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Am. J. Trop. Med. Hyg., 68(2), 2003, pp. 153–158Copyright 2003 by The American Society of Tropical Medicine and Hygiene DESCRIPTIVE STUDY ON THE EFFICACY AND SAFETY OF ARTESUNATE SUPPOSITORY IN COMBINATION WITH OTHER ANTIMALARIALS IN THE M. I. AWAD, A. M. Y. ALKADRU, R. H. BEHRENS, O. Z. BARAKA, AND I. B. ELTAYEB Department of Pharmacology, Faculty of Pharmacy, and Department of Internal Medicine and Applied Therapeutics, Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom Documentation on the efficacy of artesunate in Africa is limited, and no experience of artesunate use in Sudan is documented. Severe malaria in rural areas of Sudan, where facilities for the safe and effective use of parenteralquinine are lacking, is a frequent problem. Early treatment with artesunate suppositories would provide asimple methodfor use by unskilled staff and would be an alternative approach to treat malaria in settings with poor resources. Wedescribe a hospital-based study of rectal artesunate in 100 adult patients with severe falciparum malaria with a dosederived from pharmacokinetic data (200 mg every 8 hours) over 3 days, which halted progression of severe disease andhad a low fatality rate. The dosage schedule led to a rapid clinical response and reduced parasite clearance and feversubsidence times of (31.5 ± 10.1 hours) and (31.4 ± 11.1 hours). The sequential treatment of rectal artesunate with eitherdoxycycline or pyrimethamine/sulfadoxine or mefloquine resulted in similar clinical cure rates of around 100%, and thecombination of artesunate with either doxycycline or pyrimethamine/sulfadoxine was equally effective as mefloquine inpreventing recrudescence. There were no significant adverse effects or signs of toxicity related to the treatment observedduring the 28-day follow-up. The combination regimens could be used in areas where there is limited access to parenteraltherapy for malaria.
Suppositories of artesunate have been developed for rectal administration as an alternative to oral or parenteral therapy.
The increase in malaria disease burden in Africa is of great Clinical studies of rectal administration of artesunate in the concern nationally and internationally. An estimated 300–500 treatment of malaria have been undertaken in Thailand, My- million new cases of malaria and an estimated 1.5–2.7 million anmar, Ecuador, Kenya, and Gabon.11–16 Table 1 summarizes deaths occur each year. The highest mortality (>90%) occurs the doses used and the efficacy obtained in these studies.
in children <5 years old in Africa.1 Plasmodium falciparum Suppositories are a major advance in the treatment of severe malaria is associated with severe morbidity and mortality, and malaria, especially in rural settings, where resources are mea- in the absence of early diagnosis and effective treatment, it ger and the referral of cases is not possible. It is recommended that further studies be carried out for the quantification of the Resistance to most antimalarial therapies is well docu- efficacy of artesunate suppositories in the treatment of severe mented worldwide. Multidrug resistance is an increasing problem in Africa and poses a threat to the current manage- In Sudan, there has been a rapid spread of chloroquine- ment of malaria with inexpensive drugs such as chloroquine resistant P. falciparum infections. Parenteral quinine is the and pyrimethamine/sulfadoxine.3 Drugs derived from arte- main drug widely used in the management of severe malaria.
misinin have been shown to be extremely effective against It is available only in urban settings, where expertise and multidrug-resistant P. falciparum malaria and severe ma- equipment are available. The use of artesunate rectocaps laria.4 Because their quantitative determination in biologic (Mepha Pharmaceutical Research, Aesch-Basel, Switzerland) fluid is a challenging problem, different dosage regimens have in treatment of severe malaria may provide advantages.
been proposed that are largely empirical.5 The selection of Although artemisinin compounds are effective against mul- optimal dosage regimens requires precise information on the tidrug resistance, when administered alone, these agents have led to recrudescence rates of 10–100%, depending on the Artesunate is a semisynthetic derivative of artemisinin dose and duration of treatment and severity of the disease.19 whose water solubility facilitates absorption7 and provides an Current recommendations are that artemisinin derivatives advantage over artemisinin because it can be formulated as should be used only in combination with other antimalarials oral, rectal, intramuscular, and intravenous preparations.
to reduce the development of resistant parasite strains. Me- Artesunate is rapidly hydrolyzed to dihydroartemisinin, floquine has been used widely in combination with artemisi- which is the most active schizonticidal metabolite. Extravas- nin derivatives and has produced radical cure rates of cular administration of artesunate results in a more rapid sys- >90%.11,12 White and Olliaro20 and White et al.3 recom- temic availability of artesunate compared with intramuscular mended that clinical studies are needed to assess the efficacy artemether. This pharmacokinetic advantage may provide a and safety of artemisinin compounds in combination with clinical advantage in the treatment of severe malaria.8 Rectal artesunate has been shown to be absorbed rapidly, with a The objectives of this study were to investigate the efficacy considerable interindividual variability.9,10 Artesunate is and safety of rectal artesunate in combination with 3 other highly effective against multidrug-resistant falciparum ma- antimalarials in the treatment of severe malaria and to deter- laria and severe malaria in Vietnam, Thailand, China, and mine recrudescence rates after treatment of adult Sudanese Myanmar7; however, limited studies have been carried out in patients. The regimens evaluated were (1) artesunate sup- positories for 3 days followed by doxycycline capsules for 4 Published results of clinical trials in the treatment of P. falciparum malaria by rectal artesunate 0,4,8,12,24,36,48,60 h(1,600 mg) + MF750 mg at 72 h,500 mg at 84 h 0,4,8,12,36,48,60 h (1,400 mg)+ MF 750 mg at72 h, 500 mg at84 h 0,12,24,36,48, 60 h(1,200 mg) + MF750 mg at 72 h,500 mg at 84 h 3 da ys, MF750 mg on day 4and 500 mg 12 hapart 200 mg/12 h onday 1, 200 mgon days 2 and3, MF 750 mgon day 4 and500 mg 12 hapart day 1,200 mg/12 h ondays 2 and 3,then MF250 mg/8 hstarted on day 4 0,4,8,12,18,24,48,60 h, then MFTD 1,000 mg in2 doses 8 hapart Note. Radical cure rate (%): Clinical cure without recrudescence by day 28.
MF, mefloquine; P/S, Pyrimethamine/sulfadoxine; SD, single dose; TD, total dose.
days, (2) artesunate suppositories for 3 days followed by The inclusion criteriafor apatient to enter the study were single-dose pyrimethamine/sulfadoxine tablets, and (3) arte- evidence of severe malaria with Ն1 of the WHO criteriaof sunate suppositories for 3 days followed by mefloquine tab- severe disease, age 18–60 years, and parasitemia of >10,000 lets divided into 2 equal doses 24 hours apart.
parasites/␮l with P. falciparum alone. The exclusion criteriaincluded pregnancy, breast-feeding, hemorrhoids, previousrectal surgery, diarrhea for Ն12 hours, and recent treatment with an antimalarial over the previous 2 weeks. Patients whofulfilled the inclusion criteriawere selected randomly during Patients. The study was conducted at Omdurman Teaching
their presentation at the Accident and Emergency Depart- Hospital and the Tropical Disease Hospital in Khartoum ment and sequentially entered into 1 of 3 groups. The State. A total of 2,400 febrile patients were evaluated be- Sudanese Ethical Committee (Federal Ministry of Health, tween January 2000 and January 2001. Patients with micro- National Health Laboratory) gave ethical approval for the scopically diagnosed P. falciparum malaria were considered study. A written consent was obtained from patients or rela- for entry if they had clinical, biochemical, and parasitologic evidence of severe malaria based on the World Health Orga- Clinical procedures. A full clinical examination was under-
nization (WHO) criteria of severe diseases.2,21 taken by a general practitioner on admission. Comatose pa- tients were graded using the Glasgow Coma Scale every 6 mained so for at least 48 hours), time to consciousness (time hours until the patient recovered full consciousness with a from the initiation of therapy until the Glasgow Coma Score Glasgow Coma Scale of 15. Rectal temperature, blood pres- ס 15), clinical cure rate (the percentage of patients who had sure, pulse, and respiratory rate were measured every 6 hours initial recovery with complete initial disappearance of para- during the first 24 hours, then every 12 hours until day 4 and sitemia within 7 days), and fatality rate (the percentage of once daily to day 7, then on the follow-up days 7, 14, 21, and patients who died after the initiation of therapy). Laboratory 28. The patients were evaluated for the evolution of the signs measures included parasite clearance time (time from the ini- and symptoms, and any new events elicited during treatment tiation of therapy until the first negative blood film that re- daily for 7 days and weekly till day 28 were recorded.
mained negative for 48 hours), radical cure rate (the percent- Laboratory procedures. The species differentiation was ob-
age of patients who had clinical cure without recrudescence tained from thin smears. A parasite count was obtained using by day 28), and recrudescence rate (defined according to thick blood films, counted as the number of parasites per 200 WHO classification during 28-day follow-up). Improvement white blood cells. Parasite clearance was monitored using of impaired biochemical and hematologic parameters (time thick blood films every 6 hours during the first 24 hours, then from the initiation of therapy until the improvement of the every 12 hours to day 4 and daily to day 7. Follow-up films impaired biochemical and hematologic parameters to normal were taken on days 14, 21, and 28. The thick blood films were considered negative if no parasites were seen in 200 oil im- Safety assessment. Side effects were defined as signs and symptoms that first occurred or became more severe after Biochemical and hematologic tests included hemoglobin, treatment was started. Any new events elicited during the hematocrit, reticulocyte count, white blood cell total and dif- treatment also were considered as side effects. Biochemical ferential counts, plasma glucose, plasma total bilirubin, serum and hematologic parameters were evaluated before and after urea, creatinine, and liver function tests. These tests were initiation of therapy to detect any drug-associated effects.
done on admission and repeated on days 7, 14, 21, and 28.
Data analysis. The demographic, clinical, and laboratory
More tests were performed as necessary for the management data for each patient were entered in a form, then entered in SPSS V9 for the performance of the descriptive and compara- Management of patients. Patients with severe malaria re-
tive statistical analysis. The comparison of data within the ceived nonspecific treatment according to the guidelines pub- groups was carried out by paired Student t-test for normally lished by Gilles2 and WHO.21 The specific treatment included distributed data and by Wilcoxon signed rank test for data the use of the following antimalarial drugs: artesunate sup- that were not normally distributed. One-way analysis of vari- positories, 200 mg (Plasmotrim-200 Rectocaps-Mepha), me- ance was used for the comparison between the groups.
floquine tablets, 250 mg (Mephaquin-Mepha), doxycyclinecapsules, 100 mg (Zadorin-Mepha), and pyrimethamine/sulfadoxine, 25 mg/500 mg (Fansidar Roche).
Therapeutic regimens used. All patients were treated with
rectal artesunate, 200 mg every 8 hours for 3 days (total dose, A total of 2,400 adult patients who presented with fever or 1,800 mg), then entered into an open-label design to receive ahistory of fever to the trial site were screened with blood films during January 2000 to January 2001. Of patients, 420(17.5%) were found to have positive blood films, 404 (96.2%) 1. Group A (35 patients): Doxycycline capsules, 100 mg ev- had P. falciparum, and the rest had P. vivax. Of the 404 cases, ery 12 hours for 4 days, started 12 hours after the last dose 73.3% were considered to have uncomplicated P. falciparum malaria, and 26.7% (n ס 108) had criteria ascribed by WHO 2. Group B (35 patients): A single dose (3 tablets) of pyri- methamine/sulfadoxine, 12 hours after the last dose of A total of 100 patients (79 men and 21 women) agreed to participate in the study and received an initial treatment with 3. Group C (30 patients): Mefloquine tablets (total dose, 15 artesunate rectocaps for 3 days. For the second drug, the mg/kg body weight), split in 2 equal doses 24 hours apart, patients were divided into 1 of the 3 treatment groups (35 in started 12 hours after the last dose of artesunate group A, 35 in group B, and 30 in group C). Age range was18–65 years with a mean (SD) of 30.5 (11.7) years, and weight A pharmacokinetic study of oral and rectally administered range was 42–97 kg with a mean (SD) of 64.9 (9.1) kg. The 3 artesunate in Sudanese healthy volunteers was used to devise groups were comparable in demographic data, clinical char- the suggested dosage regimen of rectal artesunate, 200-mg acteristics, and laboratory findings (Table 2).
rectocaps every 8 hours.10 Patients were laid in a left lateral After the treatment regimens, surviving patients were fol- position, and an artesunate rectocap was inserted into the lowed for 28 days. Home visits were conducted for patients rectum beyond the anal verge by a trained nurse. The patients who failed to show for the follow-up. One patient died 7 hours were confined to bed for at least 1 hour after the insertion; if after the first dose of artesunate. Fourteen patients had cere- the rectocap was expelled within 1 hour of administration, bral malaria with a mean (SD) Glasgow Coma Scale of 6 (1); 49 patients were jaundiced with a plasma total bilirubin Evaluation criteria for the treatment efficacy and safety Effi-
greater than twice-normal laboratory range. All patients had cacy assessment. The following laboratory and clinical end a parasitemia of >10,000 parasites/␮l, 19 patients had hyper- points were used to measure response to treatment objec- pyrexia (>40.1°C), and 37 patients were hypoglycemic. Seven tively: fever clearance time (time from the initiation of patients had algid malaria with systolic blood pressure <80 therapy until body temperature decreased to 37°C and re- mm Hg, and 12 patients had elevated serum creatinine and Mean ± SD of the clinical, hematologic, and biochemical parameters at admission of the 3 second-drug treatment groups Hemoglobin (g/dl) (men, 13–17 g/dl; women, 12–15 g/dl) Serum creatinine (mg/dl) (0.5–1.5 mg/dl) Note. Values in parentheses are laboratory normal range.
blood urea greater than twice normal. Of patients, 49 had >1 parasitemia by 24 hours was 88.8% (11.2%) and by 36 hours criteria of severe malaria as ascribed by WHO (Table 3).21 was 99.8% (0.2%). At baseline enrollment, gametocytes were All patients clinically improved within 3 days of starting detected in 5 patients. No new gametocytemia was detected treatment with artesunate rectocaps. Parasitemia clearance during the treatment or follow-up. The mean (SD) clearance and fever clearance times are shown in Figures 1 and 2. The time of gametocytes was 4.2 (1.6) days, supporting the evi- (mean ± SD) of initial parasitemia was 45,683 ± 42,068 para- dence that artesunate clears gametocytes, preventing further sites/␮l (range, 13,133–25,0000 parasites/␮l). In 87 patients, parasitemia ranged from 13,133–100,000 parasites/␮l, and 13 Figure 2 shows the clearance of fever. The overall mean patients had parasitaemia >100,000–250,000 parasites/␮l.
(SD) initial rectal temperature before treatment was 39°C There was a highly statistically significant reduction in the (1.3°C) (range, 34–40.6°C). There was a highly significant re- mean parasitemia at 6 hours and thereafter following artesu- duction from the initial elevated temperatures achieved by 6 nate rectocaps administration (P < 0.001). The mean (SD) hours after starting treatment (P < 0.001). The combined decrease in parasitemia was 36.2% (2.5%) by 12 hours and mean (SD) fever clearance time was 31.4 (11.1) hours (range, After the insertion of artesunate rectocaps, the overall The mean resolution time for the signs and symptoms mean (SD) parasitemia clearance time was 31.5 hours (10.1 ranged from 24–58.3 hours. All patients had excellent initial hours) (range, 18–72 hours). The mean (SD) reduction of clinical improvement, and 87% of the patients were asymp-tomatic within 3 days of starting treatment. Full consciousnesswas gained by 78.6% of comatose patients at 24 hours, and the remaining patients regained normal higher function by 36 Patients with more than one criteria of severe malaria Hematologic parameters recovered with no evidence of marrow suppression during artesunate treatment or after thesecond drug in all treatment groups. Liver function, renal Cerebral malaria (GCS Յ 6) + hyperpyrexia function, and blood glucose were comparable at presentation Cerebral malaria (GCS > 6 Յ 8) + plasma total biliru- within the 3 treatment groups. All patients recovered except for 1 death at 7 hours after the first artesunate dose. There Cerebral malaria (GCS Յ 6) + hyperpyrexia were no recrudescences in any patient by day 28 (radical cure (>40.1°C) + plasma total bilirubin >3 mg/dl Hyperparasitemia (>100.000 P/␮l) + plasma total bili- rubin >6 mg/dl + hyperpyrexia(>40.1°C) + general-ized convulsions + hemoglobin <8.5 g/dl Hyperparasitemia (>100.000 P/␮l) + plasma total bili- rubin >3 mg/dl + hypoglycemia<40 mg/dl + gener-alized convulsions + serum creatinine >3 mg/dl Algid malaria (SBP < 80 mmHg) + plasma total bili- Algid malaria (SBP < 80 mmHg) + plasma total bili- rubin >3 mg/dl + serum creatinine >3 mg/dl Hyperpyrexia(>40.1°C) + generalized convulsions + Serum creatinine >3 mg/dl + urine output <400 ml /24 h + hypoglycemia<40 mg/dl + plasmatotal biliru-bin >3 mg/dl Hypoglycemia<40 mg/dl + generalized convulsions + * One fatal outcome.
The criteria of severe falciparum malaria as ascribed by WHO, 2000.
tory, cultural objection to the use of suppositories needed tobe considered. Cultural acceptance is variable and respondsto education. There was little resistance to the use of thesuppositories by patients or their relatives.
The clinical and laboratory findings during and after the treatment showed no evidence of toxicity or side effects to the3 combination regimens during treatment and the 28-day fol-low-up. In group B, there was an increase in the number ofpatients with hemoglobin and hematocrit below normal atdays 7 and 14, which suggested that this combination mayhave an adverse effect. Previous studies using pyrimethamine/sulfadoxine combined with artesunate in the treatment of un-complicated falciparum malaria reported that there were noadverse effects on laboratory parameters.24 The clinical sig- nificance of this finding remains to be confirmed in a largernumber of patients.
In studies in which artemisinin compounds were adminis- tered alone, recrudescence rates varied from 10% to 100%depending on the dose, duration of treatment, and severity of The present study investigated a larger number of patients the disease.19 These drugs often are combined with meflo- than reported in other studies. Using pharmacokinetic data quine to reduce the rate of recrudescence. Limited studies from healthy volunteers, an appropriate dose of artesunate reported the efficacy of doxycycline or pyrimethamine/ was selected for administration per rectum that would be ex- sulfadoxine combined with artesunate in treatment of uncom- pected to provide blood levels of dihydroartemesinin above plicated malaria. The present results indicate that sequential the minimum inhibitory concentration that eliminates 90% of treatment of severe malaria with artesunate rectocaps fol- the parasites (MIC ) for 5.3 ± 2.1 hours.10 The rapid parasite lowed by either doxycycline (100 mg every 12 hours for 4 clearance and deffervescence of fever in all 99 patients con- days) or a single dose of pyrimethamine/sulfadoxine was firms the dosing schedule in this group of patients was entirely equally effective to that followed by mefloquine in preventing appropriate. The parasitemia and fever clearance times in this recrudescence. The dosage regimen of mefloquine (total dose study were significantly shorter than that reported by Looa- 15 mg/kg body weight) divided in 2 equal doses 24 hours apart reesuwan et al.11,12 and Thwe et al.13 but not significantly used in this study improved its tolerability because no serious different from that reported by Eduardo and Gomez14 and Artesunate rectocaps in treatment of severe malaria have The choice of second agent was made based on available many advantages in rural settings in developing countries data of mefloquine from Southeast Asia and cost because such as Sudan. Their administration does not require sophis- pyrimethamine/sulfadoxine and doxycycline are inexpensive ticated facilities and skilled personnel, and they can be used as and widely available. All 3 drugs proved equally effective, an alternative to parenteral quinine with all its known side producing radical cure rates of 100%. The only death in the effects. The use of artesunate rectocaps in rural areas where study was a 50-year-old man, who despite a reduction in par- malaria transmission is higher and the disease is more preva- asitemia at 6 hours from 160,000 to 142,000 parasites/␮l died lent is more appropriate for the type of health facilities avail- suddenly 7 hours after starting treatment. Previous studies able. The early administration of treatment to patients where reported fatality rates of 40% in severely ill malaria pa- referral is not possible, especially for children, could reduce tients.23 The mortality rates reported in 2 other studies using complications and reduce mortality. The use of a single dose artesunate rectocaps for the treatment of severe malaria were of pyrimethamine/sulfadoxine or 2 doses of mefloquine in 2.5% and 13.6%.14,15 In these 2 studies, the number of pa- adults and children would improve compliance to the impor- tients and the total dose of rectal artesunate were less than in tant second drug necessary to prevent resistance. Doxycycline our study (Table 1). We accept that not all subjects meet can be used as an alternative in adults.
similar criteria to those published studies, but this study was The main goal of this study was to evaluate the efficacy and not intended to show a reduction in mortality as an outcome safety of an alternative therapy to parenteral quinine in areas measure, but this was noted, and we comment on it as a where there is poor access to well-structured health facilities, such as exist in Sudan and many other parts of the Third The selection criteriaused the WHO21 definition of severe World and where patient referral is impractical. A novel dos- malaria to include hyperparasitemia, jaundice, hyperpyrexia, age regimen of artesunate rectocaps (200 mg every 8 hours for cerebral involvement, renal impairment, and prostration, and 3 days) achieved substantial and rapid decreases in parasit- these were used for selecting patients for the study. Because emia and fever in patients presenting with severe falciparum many of these criteria are clinical and subjective, comparison malaria. The drug regimen was well tolerated and produced a of disease severity with other studies is difficult. About one clinical cure in most patients by day 3. The addition of 1 of 3 quarter of all 404 cases diagnosed as P. falciparum (26.7%) second-line drugs prevented recrudescence of malaria. The were considered severe, however, and recruited into the regimen was designed for use in settings with poor resources study. It is of note that only 1 death occurred, and recovery and limited expertise, and its ease of use may have a signifi- occurred in more than three quarters with 3 days of artesu- cant impact and effectiveness that may reduce complications nate treatment. Because the formulation was a rectal supposi- and mortality from falciparum malaria. The sequential com- binations of artesunate rectocaps followed by doxycycline or volunteers and patients with uncomplicated falciparum ma- pyrimethamine/sulfadoxine were equally effective as meflo- laria. Am J Trop Med Hyg 65: 717–721.
6. Rowland M, Thomas N, 1995. Therapeutic regimens. In Clinical quine in preventing recrudescence and in this study had a pharmacokinetics—concepts and applications, 3rd ed. Balti- 100% radical cure rate. The combination regimens seem safe more: Williams & Wilkins. 83–105.
and highly effective and could be lifesaving in patients with 7. Barradell LB, Fitton A, 1995. Artesunate: A review of its phar- severe malaria, particularly in rural areas. The present results macology and therapeutic efficacy in the treatment of malaria.
can be pooled in the future with results from other areas to 8. Hien TT, White NJ. Qinghaosu. Lancet 341: 603–608.
determine the actual efficacy of artesunate suppositories com- 9. Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST, 1996.
pared with current therapeutic options used in different re- Pharmacokinetic study of a new pharmaceutical form of arte- sunate (Plasmotrim-200 Rectocaps) administered in healthyvolunteers by rectal route. Jpn J Trop Med Hyg 24: 39–45.
10. Awad MI, Eltayeb IB, Taylor RB (submitted). Pharmacokinetics Received April 23, 2002. Accepted for publication October 14, 2002.
of artesunate following oral and rectal administration in Acknowledgments: We deeply thank all the medical staff in Omdur- man Teaching Hospital and Tropical Disease Hospital, particularly 11. Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, An- Dr. Omer Nemiri, Dr. Fatima A., Dr. Angal Almahdi, and Dr. Amel drial M, 1995. Efficacy and tolerability of a sequential artesu- Hajnour, for their assistance and collaboration in carrying out the nate suppository plus mefloquine in the treatment of severe clinical trial. We thank Mr Tarig Elfaki, Mr Salah G. Elzaki, Mr.
falciparum malaria. Annu Trop Med Parasitol 89: 469–475.
Mohamed A/gadir, and Mr. Afiefi, for their technical assistance 12. Looareesuwan S, Wilairatana P, Andrial M, 1996. Artesunate suppository for treatment of severe falciparum malaria inThailand. Jpn J Trop Med Hyg 24: 13–15.
Financial support: This work was supported by the British Chevening 13. Thwe Y, Than M, Phay S, ZawOo A, YuSoe A, 1996. Artesu- Scholarship, University of Khartoum, Tropical Research Institute, nate-mefloquine tablets (Plasmotrim Rectocaps, Mefloquine and Malaria National Administration in Sudan. We thank Mepha Lactab) in the treatment of severe malaria. Jpn J Trop Med Pharmaceutical Research, Aesch-Basel, Switzerland, for the donation 14. Eduardo A, Gomez L, 1996. Efficacy of artesunate suppository The clinical trials were conducted in Khartoum-Sudan. Data inter- followed by oral mefloquine in the treatment of severe malaria pretation and writing were undertaken at Robert Gordon University, in endemic areas where resistance to chloroquine exists in Ec- United Kingdom, and University of Khartoum, Sudan.
uador. Jpn J Trop Med Hyg 24: 17–24.
15. Bhatt K, Bhatt S, Omonge E, Otekol L, Andrial M, 1996. Efficacy Authors’ addresses: M. I. Awad and I. B. Eltayeb, Department of and tolerability of a sequential artesunate suppository- Pharmacology, Faculty of Pharmacy, University of Khartoum, P.O.
mefloquine treatment of severe review falciparum malaria. Jpn Box 1996, Khartoum, Sudan. A. M. Y. Alkadru and O. Z. Baraka, Department of Internal Medicine and Applied Therapeutics, Faculty 16. Halpaap B, Maryse N, Paris M, Benakis A, Peter G, 1998. Plasma of Medicine, University of Khartoum, P.O. Box 1063, Khartoum, levels of artesunate and dihydroartemisinin in children with Sudan. R. H. Behrens, Department of Infectious and Tropical Dis- plasmodium falciparum malaria in Gabon after administration eases, London School of Hygiene and Tropical Medicine, Keppel of 50 milligram artesunate suppositories. Am J Trop Med Hyg Street, London, UK, Telephone: +44 207 9272661, E-mail: 17. World Health Organization Severe Malaria Task Force, 1997.
Reprint requests: R. H. Behrens, Department of Infectious and Task force on artesunate suppositories for malaria treatment. Tropical Diseases, London School of Hygiene and Tropical Medicine, TDR/UNDP/World Bank/Special Programme for Research Keppel Street, London, UK, Telephone: +44 207 9272661, E-mail: and Training in Tropical Diseases. Geneva: World Health Or- 18. World Health Organization Severe Malaria Task Force, 1999.
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19. Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta 1. World Health Organization, 1996. Investing in health research for T, 1991. Clinical trial of artesunate and artemether in multi- development. Report of the Ad Hoc Committee on Health Re- drug resistant falciparum malaria in Thailand: a Preliminary search Relating to Future Intervention Options. Report No: report. Southeast Asian J Trop Med Public Health 22: 380–385.
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Doi:10.1016/j.jcrs.2008.06.016

Effect of intraoperative mitomycin-C on healthyLi-Quan Zhao, MD, Rui-Li Wei, MD, Xiao-Ye Ma, MD, Huang Zhu, MDPURPOSE: To evaluate the effect of mitomycin-C (MMC) on corneal endothelial cells after laser-assisted subepithelial keratectomy (LASEK). SETTING: Department of Ophthalmology, Changzheng Hospital, Shanghai, China. METHODS: One hundred seventy-four eyes of 89 patients who did not previo

Marcelo cea

CONFERENCIA NÓRDICA PROFESORES DE ESPAÑOL LENGUA MATERNA SUNDSVALL , 6 - 7 DE MAYO 2010 Es Licenciado en Filología Semítica por la Universidad Complutense de Madrid (1984). Se ha dedicado a la enseñanza del español en Suecia desde 1985. Es locutor, guionista y productor en la redacción de español de la Radiotelevisión Educativa de Suecia (UR). Escribe libros de texto para

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