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Am. J. Trop. Med. Hyg., 77(2), 2007, pp. 235-241
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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Therapeutic Efficacy and Effects of Artemether-Lumefantrine and Amodiaquine-Sulfalene-Pyrimethamine on Gametocyte Carriage in Children with Uncomplicated Plasmodium falciparum Malaria in Southwestern Nigeria

Akintunde Sowunmi*, Grace O. Gbotosho, Christian T. Happi, Ahmed A. Adedeji, Fatai A. Fehintola, Onikepe A. Folarin, Ernest Tambo, AND Babasola A. Fateye
Department of Pharmacology and Therapeutics and Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The treatment efficacy and effects of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) on gametocyte carriage were evaluated in 181 children ≤ 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug combination. All children recovered clinically. Fever clearance times were similar. The rate of P. falciparum reappearance (recrudescence or re-infection) between two and six weeks after the start of therapy was significantly higher in AL-treated children (P = 0.01). Parasite clearance was significantly faster in children treated with AL (mean ± SD = 1.7 ± 0.6 days, 95% confidence interval = 1.58 – 1.83, P = 0.0001) but the polymerase chain reaction–corrected cure rate (90 of 91 versus 84 of 90) and the rate of resolution of malaria-related anemia two weeks after treatment began (45 of 50 versus 33 of 46) were higher in children treated with ASP. Gametocyte carriage rates were similar. Both regimens were well tolerated. Artemether-lumefantrine clears parasitemia more rapidly than ASP but both combinations are effective in treatment of uncomplicated P. falciparum malaria in Nigerian children.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Drug resistance in Plasmodium falciparum to antimalarial monotherapy is a major public health problem in much of sub-Saharan Africa1 and is, in part, responsible for increases in malaria-related morbidity and mortality in African children.2,3 Recently, there has been considerable interest in using multiple drugs with differing mechanisms of action for treatment of malaria.1,4 In this regard, both artemisinin- and non–artemisinin-based combination therapy (ACTs and NACTs) have been proposed for use in Africa. The ACTs are useful because they quickly reduce the burden of parasitemia and gametocytemia and the likelihood of drug resistance5–8 and NACTs are useful, particularly amodiaquine-based combination therapy (AQ-CTs), because they are readily available and affordable and parasites have remained sensitive to AQ-CTs in much of Africa.9–12

Virtually all of the studies on AQ-CTs in Africa have used pyrimethamine-sulfadoxine as the partner combination despite equivalent antimalarial efficacy of pyrimethamine-sulfadoxine and pyrimethamine-sulfalene.13 In African children, ACTs appear to be effective alternatives to mono-therapy or chloroquine plus pyrimethamine-sulfadoxine.8,14 However, it is unclear whether ACTs have superior efficacy to all NACTs, particularly AQ-CTs in all settings in Africa.

In contrast to amodiaquine-pyrimethamine-sulfadoxine, experience with amodiaquine-sulfalene-pyrimethamine (ASP) is relatively limited in west Africa, which makes it imperative to evaluate such combinations in sub-Saharan Africa. In Nigeria, no study has examined clinically the effects of artemether-lumefantrine (AL) on both asexual and sexual parasites and compared it with ASP. Such a study is essential because it may influence policy and management of drug resistance in the community.

In this study, we report the tolerability, antimalarial treatment efficacy, and effect on gametocyte carriage of AL and ASP in children ≤ 10 years of age with acute, symptomatic, uncomplicated P. falciparum malaria.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study area. The study was carried out in Ibadan in southwestern Nigeria from November 2005 to January 2006. In this area of hyperendemic malaria, transmission occurs all year round but is more intense during the rainy season from April to October.15 The prevalence of artesunate-amodiaquine, amodiaquine-sulfadoxine-pyrimethamine, and chloroquine-pyrimethamine-sulfadoxine resistance in the area (0%, 0%, and 5–10%, respectively) has been reported.12,14

Patients, treatment, and follow-up. Patients were eligible to participate in the study if they were ≤ 10 years of age, had symptoms compatible with acute uncomplicated malaria with a pure P. falciparum parasitemia > 2,000 asexual forms/µL, a body (axillary) temperature > 37.4°C or a history of fever in the 24–48 hours preceding presentation, absence of other concomitant illness, no history of antimalarial drug use in the two weeks preceding presentation, negative results in urine tests of antimalarial drugs (Dill-Glazko and lignin), and written informed consent given by parents or guardians. Patients with severe malaria,16 severe malnutrition, serious underlying diseases (renal, cardiac, or hepatic), and known allergy to study drugs were excluded from the study. The study protocol was reviewed and approved by the Ethics Committee of Oyo State Ministry of Health, Ibadan, Nigeria. The disease history obtained by the attending physician was recorded by asking patients or their parents or guardians when the present symptomatic period started, and was followed by a full physical examination given by the same physician.

Enrolled patients were randomly assigned to receive AL or ASP. Artemether-lumefantrine (Coartem®; Novartis, Basel, Switzerland) was given according to body weight: patients weighing 5–14 kg received one tablet, those weighing 15–24 kg received 2 tablets, those weighing 25–34 kg received 3 tablets, and those weighing more than 34 kg received 4 tablets at presentation (0 hour), 8 hours later, and at 24, 36, 48 and 60 hours after the first dose. Each tablet of AL contains 20 mg of artemether and 120 mg of lumefantrine. Amodiaquine-sulfalene-pyrimethamine (Camoquine® plus Metakelfin®; Pfizer Global Pharmaceuticals, Tadworth, United Kingdom) was also given according to body weight: patients weighing less than 12 kg received half of a tablet of sulfalene-pyrimethamine (SP) at presentation (day 0) and half of a tablet of amodiaquine for three days (day 0–2), those weighing 12–20 kg received 1 tablet of SP and 1 tablet of amodiaquine, those weighing 21–30 kg received 1.5 tablets of SP and 1.5 tablets of amodiaquine, those weighing 31–50 kg received 2 tablets of SP and 2 tablets of amodiaquine, and those weighing more than > 50 kg received 3 tablets of SP and 3 tablets of amodiaquine. Each tablet of SP contains 500 mg of sulfalene and 25 mg of pyrimethamine. Each tablet of amodiaquine contains 200 mg of amodiaquine base. In all children, the approximate dose of amodiaquine over a three-day period ranged from 29 to 33 mg/kg.

All drugs were given orally. In patients treated with ASP, the drug was given as single-day (the SP component) or single daily doses (the amodiaquine component) in the clinic by the physician. In patients treated with AL, the 0-, 24-, and 48-hour doses were given in the clinic by the physician, and the 8-, 36-, and 60-hour doses were given by parents or guardians of the children at home. Parents or guardians were questioned at follow-up on the time and events after drug administration. After drug administration in the clinic, all patients waited for at least three hours to ensure the drug was not vomited. If it was, the patient was excluded from the study. If necessary, patients were provided with antipyrectics (paracetamol tablets, 10–15 mg/kg every 8 hours for 24 hours). The randomization was computer-generated and treatment codes were sealed in individual envelopes. Patient evaluation and follow-up after drug administration was performed by another physician blinded to the drug treatment. The study nurse obtained thick and thin blood films from each child as soon as they came to the clinic. The slides were carefully labeled with the patients’ codes and air-dried before being stained.

Follow-up with clinical and parasitologic evaluation was done daily on days 1–3 and then on days 7, 14, 21, 28, 35, and 42. This consists of enquiry about the patient’s well-being, presence or absence of initial presenting symptoms, presence of additional symptoms, measurement of body temperature, heart and respiratory rates, and a blood smear for the quantification of parasitemia.

Side effects were defined as symptoms and signs that first occurred or became worse after treatment was started. Any new events occurring during treatment were also considered as side effects.

Thick and thin blood films prepared from a finger prick were stained with Giemsa and examined by light microscopy under an oil-immersion objective at 1,000x magnification by two independent assessors who did not know the drug treatment of the patient. A senior member of the study team reviewed the slides if there was any disagreement between the microscopists. In addition, the slides of every third child enrolled in the study were reviewed by this senior member. Parasitemia (asexual or sexual) in thick films was estimated by counting asexual or sexual parasites relative to 1,000 leukocytes, or 500 asexual or sexual forms, whichever occurred first. From this figure, the parasite density was calculated assuming a leukocyte count of 6000/µL of blood.

Capillary blood, collected before and during follow-up, was used to measure packed cell volume (PCV). The PCVs were measured using a microhematocrit tube and microcentrifuge (Hawksley, Lancing, United Kingdom).

Blood was spotted on filter papers on days 0, 3, 7, 14, 21, 28, 35, and 42 and at the time of treatment failures for parasite genotyping. Paired primary and post-treatment parasites were analyzed using parasite loci that exhibit repeated numbers of polymorphisms to distinguish true treatment failures from new infections. Briefly, block 2 of MSP-1 (merozoite surface protein-1) and the block 3 of merozoite surface protein-2 (MSP-2) and region II of glutamine-rich protein (GLURP) were amplified by two rounds of polymerase chain reaction (PCR) using primers and amplification conditions described.17–20 Ten microliters of the nested PCR products were resolved by electrophoresis on a 2% agarose gel and sized against a 100-basepair molecular mass marker (New England Biolabs, Beverly, MA). The banding pattern of the post-treatment parasites was compared with matched primary parasites in each of the patients who had parasitemia after treatment with either AL or ASP. Post-treatment and primary infection parasites showing identical bands were considered true treatment failures, and non-identity in banding patterns were considered newly acquired infections.

Infections were defined as polyclonal if the parasites in matched primary and post-treatment samples from the same patient showed more than one allele from one or more genes. If an isolate had one allele from each of the three loci, the clone number was taken to be one.

Response to drug treatment was assessed using the World Health Organization (WHO) 1973 criteria21 as follows: S = sensitive, clearance of parasitemia without recurrence; RI = mild resistance, parasitemia disappears but reappears within 7–14 days; RII = moderate resistance, decrease in parasitemia but no complete clearance from peripheral blood; and RIII = severe resistance, no pronounced decrease or increase in parasitemia 48 hours after treatment. In those with sensitive or mild resistance, parasite clearance time was defined as the time elapsing between drug administration and absence of detectable parasitemia for at least 48 hours. Fever clearance time was defined as the time from drug administration until the body temperature decreased to ≤37.4°C and remained there for 48 hours. Response to drug treatment was also classified according to a modified version of the WHO 14-day in vivo clinical classification system.22 Because all patients were not febrile at enrollment, a temperature < 37.5°C was not an exclusion criterion for enrollment. The modification also involved a follow-up for 42 days in this area of intense transmission.

Cure rates were defined as the percentages of patients whose asexual parasitemia cleared from peripheral blood and who were free of patent asexual parasitemia on days 14, 21, 28, 35, and 42 of follow-up. The cure rates on days 21–42 were adjusted on the basis of the PCR genotyping results of paired samples for patients with recurrent parasitemia after day 14 of commencing treatment.

Re-treatment of drug treatment failures. All but one patients failing treatment (within 35 days) with AL or ASP were re-treated with the initial drugs they were allotted and were followed-up for another 42 days. The only exception was one patient who initially was allotted AL, and was re-treated with ASP. Patients were re-treated whenever they became symptomatic (usually between 18 and 35 days after initial enrollment). Patients with profound clinical (hyperpyrexia, oral fluid intolerance) and parasitologic deterioration during follow-up were treated with parenteral quinine and were regarded as treatment failures.

Data analysis. Sample size was calculated so that the study would be able to detect a 15% absolute difference in parasitologic failure rate between AL and ASP groups with 95% power and at a 5% significance level. The expected treatment success rates were 100% for AL and 85% for ASP on day 28. Data were analyzed using version 6 of Epi-Info software23 and the statistical program SPSS for Windows version 10.01.24 Variables considered in the analysis were related to the densities of P. falciparum gametocytes and trophozoites. Proportions were compared by calculating {chi}2 with Yates’ correction or by Fisher exact or by Mantel-Haenszel tests. Normally distributed, continuous data were compared by Student’s t-tests and analysis of variance. Data not conforming to a normal distribution were compared by the Mann-Whitney U test and Kruskal-Wallis test (or by the Wilcoxon ranked sum test). All tests of significance, except where specifically indicated, were two-tailed. P values < 0.05 were taken to indicate statistically significant differences. Data were double-entered serially using the patients codes and were only analyzed at the end of the study.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient characteristics. Between November 2005 and January 2006, 181 patients entered the study: 90 in the AL group and 91 in the ASP group (Figure 1Go). There were 75 children less than 5 years old: 40 (44%) in the AL group and 35 (39%) in the ASP groups. Overall, 177 patients completed 42 days of follow-up, and the remainder, 2 in each treatment arm, completed 28 days of follow-up. Overall results are given for 181 children. The demographic and clinical characteristics of patients at enrollment are shown in Table 1Go. These characteristics were similar in the two treatment arms.


Figure 1
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  		FIGURE 1. Trial profile.

 

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TABLE 1
Demographic and clinical characteristics of patients at enrollment*
 
Fever, and parasite clearance, and gametocyte carriage. One hundred forty-seven children were febrile at enrollment: 75 in the AL group and 72 in the ASP group. Fifty-six of the children treated with AL and 51 of those treated with ASP received paracetamol during the first 24 hours. By day 1, fever cleared in 74 and 72 children, respectively. There was no significant difference in the proportion of patients in whom fever cleared by day 1 (P = 0.95, by Fisher exact test). Fever clearance was similar in the two treatment arms (mean ± SD = 1.2 ± 0.5 days versus 1.1 ± 0.4 days, P = 0.72) (Table 2Go).


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TABLE 2
Therapeutic responses to artemether-lumefantrine or amodiaquine plus pyrimethamine-sulfalene*
 
Compared with ASP, AL substantially accelerated the clearance of parasitemia. By day 2, 84 children in the AL group and 57 children in the ASP group had cleared their parasitemias. The difference in this proportion was statistically significant ({chi}2 = 23.1, P = 0.000001). Parasite clearance was significantly shorter in those treated with AL (1.7 ± 0.6 versus 2.1 ± 0.7, P = 0.0001) (Table 2Go). The cure rates on days 14–42 were similar in the two treatment arms (Table 2Go).

Response to both treatment regimens was not related to age: one child each from the 40 and 50 children < 5 and ≥ 5 years of age, respectively, treated with AL failed treatment by day 28. Similarly, 1 and 2 children from the 35 and 56 children < 5 and ≥ 5 years of age, respectively, treated with ASP failed treatment by day 14 (P = 1.0 by Fisher exact test in both groups). All patients treated with AL and ASP had adequate clinical and parasitologic response up to day 14.

Gametocyte carriage. Gametocyte carriage at enrollment and after treatment was similar in both treatment groups. In those treated with AL, 8, 1, 1, 3, 3, and 3 children were gametocyte carriers on days 0, 3, 7, 14, 21, and 28, respectively. Similarly, in those treated with ASP, 10, 1, 3, 5, 2, and 1 children were gametocyte carriers on days 0, 3, 7, 14, 21, and 28, respectively. One child from each of the two treatment arms was a gametocyte carrier during the entire period of the study.

Rate of reappearance of parasitemia. There were 21 patients, 16 in AL group and 5 in ASP treatment group in whom after initial clearance, parasitemia reappeared between days 15 and 42 (Table 2Go). There was a statistically significant difference in the proportion of patients with re-appearance of parasitemia between the two treatment groups ({chi}2 = 5.51, P = 0.01). All of the patients were symptomatic within 10 days of reappearance of parasitemia.

PCR findings. A total of 2,760 samples collected before and during follow-up were successfully amplified at all three loci (MSP-1, MSP-2, and GLURP). Genotyping of these samples showed that the allelic families of MSP-1 and MSP-2 were often represented in parasite DNA derived from one patient, which indicated a polyclonal infection, especially at enrollment. Specifically, three and two allelic families of MSP-1 and MSP-2, respectively, were assessed. Alleles were classified according to the size of PCR fragments. Comparison of the prevalence between the allelic families of MSP-1 and MSP-2 at enrollment showed a difference, which indicated a diverse Plasmodium population per infection.

Twenty one patients, 16 treated with AL and 5 treated with ASP and who were parasitemic during follow-up, had their samples analyzed at enrollment and on follow-up days 3, 7, 14, 21, 28, 35, or 42. Ten (48%) of 21, 18 (86%) of 21, and 4 (19%) of 21 isolates were polymorphic for MSP-1, MSP-2, and GLURP, respectively, which suggested polyclonal infections with at least two parasite genotypes. Up to six different fragments were found in the allelic families of MSP-2 in the isolates. Parasite genotypes in the pre-treatment and post-treatment isolates obtained from 6 (37.5%) of the 16 children treated with AL were identical. Two of the 6 children with parasites harboring identical genotypes in AL pretreatment-and post-treatment isolates had infections with a single clone identified by single alleles in the MSP-1, MSP-2, and GLURP loci. Analysis of genotypes in post-treatment isolates obtained from the remaining four isolates showed parasites similar to pre-treatment isolates but also contained new parasite populations with different genotypes. Although we considered these infections recrudescent, it is possible that these infections could be newly acquired infections with the same strain of circulating parasites in the study area, where malaria transmission is intense. Of the five ASP-treated patients that were parasitemic during follow-up, only one patient showed the same parasite population before and after treatment and was classified as a recrudescent infection. Paired samples from the remaining four patients showed different parasite populations in pre-treatment and post-treatment isolates and were therefore classified as reinfections.

Adverse events. Twenty-one children, 9 in AL group and 12 in ASP group, reported at least one adverse event within the first week of commencing treatment. There was no significant difference in the proportions of patients reporting adverse events in both treatment groups (P = 0.49). Three children treated with ASP reported more than one adverse event. Many (18 of 21) of the children reporting adverse events were more than five years of age. Table 3Go shows adverse events reported within the first week. Pruritus and weakness were significantly more frequently reported by those treated with ASP, and vomiting was significantly more frequently reported by those treated with AL. No child was withdrawn because of drug intolerance.


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TABLE 3
Adverse events reported within the first week of the study*
 
Resolution of anemia after treatment. Overall, 114 children were considered anemic (PCV < 30%) at presentation, 57 in each treatment arm. Ten of the 114 children with anemia were gametocyte carriers at presentation, and 8 of the 67 children without anemia were gametocyte carriers at presentation. The difference between the two proportions was not significant ({chi}2 = 0.19, P = 0.67). Table 4Go shows the rate of resolution of anemia after treatment. These rates were similar except on day 14 when a significantly higher proportion of patients were still anemic in the AL group.


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TABLE 4
Resolution of malaria-associated anemia following treatment*
 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have documented the tolerability and efficacy of AL and ASP in the treatment of uncomplicated P. falciparum malaria in children in a malaria-endemic area of southwestern Nigeria. The study was based on a follow-up period of 42 days. Many malaria-endemic countries in Africa now favor the use of ACTs, but in many of these countries ACTs are unaffordable and/or not readily available, which creates urgent needs to consider NCATs including amodiaquine- or pyrimethamine-sulfalene-based combinations in resource-poor African countries.9–12 In the current study, AL cleared parasitemia significantly faster than ASP but the cure rates on days 14–42 were similar to those of ASP. A similar proportion of patients allocated to each treatment regimen received paracetamol during the first 24 hours of the study. Therefore, it would appear that the similar fever clearance times, despite a slower rate of clearance of parasitemia by ASP, was caused by the enhanced antipyretic effect of amodiaquine in the ASP combination.

Recent studies from many other malaria-endemic areas of Africa have showed that amodiaquine-pyrimethamine-sulfadoxine is superior to amodiaquine alone in the treatment of uncomplicated malaria infections.12,25 The similar cure rate (on day 28) produced by amodiaquine-pyrimethamine-sulfadoxine12 and ASP in the present study suggests that both combinations may have equivalent antimalarial efficacy, at least in children from the study area. The sensitivity of P falciparum to the amodiaquine-antifolate combination appears encouraging in many areas of Africa,11,12,25–31 but in none of these studies was AL or the antifolate sulfalene-pyrimethamine the comparator drug. It would appear from the results of the present study that ASP, the individual components of which are cheap and readily available in much of Africa, is an alternative combination antimalarial drug in resource-poor communities that cannot afford AL.

The drug combinations were usually well-tolerated. Many of the children who reported adverse reactions were older children; younger children often were unable to readily volunteer drug-related adverse reactions. Therefore, frequencies of the documented adverse reactions are underestimates. The most frequently reported adverse reactions were of gastrointestinal origin and most were indistinguishable from the symptoms of malaria. Although pruritus can be caused by sulfalene, a more likely cause of pruritus in ASP-treated children is the amodiaquine component. The frequency of pruritus in ASP-treated children is considerably less than that reported in children treated with AQ alone in the same area in the late 1980s (6% versus 27%).32 The icterus and dark urine (blackwater fever) in the child treated with ASP is most likely a sulfalene-induced hemolysis consequent to glucose-6-phosphate dehydrogenase (G6PD) deficiency, but G6PD status was not determined in this patient. Amodiaqune may induce leukopenia or agranulocytosis when used repeatedly (or prophylactically).33 Thus, in many malaria-endemic areas where many people with imagined malaria self-medicate with antimalarial drugs with a regularity that borders on prophylaxis,34 caution is required as with many amodiaquine-based combinations and ASP in many malaria-endemic areas.

In spite of significantly faster parasite clearance in the AL-treated children, gametocyte carriage after treatment was similar to that in those treated with ASP. This outcome was unexpected for a number of reasons, e.g., slower clearance of parasitemia is associated with an increased risk of game-tocyte carriage;35–37 and pyrimethamine-sulfalene, presumably similar to pyrimethamine-sulfadoxine and trimethoprim-sulfamethoxazole, should enhance gametocyte release into the circulation,36–41 but this effect of antifolates could have been modulated by their combination with amodiaquine. The latter is supported by the finding that combination of anti-folates with other antimalarial drugs, e.g., 4-aminoquinolines12,25,39,41 or artesunate,42 results in reduced frequency of gametocyte carriage compared with the antifolates alone.

In many settings, e.g., in The Gambia and Thailand, ACTs result in significantly reduced gametocyte carriage,36,42 reduce infectiousness of gametocytes to mosquitoes,43–45 and may interrupt transmission in areas of low endemicity.6 Because the frequency of gametocyte carriage was similar in patients treated with AL and ASP in our cohort of children, it may be necessary to further evaluate the effects of ASP on gametocyte release and infectiousness to mosquitoes in children from this malaria-endemic area. In both treatment groups, it is likely that our estimates of the frequency of gametocyte carriage are underestimates because submicroscopic gametocytemia detectable by PCR is common after antimalarial treatment.46

Children who were anemic at presentation were not more likely to develop gametocytemia, a result that is consistent with our previous finding,37 but in contrast with this finding from other settings.25,35,44 In addition, children treated with ASP were more likely to resolve their anemia by day 14 than those treated with AL. This outcome was unexpected because clearance of parasitemia was significantly faster in AL-treated children. We have no explanation for this finding. Other factors may contribute to the anemia seen in children from this malaria-endemic area, e.g., helminth infections.

Overall, the PCR findings showed that polyclonal infections are common in children from this malaria-endemic area, which is consistent with previous findings.17–19 In addition, the PCR finding of recrudescent infections in six of the AL-treated children has significant implications for the use of ACTs in the area However, this finding is not surprising because it has been shown that parasites with reduced sensitivity to artemisinin, the parent drug from which artemether, a component of AL, is derived, are present in Nigeria.47 There are also implications for the use of ASP in the area because isolates resistant to amodiaquine are also present in the area.20

Received December 14, 2006. Accepted for publication April 24, 2007.

Acknowledgments: We thank Drs. Chris Migom and Segun Dogunro for their unparalleled support, and our clinic staff, especially Moji Amao and Adeola Alabi, for assistance with the study. The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.

Financial support: The study was supported by Pfizer Global Pharmaceuticals.

* Address correspondence to Akintunde Sowunmi, Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. E-mail: akinsowunmi{at}hotmail.com Back

Authors’ addresses: Akintunde Sowunmi, Grace O. Gbotosho, Christian T. Happi, Ahmed A. Adedeji, Fatai A. Fehintola, Onikepe A. Folarin, Ernest Tambo, and Babasola A. Fateye, Department of Pharmacology and Therapeutics and Institute for Medical Research and Training, University College Hospital, University of Ibadan, Ibadan, Nigeria, Telephone: 234-2-241-2101, Fax: 234-2-241-1843, E-mail: akinsowunmi{at}hotmail.com.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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