch had no significant effects on 24 hour urinary Na+, K+ outputs and MAP.
The current study has demonstrated that the pectin-CHQ matrix patch formulation not only clears the malaria parasites from the systemic circulation, but sustains normal blood glucose concentrations and does not affect renal function of malaria infected animals. This suggests that transdermal CHQ delivery has the potential to ameliorate the pathophysiological effects that are associated with oral CHQ treatment and could provide an alternative method for the management of malaria.||en