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Am. J. Trop. Med. Hyg., 76(1), 2007, pp. 1-6
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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DIHYDROARTEMISININ SUPPOSITORY IN MODERATELY SEVERE MALARIA: COMPARATIVE EFFICACY OF DIHYDROARTEMISININ SUPPOSITORY VERSUS INTRAMUSCULAR ARTEMETER FOLLOWED BY ORAL SULFADOXINE-PYRIMETHAMINE IN THE MANAGEMENT OF MODERATELY SEVERE MALARIA IN NIGERIAN CHILDREN

CATHERINE O. FALADE*, FRANCIS F. FADERO, CHRISTIAN T. HAPPI, HANNAH O. DADA-ADEGBOLA, GRACE O. GBOTOSHO, IDOWU AYEDE, ADEGOKE G. FALADE, AYOADE M. J. ODUOLA, AND LATEEF A. SALAKO
Malaria Research Laboratories, IMRAT, College of Medicine, University of Ibadan, Ibadan, Nigeria: St Mary’s Catholic Hospital, Eleta, Ibadan and Department of Pediatrics Ladoke Akintola University of Technology, Oshogbo, Nigeria; Department of Pediatrics, College of Medicine, University of Ibadan, Ibadan, Nigeria; Department of Medical Microbiology, College of Medicine, University of Ibadan, Ibadan, Nigeria


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We compared two dose forms of artemisinin derivatives, dihydroartemisinin suppository (DHA) and intramuscular artemether (ART), in children 6 months to 10 years of age with moderately severe malaria for which oral therapy was not appropriate. Children were randomly allocated to receive three daily doses of DHA or ART followed by a single oral dose of sulfadoxine-pyrimethamine on the third day of both treatment regimens and were monitored for parasitologic and clinical response for 14 days. At enrollment, parasite density was 1,640–523,333/µL (geometric mean parasite density [GMPD] = 58,129/µL) in patients treated with DHA, whereas that for children who received ART was 1,440–559,400/µL (GMPD = 60,387/µL). Mean parasite and fever clearance times were similar in both groups. Days 14 and 28 parasitologic cure rates were 100% (34 of 34) and 96.2% (25 of 26) versus 96.2% (25 of 26) and 91.7% (22 of 24) for children treated with DHA and ART, respectively. In conclusion, both treatment regimens were efficacious and well tolerated.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Malaria continues to exert an unacceptably high death toll among African children despite efforts aimed at its control.1,2 Annually, 300–500 million clinical cases of malaria and an estimated 1.5–2.7 million deaths occur in the world. At least 70% of malaria cases and deaths occur in Africa, south of the Sahara.3 Death in fatal cases often occurs within 48 hours of admission into hospital,4 whereas up to 80% of deaths occur before the child reaches any hospital facility in some areas.1,5,6 One strategy that has been proven effective in reducing the morbidity and mortality caused by malaria is early diagnosis and prompt treatment with effective drugs.7 Nausea and vomiting often make oral treatment impossible. Convulsions and coma are other common complications of severe malaria in children, which make administration of oral formulations impracticable when most needed.1 To reduce the morbidity and mortality from malaria, parents need to be empowered to diagnose and treat it at home. One way of giving treatment to children who cannot take oral medication at home is the use of suppositories. In Nigeria and parts of Africa, the culture has a bias toward injection rather than suppository.8 Unfortunately, malaria is more severe in the rural areas,9 where manpower, syringes, water, and electricity to sterilize equipment are often lacking. Artemisinin derivatives in various formulations including suppositories have been shown to be rapidly schizonticidal and effective in the treatment of malaria of varying severity and drug sensitivity.10–13. Dihydroartemisinin (DHA) suppositories recently became available in Nigeria. This study was conducted to evaluate the efficacy, safety, and acceptability of the dihydroartemisinin suppository in the management of moderately severe malaria in southwestern Nigeria with a view to providing modalities for managing this category of patients in Primary Health Care facilities.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study design. The design was an open randomized study. Patients were randomly allocated to receive DHA suppository (Cotecxin; Beijing COTEC New Technologies; Beijing, China) or intramuscular artemether (ART; Paluter; Rhõne-Poulec, France) daily for 3 days plus a single dose of sulfadoxine-pyrimethamine (SP; Fansidar; Swipha, Nigeria) at the time of last dose of DHA suppository or ART. Beijing COTEC New Technologies, now Beijing Holly-Cotec Pharmaceutical, has a certificate of Good Manufacturing Practices for pharmaceutical products from The People’s Republic of China.

Study site. This study was conducted at the pediatric emergency wards and clinics of the University College Hospital and St Mary’s Catholic Hospital, Eleta, both in Ibadan, southwestern Nigeria. Ibadan is located in the rainforest zone of Nigeria, where malaria transmission is hyperendemic. The inhabitants of Ibadan are exposed to intense malaria transmission year round, with peak transmission occurring during the raining season months of June to September. Walk-in clinics, which are manned by physicians who are conversant with the management of malaria, run daily at both hospitals.

Ethical issues. The Joint University of Ibadan/University College Hospital ethical review board reviewed the protocol and provided ethical approval before commencement of the study. The informed consent document was read to the parent or guardian of prospective study participants in English or the local language (Igbo, Hausa, and Yoruba), whichever language was best understood by the parent or guardian. A written or witnessed verbal informed consent was subsequently obtained from the parent or guardian of each study participant before any protocol-specific procedures or interventions were carried out. The study was done according to "Good Clinical Practice" and followed the principles of the declaration of Helsinki.

Patients. Although the study was designed to evaluate 100 children with moderately severe malaria, the study was prematurely stopped after enrollment of 72 children because patient enrollment was slow. Our sample size calculation was time bound. We planed to enroll all patients that satisfied the enrollment criteria and gave informed consent in 1 year and expected to have at least 100 patients within the year. However, we were able to enroll 72 patients in 2 years and had to terminate the study after 2 years. In our opinion, enrollment of only 72 patients instead of 100 has no effect on our study results.

Children 6 months to 10 years of age with fever suspected to be caused by malaria were screened between August 2001 and August 2003 in the two study centers. Children with Plasmodium falciparum infection (minimum parasitemia 1000 asexual parasites/µL of blood) were enrolled into the study if two or more of the following conditions were present: axillary temperature ≥ 39°C, recurrent vomiting (≥ 3 in 24 hours), prostration without loss of consciousness, and two or more convulsions in the 24 hours preceding presentation. Exclusion criteria were refusal to give informed consent, known hypersensitivity to any ART derivative and sulfadoxine-pyrimethamine, severe anemia (hematocrit < 15%) requiring blood transfusion, local disease of the rectum (e.g., prolapsed hemorrhoids or rectal prolapse), coma, jaundice, and treatment within the preceding 7 days with any ART derivative and/or sulfadoxine-pyrimethamine. However, patients with pre-existing diarrhea were not excluded from the study. Patients with severe anemia were excluded to eliminate the risk of transfusion malaria to study patients, which could affect study outcome. Children with chronic diseases (e.g., sickle cell anemia), concurrent infections that may mask evaluation of response to treatment, and patients whose parents were judged unable to comply with study protocol by the investigators were also excluded from the study. Patients who violated the study protocol were withdrawn from the study. Other withdrawal criteria were repeated expulsion of suppository (> 1 time), development of a serious adverse event, or at the wish of the parents/guardian.

A thorough medical history and physical examination was carried out on every patient before enrollment. Thick and thin blood films were prepared from a finger prick and stained with 10% fresh Giemsa stain for parasite identification and quantification. Parasite density was determined by counting the number of asexual parasites relative to 200 leukocytes in each thick blood film, assuming a mean leukocyte count of 8,000/µL of blood. Capillary blood was collected on filter paper for parasite DNA amplification at enrollment and recurrence of parasitemia to enable us differentiate recrudescence from re-infection. Venous blood was also obtained by venepuncture at Days 0 and 7 for evaluation of serum bilirubin, alanine transaminase (ALT), and aspartate transaminase (AST). Hematologic evaluation at enrollment and at Day 7 included hematocrit, white blood cell count, and differential.

Study medication administration and follow-up. Randomization was done by the use of table of random numbers. Because of the markedly different drug forms and routes of administration (DHA as a suppository and ART by intramuscular route), it was not possible to blind the study. However, bias was avoided by ensuring that the persons who did the follow-up clinical examinations and laboratory tests did not know to which group the patients belonged. Patients in Group 1 ≤ 2 years of age received a 40-mg DHA suppository, whereas those > 2 years of age received a 80-mg DHA suppository at 0 hours. Follow-up doses of a 40-mg DHA suppository at 24 and 48 hours completed the dose for all age categories; only 80- and 40-mg suppositories were available. Those in Group 2 received intramuscular ART (Paluter; Rhõne Poulec) at a dose of 3.2 mg/kg at 0 hours and 1.6 mg/kg at 24 and 48 hours. SP (Fansidar; Swipha) was administered orally at 48 hours to both treatment groups as a single dose. SP was administered according to the following dose schedule by child weight: 5–10 kg, 0.5 tablet; 11–20 kg, 1 tablet; 21–30 kg, 1.5 tablets. Each tablet of Fansidar contains 500 mg sulfadoxine and 25 mg pyrimethamine.

The study consisted of two phases: the treatment and follow-up phases. Patients were hospitalized during Phase 1, which was the treatment phase. Drugs were administered supervised by a trained nurse or physician. During this phase, which lasted for 3 days, children who received the DHA suppository were laid in the left lateral position, and the DHA suppository was inserted into the rectum beyond the anal sphincter. Patients were encouraged to lie in this position for at least 30 minutes afterward. A parent or guardian of each child was requested to hold the buttocks together to prevent expulsion of suppository. Rectal suppositories expelled within 30 minutes of insertion were replaced. Children who expelled the suppository more than once were withdrawn from the study. Clinical and parasitologic monitoring was done every 6 hours while the patients were in the hospital. Phase 2 covered the period of outpatient visits after discharge from hospital on Days 3–14. During this period, patients were seen daily up to Day 7 and then on Day14. Although the study was designed to end on Day 14, patients were encouraged to come for follow-up on Days 21 and 28. Adverse events and concomitant medication details were carefully documented throughout the follow-up period.

Additional supportive management included tepid sponging and/or fanning of patients and administration of paracetamol at a dose of 10–15 mg/kg when patients could take and retain oral medication. Severely dehydrated patients received intravenous fluids consisting of dextrose saline at 30 mL/kg. Intramuscular paraldehyde or intrarectal diazepam was used for control of recurrent seizures. Children whose hematocrit dropped to 15% or below were transfused with fresh whole blood or packed red blood cells. Blood chemistry and hematological examination were repeated on Day 7. Repeat blood chemistry and full blood count were done on Day 14 only if abnormalities were noted on Day 7 results. All information collected during the study was entered into case record forms specifically designed for the purpose.

Safety and efficacy assessment. The primary efficacy variables were defined as development of an adverse event, which was thought to be drug related and severe enough to warrant no further drug exposure, and progression to World Health Organization (WHO)-defined severe malaria.14

In the protocol, the secondary efficacy evaluation of the two drugs was based on the 1996 WHO15 in vivo test. The 200316 modification has, however, subsequently become available. Treatment outcome was also determined using mean parasite clearance time (PCT) and fever clearance time (FCT). PCT was defined as the time required to clear patent parasitemia, which remained clear for the period of the 14-day follow-up, whereas FCT was defined as time taken from instituting therapy for temperature > 37.5°C to come down to < 37.5°C and remain < 37.5°C for at least 72 hours. Associated adverse effects of therapy and treatment outcome, early treatment failure (ETF), late treatment failure (LTF), or adequate clinical response (ACR) (Day 7 and 14 cure rates), were compared in the two groups to assess the efficacy and safety of the two regimens.

An interim analysis was carried out after the first 40 patients had completed the study. This was done to detect any major advantage of the parenteral regimen over the suppository formulation. The study design made provision for discontinuation of enrollment into the suppository arm if there was > 10% difference in efficacy between the two treatment regimens. However, the DHA suppository was found to be as effective as intramuscular ART during the interim analysis.

Discrimination between recrudescence and re-infections in treatment failures. Previous studies17,18 on molecular analysis of P. falciparum malaria in Ibadan, Nigeria, have shown that the merozoite surface protein-2 (msp-2) was the most informative genetic marker to evaluate parasite diversity and the complexity of P. falciparum infections. Isolates from each P. falciparum infection in the study were characterized on the basis of the fragment size of alleles of msp-2 after amplification by polymerase chain reaction (PCR). Infections were defined as polyclonal if parasites in matched primary and post-treatment samples from the same patient showed more than one allele of the FC27 or IC1/3D7 families of msp-2. If an isolate had one allele at each of the families, the clone number was taken to be one. A recrudescent infection was defined as the occurrence of the same or a subset of the alleles at each of the families (FC27 or IC1/3D7) of msp-2 in the primary and post-treatment samples. A lack of allelic identity in the two families of msp-2 in matched primary and post-treatment samples indicated a newly acquired infection. The complexity of infection was calculated as the average number of distinct fragments of FC27 and IC1/3D7 per PCR-positive sample.

Attitude of parents and caregivers to DHA suppository use. Attitudinal disposition of caregivers to suppository use was introduced as a result of the spontaneous questions doubting its efficacy from the mothers of the first two enrolled children during the informed consent procedure. Subsequently, many more mothers expressed the same concern. Mothers who did not spontaneously express skepticism were asked whether they felt it will work with a "yes, don’t know, or no" answer option. Attitudinal disposition was re-evaluated before discharge from the hospital.

Data analysis. Efficacy and safety data were analyzed using Epi-info software (version 6.04, Centers for Disease Control and Prevention (CDC), Atlanta, GA). Proportions were compared by calculating {chi}2 with Yates proportion or Fisher exact test. Normally distributed continuous data were compared by Student t test and one-way analysis of variance (ANOVA). Mean values are given in the text and tables as mean ± SD, and values of P < 0.05 were considered statistically significant.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient demography. Thirty-five of the 72 randomized patients received ART plus SP, whereas 37 received DHA plus SP. Forty-six (63.9%) enrolled patients were < 5 years of age and comprised 23 in each treatment arm. All randomized patients are included in the intention-to-treat population (ITT). Enrollment characteristics were similar in both treatment groups (Table 1Go). Sixty-eight (94.4%) of the 72 randomized patients had enough data for analysis and are regarded as the per protocol population (PPP). Thirty-four patients each in the PPP received DHA and ART, respectively. Thirty-one were boys, and 41 were girls. The frequencies of occurrence of manifestation of malaria were comparable among the patients and are shown in Table 2Go.


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TABLE 1
Enrollment characteristics of children with moderately severe malaria treated with DHA suppository or intramuscular ART
 

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TABLE 2
Frequency of occurrence of danger signs among children with moderately severe malaria treated with DHA suppository or intramuscular ART
 
Therapeutic efficacy. No deaths were recorded during the study. Four patients were withdrawn from ITT analysis (three received DHA and one received ART). Two of those who received DHA were lost to follow-up, having traveled out of the study area. The third patient was withdrawn as a result of protocol violation, haven taken co-trimoxazole (known to have potent antimalarial properties) for a supposed acute respiratory infection before Day 14. One patient who received ART was lost to follow-up after Day 7. Although no patient was withdrawn as a result of repeated suppository ejection, three (8.8%) patients who received DHA expelled the suppositories. Two of the three patients expelled the suppository after the first dose, whereas the third patient expelled the suppository after the second dose. None of the three patients suffered repeated suppository expulsion after re-insertion. One patient who received intramuscular ART progressed to cerebral malaria within 24 hours of enrollment. This patient was regarded as a treatment failure, and rescue therapy was instituted. The patient was 3 years old and presented with convulsions, irritability, and hyperparasitemia (parasite density = 559,400/µL). Antimalarial therapy with intramuscular artemether was continued instead of quinine for rescue therapy, because the child was known to have G6PD deficiency. The enrollment parasite density of 559,400/µL reduced to 395,082/µL, 254,778/µL, 71,287/µL, and 1,804/µL at 6, 12, 18, and 24 hours, respectively, with patent parasitemia cleared by 36 hours.

Although the study was designed to terminate at Day 14, patients were encouraged to continue follow-up until Day 28. Forty-seven of 50 patients who were available for evaluation at Day 28 recorded adequate clinical and parasitologic response. Table 3Go shows details of response of infection to the two treatment regimens. Mean parasite clearance rates are comparable. Parasite clearance was rapid, with 88.2% and 91.2% of patients who received ART and DHA, respectively, being free of patent parasitemia at 48 hours after the first dose of drug. Day 14 cure rates in the PPP were comparable at 97.14% (33 of 34) and 100% (34 of 34) for those who received ART and DHA, respectively (P = 1.00). The mean parasite clearance times were 32.5 ± 14.3 and 31.4 ± 17.7 hours among patients who received ART and DHA, respectively (P = 0.32). Patients who had patent parasitemia at Day 28 were treated with amodiaquine and SP combination. Response of infection to therapy was good, with prompt clearance of patent parasitemia within 3 days in all three patients.


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TABLE 3
Therapeutic response of children with moderately severe malaria treated with DHA suppository or intramuscular ART plus SP
 
The dose of DHA suppository received by the children in this study ranged from 2.3 to 8 mg/kg. Only 9 of 34 (26.5%) children received < 4 mg/kg (range, 2.3–3.6 mg/kg), 8 (23.5%) received 4–5 mg/kg, 14 (41.2%) received 5–6.7 mg/kg, and 3 (8.8%) received 7–8 mg/kg (range, 5–8 mg/kg). There was no difference in the parasite clearance times of patients who received the lowest doses of the DHA suppository and the highest ranges.

Fever clearance. Mean fever clearance times among patients treated with both regimens were similar at 23.0 ± 17.35 and 18.7 ± 10.21 hours among children who received ART and DHA (P = 0.50), respectively. The survival between the two groups was compared using Kaplan-Meier survival. A log-rank test showed that the difference was not statistically significant. The median time was the same in both groups at 18 hours. In no patient was there a need to delay the administration of SP, because all randomized patients were well enough to take drugs and food orally at 48 hours.

Adverse events. One of the patients who received ART progressed to cerebral malaria. The patient regained consciousness on Day 3 and recovered fully without any neurologic sequelae. The patient who progressed to cerebral malaria and another patient who was also treated with ART received blood transfusions because of the development of severe anemia (hematocrit < 15%). They were both anemic at enrollment (packed cell volume [PCV] = 24% and 25%).

One of the patients treated with DHA recorded peri-anal redness, which was considered drug related. Other adverse events were mild, and most were not considered to be related to drug therapy (Table 4Go). These include diarrhea, otitis media, vague abdominal discomfort, and passage of round worms (Ascaris lumbricoides) in stool.


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TABLE 4
Adverse events recorded among children with moderately severe malaria treated with DHA suppository or intramuscular ART plus SP
 
PCR analysis. All 68 patients in the PPP were free of parasitemia on Day 14. Three of the 50 patients who were available for Day 28 evaluation had reoccurrence of patent parasitemia by Day 28. Genotyping by msp2 of pre- and post-treatment samples obtained from the three patients who failed treatment showed four, two, and two clones, respectively. Post-treatment isolates showed two, one, and three completely different P. falciparum clones, respectively, compared with pre-treatment isolates.

Attitude of parents and caregivers to DHA suppository use. Sixty percent of mothers and other caregivers were skeptical about the use of a suppository formulation during the informed consent procedure. The remaining 40% had no objection or reservation about suppository use in the management of their children and wards suffering from moderately severe malaria. Further questioning revealed that this subset had confidence in the hospital staff to do what was best for their children. However, the attitudinal disposition changed from skepticism to acceptance, followed by enthusiasm and finally request for information as to the source of purchase of the "antimalarial suppository drug" after 24 hours of initiating treatment. Parents and guardians were glad to know about the availability of antimalarial drug in suppository form that could be administered at home to children who were vomiting repeatedly or those who were simply uncooperative whenever they needed to take drugs.


DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Plasmodium falciparum, the most virulent of the plasmodia species, is responsible for > 90% of malaria infections in Nigeria.9 Disease manifestation can rapidly progress to severe and complicated malaria and death within a few hours.1,14 Access to health care facilities and qualified health care personnel is often lacking in tropical endemic areas. The efficacy of the ART derivatives in the management of severe malaria is well established.1,9,10,14 The finding of this study has further confirmed this and shown that a 3-day dose regimen of a DHA suppository plus a single dose of SP and a 3-day dose of intramuscular ART plus a single dose of SP are effective and safe in the treatment of severe non-cerebral malaria. This is consistent with the findings of previous workers in the same environment that recorded 100% efficacy at Day 14 among children treated with intramuscular ART.1,9,11,13,19 Those working in Kenya and Sudan have also shown the efficacy of DHA and artesunate suppositories in the treatment of severe malaria.

There were no deaths in this study. Our rapid PCT, FCT, and Days 7 and 14 cure rates of 100% among patients treated with DHA and 97.05% among those treated with ART is comparable with the results obtained by Esamai and others11 and Awad and others.13 The PCT and FCT of 38.4 ± 6.5 and 27.9 ± 8.3 hours, as well as a Day 7 cure rate of 100%, were recorded among patients who received DHA in the study by Esamai and others.11 Awad et al13 recorded a Day 28 cure rate of 99% among patients treated with an artesunate suppository in combination with one of the following: doxycycline, SP, or mefloquine. The series reported by Awad and others13 included patients with cerebral malaria. Patients with cerebral malaria were not included in our study because our study was designed to look at moderately severe malaria with a view to providing modalities for managing this category of patients in primary health care facilities.

All patients enrolled in our study improved rapidly and were able to take oral SP at 48 hours. It is noteworthy that none of the patients who received DHA deteriorated, including patients with recurrent seizures, hyperparasitemia, and drowsiness. One of the patients who received intramuscular ART progressed to cerebral malaria. This may not be unrelated to the erratic bioavailability of intramuscular ART. The rate of parasite clearance (Figure 1Go) and fever defervescence among patients in both treatment groups were also comparable. Given our dose schedule, which was based on age, 73.5% (25 of 34) of the patients who received ART received above (4 mg/kg) minimal dosing for the first dose. It is note-worthy that parasite clearance was not delayed among children who received the lowest and highest dose ranges.


Figure 1
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  		    FIGURE 1. Comparative parasite clearance among Nigerian children with moderately severe malaria treated with DHA suppository plus SP or ART plus SP. This figure appears in color at www.ajtmh.org.

 
Both treatment regimens were well tolerated. Pain at injection site is expected after intramuscular injections. Gastrointestinal disturbances are common in patients with malaria, and the relationship to drug therapy is often difficult to access. However, we suspect that the occurrence of peri-anal redness in one patient in the DHA group, which was not present at enrollment, was drug related. There was no record of intravascular hemolysis during the study, even though two patients received blood transfusions during the study.

Our therapeutic regimen of 3-day dose of an ART derivative with a combination of SP is in keeping with the WHO recommendation of ART-containing combination therapy for malaria. Compliance with antimalarial drugs > 3 days is very poor in our community. Availability of rectal formulations of ART and its derivatives is a welcome advancement in improving management of severe malaria, especially in rural areas where means of parenteral therapy is often not available.20 Early administration of DHA suppositories by mothers or village health workers has the potential benefit of reducing or halting deterioration and complications before access to a health care facility where parenteral therapy can be administered. This can be of tremendous advantage in malaria control programs in endemic areas. DHA suppositories will provide emergency treatment in rural areas where injections cannot be given and help the patient through this critical period. However, transportation and transfer from rural to secondary health care facilities where injectables are available is often quite problematic in endemic areas, and patients may not go at all or delay until the child’s condition is critical. Empowering rural practitioners to use suppositories and teaching them to follow up with oral therapy once patients have improved will be an essential component of deploying suppositories in a malaria control program. The rate of suppository ejection obtained in this study was low (8.8%). Suppository ejection was less common in our study compared with a previous study by Barnes and others,21 who recorded a 19.5% (17 of 87) incidence of suppository ejection among Malawian children. This noted difference in suppository ejection rate is probably multifactorial. We had a simpler dosing regimen that involved the use of just one suppository at any time because we had only two strengths of DHA suppository (Cotecxin): 40 and 80 mg. The Malawi study21 used artesunate suppositories of smaller dose size, with the result that many children received more than one suppository at each dosing time; some children received three suppositories compared with our one suppository. This could cause more rectal irritation, leading to ejection. Suppository ejection may also be affected by the level to which the suppository was inserted. In our study, children who received the DHA suppository were placed in the left lateral position, and the suppository was inserted into the rectum beyond the anal sphincter. Patients were encouraged to lie in this position for at least 30 minutes afterward. A parent or guardian of each child was requested to hold the buttocks together for 30 minutes to prevent expulsion of suppository.

Given the general preference for parenteral drug therapy in Nigeria, we are surprised that there was no overt resistance, but rather easy acceptability. This is an encouraging attitude among parents/guardians of study participants. Although the number of patients studied is small, it is reasonable to expect that introduction of this formulation will be relatively easy once the community members receive Information Education and Communication (IEC) materials and or health education on its use.

In conclusion, a 3-day course of DHA suppository in combination with SP was found to be as efficacious as a 3-day course of intramuscular ART plus SP in the management of moderately severe malaria in southwestern Nigeria. DHA suppository is indeed a welcome addition to the armamentarium for the management of malaria in Nigeria.

Received November 30, 2005. Accepted for publication July 25, 2006.

Acknowledgments: The American Society of Tropical Medicine and Hygiene (ASTMH) and the American Committee on Clinical Tropical Medicine and Travelers’ Health (ACCTMTH) assisted with publication expenses.

* Address correspondence to Catherine O. Falade, Malaria Research Laboratories, IMRAT, College of Medicine, University of Ibadan, Ibadan, Nigeria. E-mail: fallady{at}scannet.com or lillyfunke{at}yahoo.com Back

Authors’ addresses: Catherine O. Falade, Christian T. Happi, Grace O. Gbotosho, and Ayoade M. J. Oduola, Malaria Research Laboratories, IMRAT, College of Medicine, University of Ibadan, Ibadan, Nigeria, Telephone: 234-803-326-4593, E-mail: fallady{at}skannet.com or lillyfunke{at}yahoo.com. Christian T. Happi, E-mail: christianhappi{at}hotmail.com. Grace O. Gbotosho, E-mail: sgbot{at}skannet.com. Ayoade M. J. Oduola, E-mail: oduolaa{at}who.int. Lateef A. Salako, Malaria Research Laboratories, IMRAT, College of Medicine, University of Ibadan, Ibadan, Nigeria, and Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria, Telephone: 234-2-2410954. Francis F. Fadero, St. Mary’s Catholic Hospital, Eleta, Ibadan, Nigeria, and Department of Pediatrics, Ladoke Akintola University, Oshogbo, Nigeria, E-mail: folifad{at}gmail.com, Telephone: 234-8033536410. Idowu Ayede and Adegoke G. Falade, Department of Pediatrics, College of Medicine, University of Ibadan, Ibadan, Nigeria, Telephone: 234-803-353-6410, E-mail: afalade33{at}yahoo.com. Hannah O. Dada-Adegbola, Department of Medical Microbiology, College of Medicine, University of Ibadan, Ibadan, Nigeria, Telephone: 234-802-345-1676, E-mail: dadaadegbola{at}yahoo.com.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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