ABSTRACT

Background: Previous animal studies have shown that ciprofloxacin has effect on the antimalarial activity of some antimalarials. Presently in Nigeria, combination of ciprofloxacin and ACTs are commonly prescribed in the treatment of malaria and enteric fever co-infection.

Objectives: To evaluate the effect of ciprofloxacin on the antimalarial activity of Artesunate, Artemether-lumefantrine and Artesunate-amodiaquine using mice model.

Methods: One hundred and twenty mice infected with chloroquine sensitive Plasmodium berghei NK65 strain were used for this study. The study was carried out in three phases.  Phase 1 consisted of AS, AL, ASAQ and CIP treatment groups, the Artesunate (AS)  treatment group consisted of three treatment subgroups of four mice per group treated with 3, 6 and 12 mg/kg doses respectively;  Artemether-lumefantrine (AL)  treatment group consisted of three treatment subgroups of four mice per group treated with 16, 32 and 64 mg/kg doses respectively; Artemether-amodiaquine (ASAQ)  treatment group consisted of three treatment subgroups of four mice per group 11, 22 and 44 mg/kg doses respectively, and Ciprofloxacin (CIP1&2) subgroups treated with 7 and 14 mg/kg doses respectively.  Phase II consisted of groups of mice treated with 7 mg/kg ciprofloxacin (CIP1) combined with different doses of Artesunate, Artemether-lumefantrine, Artesunate-amodiaquine as used in phase 1 respectively.  Phase III consisted of groups of mice treated with 14 mg/kg ciprofloxacin (CIP2) combined with different doses of Artesunate, Artemether-lumefantrine, Artesunate-amodiaquine respectively as in phase I. The dosing of these drugs was based on body weight and administered orally as daily single dose. Thin blood films were used to assess parasitaemia level daily after administration of drugs for 72 hours. The effect of the drugs on the activities of serum Alanine transaminases (ALT) and Aspartate transaminases (AST) were also evaluated. Statistical analysis was done using Student-test and ANOVA.

Results: Antimalaria activity of Artesunate was enhanced by ciprofloxacin (7mg/kg) through increased percentage reduction of parasitemia level by Artesunate. The effect of ciprofloxacin 14mg/kg on the three doses of Artesunate was found to be statistically significantly different from that of the same doses of Artesunate at 48 and 72 hr. As the dose of AL combined with CIP2 increased, the percentage maximum reduction decreased. Only the effect of ciprofloxacin on the antimalarial activity of AA 22mg/kg at 72hrs showed a significant difference from the AA at the same doses. Ciprofloxacin significantly decreased ALT and AST activities. Artesunate combined with CIP1 produced a statistically significant decrease in ALT when compared to the control group. All the groups treated with AL showed no statistically significant difference in the ALT and AST activities; apart from AL: CIP2 (64:7mg/kg) which showed significantly increased AST activities. All the groups treated with ASAQ in combination with ciprofloxacin showed a statistically significant decrease in the AST activities apart from ASAQ: CIP2 (44:14mg/kg). Only the groups treated with ASAQ: CIP2 produced a significant decrease in the serum ALT activities.

Conclusion:Ciprofloxacin enhanced the antimalarial effects of Artesunate, Artemether-lumefantrine and Artesunate-amodiaquine against the chloroquine sensitive P.berghei in albino mice. This may be beneficial in the management of plasmodium falciparum infection or co-infection with salmonellosis.

CHAPTER ONE

INTRODUCTION

1.1   Background

Drug interactions have been recognized for over 100 years. With the increasing availability of complex and highly effective therapeutic agents and widespread poly-pharmacy, the rate of drug interactions has become so enormous with associated adverse reactions. The risk of drug interactions has been reported to increase from approximately 6% in patients taking only two medications to 50% in those taking five medications and 100% in those taking 10 medications (Khan et al, 2011).   Drug interaction occurs when the pharmacokinetics and/or the pharmacodynamics of a drug are altered by the presence of another drug, food, drink, or herb (Esimone, 2011).

                Malaria is a leading cause of morbidity and mortality in children and adults, especially in developing countries, and remains a major public health problem in endemic regions (Breman et al, 2004; WHO, 2010). In 2002, more than 2 billion people in the world and 521 million in Africa were at risk of malaria (Snow et al, 2005). According to Ughasoro et al (2013), in Nigeria, malaria accounts for approximately 40% of hospital admissions and 30% of mortalities. Approximately one million deaths among children under 5 years old are attributed to malaria alone or in combination with other diseases (WHO, 2009). Malaria can be associated with other infections such as enteric fever, diarrhoea, HIV, TB. Enteric fever is also a widely recognized major public health problem in most developing tropical countries, with estimated global burden of greater than 27 million cases per annum and clinical relapse rate of 5% to 20% (Parikh, 2012). Its impact is difficult to estimate because the clinical picture is confused with those of other febrile infections (WHO, 2003). The disease is also underestimated because there are no bacteriology laboratories in most areas of the developing countries. However, the precise incidence of the concurrent malaria and typhoid fever in most geographical areas is largely uncertain. Since both typhoid and malaria share social circumstances which are imperative to their transmission, individuals in areas endemic for both diseases are at substantial risk of contracting both diseases, either concurrently or an acute infection superimposed on a chronic one  (Keong et al, 2006).

1.2 Statement of Research Problem

Malaria still remains a heavy health burden in tropical communities, threat to non-endemic countries and danger to travelers to endemic countries. In Nigeria, morbidity associated with illnesses due to salmonella continues to be on the increase and, in some cases, results in death (Akinyemi et al, 2000). There is also high incidence of malaria and enteric fever co-infection (Uneke, 2008).  The frequent co-existence of these infections has led to the co-administration of an antimalarial and antibiotic. The chemotherapeutic arsenal for malaria treatment today is limited to three main families of compounds: quinolines, antifolates and Artemisinin derivatives (Griellier et al, 2012). Artemisinin combination therapies (ACTs) are the only antimalarial drugs with very minimal resistance recorded (Noedl et al, 2008). It has been recorded that from 2000-2008, the use of ACTs combined with vector control reduced considerably the number of cases of malaria in some African countries (Enserink, 2010).