Effects of novel chloroquine formulation on blood glucose concentration, renal and cardiovascular function in experimental animal paradigms.
Malaria disease poses a serious global health burden as recent reports have indicated that nearly half of the world’s population is at risk (WHO 2008). The World Health Organization (WHO) Expert Consultative Team has reported that 90% of all malaria deaths occur in Sub Saharan Africa. (WHO, 2008). Despite the numerous global efforts to control and manage the disease, through various ways, use of chemotherapeutic agents continues to be the major intervention strategy in the control of malaria. The WHO recommended use of Artermisinin combination therapy (ACT) has been hampered by an imbalance between demand and supply in the poor socioeconomically challenged rural populations of Sub Saharan Africa, the epicenter of malaria infection. Chloroquine (CHQ), therefore, continues to be used in most malaria endemic areas in developing countries despite development of P. falciparum resistance to the drug (WHO, 2006). Oral administration is the major delivery route for CHQ. However, CHQ is a bitter drug, with an inconvenient dosing schedule leading to incomplete courses of therapy by most malaria patients. Oral CHQ administration is also associated with adverse effects in various organ systems resulting from deposition of CHQ in these organs to elicit impairment of glucose homeostasis, renal and cardiovascular function. Alternative methods of CHQ administration such as transdermal delivery have, therefore, been suggested, in an effort not only to avoid the bitter taste, but also to modify the dosing schedule, which may improve patient comfort and compliance. Transdermal delivery of CHQ via an amidated matrix patch, which is envisaged to ensure a slow, controlled and sustained release of therapeutic concentrations of CHQ, may circumvent the previously reported adverse effects of oral CHQ. It is against this background that the current study compared the effects of transdermal CHQ patch and oral chloroquine in the management of malaria as assessed by the ability to clear parasites of P. berghei infected rats. The other aims were to investigate and distinguish between the patho physiological effects of malaria and CHQ treatments on blood glucose and plasma insulin concentration, renal and cardiovascular function in male Sprague-Dawley rats. To investigate and distinguish between the pathophysiological effects malaria infection and CHQ treatments on blood glucose homeostasis, renal and cardiovascular function markers, separate groups of non infected and P. berghei infected male Sprague Dawley rats (90g-150g) were used. The animals were treated twice daily with oral CHQ (60mg/kg) and a once off transdermal delivery of CHQ via topical application of pectin CHQ matrix patch (53mg/kg) in a 21 day study divided into pre treatment, (days 0-7) treatment (days 8-12) and post treatment (days 13-21) periods. The animals were housed individually in metabolic cages for the duration of the study. Treatment was for 5 consecutive days. Measurements of body weight, food and water intake, mean arterial pressure (MAP), blood glucose concentration, % parasitaemia, haematocrit, and 24 hour urine volume, Na+, K+, urea and creatinine outputs were done every day during the treatment period, and every third day during the pre and post treatment periods. Separate groups of non fasted conscious animals (n=6) were sacrificed on days 0, 7, 8, 9, 10, 12, 14 and 21, at 24 hours after the last treatment for oral CHQ administration and after a once off patch application on the first day of treatment. The plasma obtained was assayed for plasma insulin, lipid profile parameters and plasma Na+, K+, urea and creatinine. The harvested liver and gastrocnemius muscle were used for determination of glycogen concentration. The current study has demonstrated the sustained controlled release of CHQ from the pectin matrix patch, demonstrating the therapeutic ability to clear P. berghei malaria parasites from systemic circulation. Malaria infection and oral CHQ treatment exhibited blood glucose lowering effects which were circumvented by topical application of the pectin CHQ matrix patch. Oral CHQ elevated hepatic glycogen concentration through mechanisms that are still to be elucidated. Topical application of CHQ via pectin matrix patch did not alter hepatic and gastrocnemius muscle glycogen concentrations. Malaria infection and oral CHQ delivery reduced food intake, water intake and % body weight changes of the animals as well as inducing natriuresis, reduced urine output and increased urinary creatinine outputs. Malaria infection was also shown to elicit hyperkalaemia and kaliuresis in experimental animals. Hypotensive effects of malaria infection and oral CHQ delivery were also demonstrated in the current study. Malaria infection and oral CHQ delivery elevated plasma total cholesterol and LDL-c as well as reduction in the cardio protective particle, plasma HDL-c, concentrations. Topically delivered CHQ via pectin CHQ matrix patch did not evoke any such alterations, suggestive of its ability to circumvent the observed adverse effects of oral CHQ delivery due to sustained, controlled release of therapeutic concentrations of CHQ from the transdermal formulation. To the best of our knowledge, the results of the present study provides the first evidence of the release of therapeautic CHQ concentrations from pectin CHQ matrix patch that cleared the malaria parasites from systemic circulation as well as demonstrating the ability of the transdermal formulation to circumvent the adverse effects of oral CHQ delivery in glucose homeostasis, renal and cardiovascular function markers. This is clinically relevant as it provides a feasible and novel alternative method of CHQ delivery that could play a major role in the effective management of malaria.