Nwobodo, Okonkwo P. O. Comparative Study on the Efficacy of Sulfadoxine- Pyrimethamine, Amodiaquine and Amodiaquine + Sulfadoxine-Pyrimethamine Combination in the Treatment of Acute Uncomplicated Malaria in Enugu State, Nigeria. Biomed. Pharmacol. J.2008;1(2)

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Manuscript received on :September 30, 2008
Manuscript accepted on :November 01, 2008
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Nwobodo^¹* and P. O. Okonkwo^²

^¹Department of Pharmacology and Therapeutics, College of Medicine, Enugu State University of Science and Technology Enugu Nigeria.

^²Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Nigeria.

Abstract

Malaria is a major killer disease affecting one third of the world’s population with untold morbidity and mortality especially in under five children in Sub-Saharan Africa. In a randomized controlled trial, involving 180 children aged 6 to 59 months, (M:F, 1:1.37) with clinically characterized malaria; the efficacy of Amodiaquine (AQ) and Sulfadoxine-Pyrimethamine (SP) as monotherapy and in combination as AQ + SP was evaluated. Results revealed that Fever Clearance Time (FCT) of 28.3±2.3 hours in AQ + SP was significantly different (P<0.05) from 51.2±2.3 hours and 74.6±2.5 hours in AQ and SP respectively. Similarly, the Parasite Clearance Time (PCT) in AQ + SP combination differed significantly (P<0.05) from AQ and SP respectively. There was no reported treatment failure in AQ + SP with a Radical Cure Rate (RCR) of 100%. This contrasts with RCR of 83.5±0.34% and 73.8±0.42% reported for AQ and SP respectively in this study. There was no statistically significant difference P>0.05 in the haematocrit and axillary temperatures at pre and post-treatment in the various treatment groups. In conclusion, the AQ+SP combination is strongly recommended for treatment of uncomplicated P.falciparum malaria especially in under 5 children in Enugu, Nigeria.

Keywords

Combination therapy; efficacy; monotherapy; malaria

Introduction

It has been shown that artemisinin-based combination therapy (ACT) could improve therapeutic effectiveness, reduce gametocyte carriage and delay the emergence and spread of drug resistant parasite.¹  It is noteworthy, that despite the recent change in national malaria drug policy in favour of artemisinin-based combination therapy (ACT) in Nigeria, the non-ACT regimens still remain the commonest antimalarial drugs widely prescribed as a result of low cost and availability.²  There is, therefore, the need for continuous monitoring and evaluation of the efficacy of these combination therapies in the management of acute uncomplicated P.falciparum malaria.  This study attempts to evaluate the current status in respect of clinical and therapeutic efficacy of      non-ACT (AQ + SP) and ACT (AT + AQ) in the treatment of acute uncomplicated P.falciparum malaria among under five children in Enugu State, Nigeria.

Patients and Methods

Patients (n = 120) enrolled in this study were selected by stratified random sampling from children with clinically characterized uncomplicated malaria aged 6 to 59 months (M:F = 1:1.32) who presented at Amafor primary healthcare facility, Ugbakwa; a rural farming population with high endemicity of malaria  transmission, under the Asu Nkanu Local Health Authority of Enugu State.  They presented with a history of fever in the preceding 24 to 48 hours or axillary temperature > 37.5^oC and parasitemia > 2000 asexual forms/mL of blood.  Patients with concomitant illness, intense vomiting, recent history of convulsion, lethargic or unconscious state and sickle cell anaemia were excluded.  Ethical clearance was obtained and informed consent of the parent or guardian for each child was sought.  The patients were subsequently assigned randomly to any of the drug treatment groups: AQ + SP or AT + AQ.  Thus, 60 patients were allotted to each treatment group.  Drug dosages were computed using the weight of the patients.  AQ was given at a dose of 10mg/kg daily for 3 days and SP at 25mg/kg as single dose on Day 0.  AT was given at a dose of 2mg/kg twice daily on Day 0, and 1mg/kg twice daily for the next 4 days.  Drugs were administered orally by direct observation and monitored by the clinician to ensure they were not vomited.  Drugs were re-administered within 1 hour following initial vomiting but withdrawn from the study with another episode of vomiting. Patients were followed up for 2 weeks after treatment.  Evaluation of response carried out on days 1,2,3,7 and 14 according to WHO criteria¹.  Data obtained were statistically analyzed using Student t-test and presented in tabular form.

Results

Table 1, clearly depicted the therapeutic response of patients in both    AQ + SP and AT + AQ combinations.  In the AQ + SP treatment group, mean Fever Clearance Time (FCT) of 28.3+2.3 hours was not significantly different (P>0.05) from 25.4+2.3 hours reported for AT + AQ combination therapy.  Similarly mean Parasite Clearance Time (PCT) of 3.5+0.15 days in ACT (AT + AQ) did not differ significantly from 3.7+0.15 days reported in non–ACT (AQ + SP).  Interestingly, there was no reported treatment failure in both combinations, with a radical cure rate of 100% reported for both ACT and non-ACT.  It was also noted as shown in tables 2 and 3, that there was no statistically significant difference (P>0.05) in the haematocrit and axillary temperature of patients both at initial presentation, Day 0 and post-treatment, Day 14 in both AQ + SP and AT + AQ combination therapies.

Table 1:   Therapeutic Response of Patients in the Various Treatment Groups. 

Table 2:   Pre and Post- Treatment Haematocrit and Axillary Temperature Of Patients in the Aq + Sp (Non-Act) Treatment Group.

Table 3:   Pre and Post-Treatment Haematocrit and Axillary Temperature of Patientsi in the  At + Aq (Act) Treatment Group

Discussion

The non-ACT regimen AQ + SP in this study has been demonstrated to be quite effective in the treatment of uncomplicated P.falciparum malaria with a radical cure rate recorded as 100%.  This study also revealed as shown in table 1, that there was no statistically significant difference (P>0.05) in the various criteria used to assess therapeutic response between AQ + SP and AT + AQ combinations.  Amodiaquine, a 4-aminoquinoline and effective blood schizonticide, is useful in areas where there is low-grade chloroquine resistance but recrudescence is not uncommon³.  The AQ + SP combination was shown to be more effective than ACT for the treatment of uncomplicated malaria in Burkina Faso⁴.  Although SP is still relatively effective in most areas in Africa, resistance is increasing and could potentially develop as it has in Asia, to render the drug useless in the near future⁵.  The use of AQ + SP combination could also slow down development of parasite resistance to the individual drugs, increasing the life-span of each of them as an effective anti-malarial drug⁶.  In the AT + AQ combination (ACT), a cure rate of 100% was also recorded in this study.  Artesunate (AT) is a water soluble analog of artemisinin, a sesquiterpene lactone endpoperoxide.  It is a very rapidly acting blood schizonticide.  Its antimalarial activity results from the production of free radicals following the iron-catalyzed cleavage of the endoperoxide bridge in the parasite.  The enhanced, cumulative blood schizonticidal effect of AT + AQ combination, therefore, is very beneficial in ensuring rapid fever clearance and relief of symptoms.  Notwithstanding, the effectiveness and good therapeutic response of AT + AQ combination reported in this study, as evidenced by exceptionally high cure rate and no treatment failures; high cost and non-availability have seriously limited the effective use of ACT⁷.  The change in treatment policy in Nigeria to ACT without adequate sensitization and education of medical personnel may pose some difficulties that could lead to high morbidity and mortality⁸.  A resultant increase in resistance of P.falciparum to these new combinations may also arise since transition into an alternative compound may take some years before they are accepted and put into proper use⁹. Current World Health Organisation (WHO) recommendations have focused on the use of combination antimalarial therapy, particularly artemisinin-based combination therapy (ACT)^10,11.  However, several control programmes in Africa have switched to non-ACT, for example AQ + SP¹².  In conclusion, the AQ + SP combination (non-ACT) is strongly recommended as a cost effective and therapeutic alternative to ACT, for the treatment of acute uncomplicated P.falciparum malaria especially in under five children in Enugu State, Nigeria.

References

1. WHO – World Health Organization. (2006) Guidelines for the treatment of malaria. WHO Press, Geneva.
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3. Olliaro P. and Mussano P. (1997). Amodiaquine for the treatment of malaria.  Infectious diseases module of the cochrane database of systematic reviews.  BMJ Publishing.
4. Zongo I., Dorsey G., Rouamba N., Tinto H., Dokomajilar C., Guiguemde R.T., Rosenthal P.D. and Ouedraogo J.B. (2007). Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomized non-inferiority trial.  Lancet. 369: 491 – 498.
5. Trigg J.K., Mbwana H., Chambo O., Hills E., Watkins W. and Curtis C.F. (1997). Resistance to sulfadoxine-pyrmethamine in falciparum in 12 Villages in North East Tanzania and a test of Chloroproguanil/dapsone.  Acta Tropica. 63:185 – 189.
6. Kremsner P.G., Luty A.J.F and Granninger W. (1997).  Combination chemotherapy for falciparum malaria.  Parasitology Today. 13: 167 – 168.
7. Yeung S., Pongtavornpinyo W., Hastings I.M., Mills A.J and White N.J. (2004). Antimalarial drug resistance, artermisinin-based combination therapy and the contribution of modeling to elucidating policy choices.  Am J. Trop Med Hyg. 71: 179 – 186.
8. Ogungbameigbe T.O., Ojurongbe O., Ogunro P.S., Okanlawon B.M. and Kolawole S.O. (2005) Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment.  Mem Inst Oswaldo Cruz. 103 (1): 79 – 84.
9. Shretta R., Omumbo J., Rapuoda B. and Snow R.N. (2000). Using evidence to change antimalarial drug policy in Kenya. Trop Med Int Health. 5:755 – 764.