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EHP Library Malaria Bulletin No. 25:  November 2-15,  2001

Full-text Reports

  • MIM Symposium on Insecticide Resistance in African Malaria Vectors

  • WHO/TDR No.36 Malaria 
    Encouraging results from studies to improve the safety and efficacy of natural drug compounds
  • WHO/TDR No.34 Malaria 
    'GPI' identified as the dominant toxin in malaria pathology and developed as an anti-disease vaccine candidate
  • WHO/TDR No.33 Malaria 
    Promising new results for malaria vaccine candidate, MSP-5
  • WHO/TDR No.30 Malaria
    New information on the structure of malaria beta-haematin will help in the design of new antimalarial drugs
  • WHO/TDR No.29 Malaria
    Pre-packaged antimalarials reduce progression to severe disease 

Social Sciences and Malaria 

Trop Med Int Health 2001 Nov;6(11):922-7

Controlling malaria: challenges and solutions.

Olliaro P, Taylor WR, Rigal J.

UNDP/World Bank/World Health Organization Special Program for Research & Training in Tropical Diseases (TDR), Geneva, Switzerland Centre for Infectious Diseases, Royal Free and University College Medical School, London, UK.

Antimalarial drug resistance is a major public health challenge and the principal reason for the erosion of efficacious treatments. Cost and the limited number of antimalarial drugs in current use impose considerable constraints on malaria control, especially in sub-Saharan Africa. The paper describes a multilateral, multidisciplinary research project on artemisinin-based combination therapy, which offers a new and potentially highly effective way to prevent or retard the development of drug resistance.

Bull World Health Organ 2001;79(10):933-41

Diagnosis of malaria in a remote area of the Philippines: comparison of techniques and their acceptance by health workers and the community.

Bell D, Go R, Miguel C, Walker J, Cacal L, Saul A.

Australian Centre for International and Tropical Health and Nutrition, The Queensland Institute of Medical Research, Australia. 
[email protected]

OBJECTIVE: To compare the efficacies of remote symptom-based diagnosis of malaria, rapid diagnostic tests and microscopy in an area of low endemicity in the Philippines. METHODS: In Trial I, 350 symptomatic patients were tested within their villages using malaria Plasmodium falciparum (Pf)/Plasmodium vivax (Pv) immunochromatographic tests (ICT tests) and blood films stored and read under local conditions. The slides were later restained and read. In Trial II, unsupervised volunteer barangay health workers prepared ICT tests and slides after brief training. These slides were read at rural health units. Twenty-seven barangay health workers and 72 community members were later questioned about the three diagnostic strategies. FINDINGS: A history of fever alone was sensitive (95.4%) but poorly specific (16.5%) for predicting parasitaemia. The inclusion of other symptoms reduced the sensitivity to below 85%, while specificity remained low. The axillary temperature was poorly predictive. ICT tests achieved high sensitivity (97.9%) but many cases indicated as positive by ICT tests were negative by microscopy. Further analysis of these cases in Trial I indicated that ICT tests were detecting low-level parasitaemias missed by microscopy, and that local microscopy had poor accuracy. ICT tests were well accepted and accurately performed by barangay health workers. CONCLUSION: These tests meet a strong desire in the community for blood-based diagnosis and may increase the compliance and treatment-seeking behaviour of patients.

Am J Trop Med Hyg 2001 Oct;65(4):279-84

Cost-effectiveness and sustainability of lambdacyhalothrin-treated mosquito nets in comparison to DDT spraying for malaria control in western Thailand.

Kamolratanakul P, Butraporn P, Prasittisuk M, Prasittisuk C, Indaratna K.

Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

The cost-effectiveness of lambdacyhalothrin-treated nets in comparison with conventional DDT spraying for malaria control among migrant populations was evaluated in a malaria hyperendemic area along the Thai-Myanmar border. Ten hamlets of 243 houses with 948 inhabitants were given only treated nets. Twelve hamlets of 294 houses and 1,315 population were in the DDT area, and another 6 hamlets with 171 houses and 695 inhabitants were in the non-DDT-treated area. The impregnated net program was most cost-effective (US$1.54 per 1 case of prevented malaria). Spraying with DDT was more cost-effective than malaria surveillance alone ($1.87 versus $2.50 per 1 case of prevented malaria). These data suggest that personal protection measures with insecticide-impregnated mosquito net are justified in their use to control malaria in highly malaria-endemic areas in western Thailand.


Protein Eng 2001 Sep;14(9):691-698

Rapid and precise epitope mapping of monoclonal antibodies against Plasmodium falciparum AMA1 by combined phage display of fragments and random peptides.

Coley AM, Campanale NV, Casey JL, Hodder AN, Crewther PE, Anders RF, Tilley LM, Foley M.

Department of Biochemistry, La Trobe University, Bundoora, 3083, Victoria, Cooperative Research Centre for Diagnostics, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria and Cooperative Research Centre for Vaccine Technology, Australia.

We describe an approach for the rapid mapping of epitopes within a malaria antigen using a combination of phage display techniques. Phage display of antigen fragments identifies the location of the epitopes, then random peptide libraries displayed on phage are employed to identify accurately amino acids involved in the epitope. Finally, phage display of mutant fragments confirms the role of each residue in the epitope. This approach was applied to the apical membrane antigen-1 (AMA1), which is a leading candidate for inclusion in a vaccine directed against the asexual blood stages of Plasmodium falciparum. As part of the effort both to understand the function of AMA1 in the parasite life cycle and to define the specificity of protective immune responses, a panel of monoclonal antibodies (MAbs) was generated to obtain binding reagents to the various domains within the molecule. There is a pressing need to determine rapidly the regions recognized by these antibodies and the structural requirements required within AMA1 for high affinity binding of the MAbs. Using phage displaying random AMA1 fragments, it was shown that MAb5G8 recognizes a short linear epitope within the pro-domain of AMA1 whereas the epitope recognized by MAb 1F9 is reduction sensitive and resides within a disulphide-bonded 57 amino acid sub-domain of domain-1. Phage displaying random peptide libraries and mutant AMA1 fragments were employed for fine mapping of the MAb5G8 core epitope to a three-residue sequence in the AMA1 prodomain.

J Biol Chem 2001 Nov 13  Full-text article at: http://www.jbc.org

Clotrimazole binds to heme and enhances heme-dependent hemolysis: proposed antimalarial mechanism of clotrimazole.

Huy NT, Kamei K, Yamamoto T, Kondo Y, Kanaori K, Takano R, Tajima K, Hara S.

Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585.

Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Since free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K(A) = 6.54 X 10(8) M(-2)). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low-spin state (S = 1/2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):545-9

Complement binding to erythrocytes is associated with macrophage activation and reduced haemoglobin in Plasmodium falciparum malaria.

Goka BQ, Kwarko H, Kurtzhals JA, Gyan B, Ofori-Adjei E, Ohene SA, Hviid L, Akanmori BD, Neequaye J.

Department of Child Health, Korle-Bu Teaching Hospital, P.O. Box 4236, Accra, Ghana. 
[email protected]

We have examined IgG and complement factor C3d deposition on erythrocytes by means of the direct Coombs' test (DAT) and looked for an association with the anaemia seen in falciparum malaria in children living in an area of hyperendemic malaria transmission (in Ghana). In one study (in 1997), 53 out of 199 patients had a positive DAT. Of these, 45 samples reacted with anti-C3d antibodies, 2 with anti-IgG and 6 with both reagents. There were significantly lower haemoglobin (Hb)-levels and higher prevalence of spleen enlargement in DAT-positive than in DAT-negative patients. Hb-levels were independently associated with DAT and age. This initial study was designed to investigate the role of intravascular haemolysis (IVH), but we found no association between IVH and either DAT result or anaemia. Because of the risk of selection bias we repeated the study using consecutive enrollment of malaria patients and were able to confirm the results in a total of 49 DAT-positive and 183 DAT-negative patients. This second study (in 1998) was designed to look at the importance of erythrophagocytosis through measurement of plasma neopterin levels and total nitrite and nitrate as markers of NO-release. Both parameters were significantly higher in DAT-positive than in DAT-negative patients (P < 0.001), indicating that complement binding to erythrocytes was associated with macrophage activation. Plasma levels of haptoglobin, interleukin-10 and tumour necrosis factor-alpha did not vary between the groups. The studies support the role of complement activation and erythrophagocytosis in the pathogenesis of anaemia in falciparum malaria in African children.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):524-8

Therapeutic responses to antibacterial drugs in vivax malaria.

Pukrittayakamee S, Clemens R, Chantra A, Nontprasert A, Luknam T, Looareesuwan S, White NJ.

Department of Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.

Some antibacterial drugs have antimalarial activity that can be exploited for the prevention or treatment of malaria. Monotherapy with tetracycline, doxycycline, clindamycin or azithromycin was assessed in 1995-98 in 92 adult patients in Thailand with Plasmodium vivax malaria. All patients recovered following treatment and the early therapeutic responses were similar among the 4 groups. The overall median fever clearance time was 57 h and the mean (SD) overall time to parasite clearance was 134 (48) h. Of 66 patients who completed a 28-day follow-up, reappearances of vivax infection occurred in 27 patients (41%) from all groups; delayed appearances of falciparum malaria occurred in 6 patients (9%), only from the azithromycin group. The overall mean (SD) time to reappearance of P. vivax was 23 (5) days and time taken for detection of falciparum malaria was 13 (4) days after starting treatment for vivax malaria. The 28-day cumulative cure rates of clindamycin (n = 12), tetracycline (n = 18) and doxycycline (n = 18) groups were similar (P > or = 0.14) and all were significantly higher compared to the azithromycin group (n = 18; P < or = 0.04). The intervals until vivax reappearance were also significantly shorter in the azithromycin group [mean (SD) = 21 (6) vs 25 (3) days, P q 0.05] suggesting that some of these were recrudescences. The apparent success rate (no subsequent appearances of either vivax or falciparum infection) was significantly lower for the azithromycin group (11%) compared to the other groups (34-78%; P < 0.01). In current antibacterial treatment regimens, short-course azithromycin has inferior antimalarial activity compared to clindamycin or the tetracyclines.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):519-23

A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria.

Newton PN, Chierakul W, Ruangveerayuth R, Silamut K, Teerapong P, Krudsood S, Looareesuwan S, White NJ.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

In some areas clinicians have combined parenteral artesunate and quinine in the belief that the 2 drugs would be additive or synergistic in severe malaria. A randomized comparison of the effectiveness of intravenous (i.v.) artesunate versus i.v. artesunate and i.v. quinine together on parasite clearance was conducted in 1998/99 amongst 69 patients with uncomplicated and severe Plasmodium falciparum malaria in western Thailand. The parasite clearance time did not differ significantly between the 2 treatment groups (P = 0.12), but adverse events were significantly more frequent in the artesunate plus quinine group (P = 0.05). Quinine did not have a significant antipyretic effect and artesunate did not affect the electrocardiographic QTc interval. There is no benefit evident from combining parenteral administration of these 2 antimalarial drugs in the acute phase of treatment.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):517-8

Acute asymptomatic hepatitis in a healthy normal volunteer exposed to 2 oral doses of amodiaquine and artesunate.

Orrell C, Taylor WR, Olliaro P.

Department of Pharmacology, University of Cape Town, Cape Town, South Africa. [email protected]

Combination antimalarial therapy is being explored to delay development of resistance to falciparum malaria. This report describes an unexpected drug-induced hepatitis in a previously healthy young woman exposed to 2 doses of amodiaquine and artesunate. Use of these combinations should be closely monitored.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):513-7

Assessment of susceptibility of Plasmodium falciparum to chloroquine, quinine, mefloquine, sulfadoxine-pyrimethamine and artemisinin in southern Viet Nam.

Thanh NV, Cowman AF, Hipgrave D, Kim TB, Phuc BQ, Cong LD, Biggs BA.

National Institute of Malariology, Parasitology and Entomology, Hanoi, Viet Nam.

Resistance to antimalarial chemotherapy is a major concern for malaria control in Viet Nam. In this study undertaken in 1998, 65 patients with uncomplicated Plasmodium falciparum malaria were monitored for 28 days after completion of a 5-day treatment course with artemisinin. Overall 36.9% (24/65) of patients had recurrent parasitaemia during the surveillance period. P. falciparum isolates were tested for sensitivity in vitro to chloroquine, mefloquine, quinine, sulfadoxine-pyrimethamine and results were compared to those from a similar study in 1995. Increased parasite sensitivity to sulfadoxine-pyrimethamine, chloroquine and quinine was demonstrated, with significantly lower mean EC50 and EC99 values in 1998 compared to 1995. Parasite sensitivity to mefloquine did not differ significantly in the 2 surveys. Isolates were also tested for sensitivity in vitro to artemisinin in the 1998 survey. The mean EC50 was 0.03 mumol/L and the EC99 was 0.94 mumol/L. Parasite sensitivity to artemisinin will need to be monitored in view of its increasing use in Viet Nam.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):497-501

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Eichner M, Diebner HH, Molineaux L, Collins WE, Jeffery GM, Dietz K.

University of Tubingen, Department of Medical Biometry, Westbahnhofstr. 55, D-72070 Tubingen, Germany. 
[email protected]

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):469-76

The availability of potential hosts as a determinant of feeding behaviours and malaria transmission by African mosquito populations.

Killeen GF, McKenzie FE, Foy BD, Bogh C, Beier JC.

Department of Tropical Medicine, School of Public Health and Tropical Medicine, Center for Infectious Diseases, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. 
[email protected]

A simple model for the influence of host availability on vector bloodmeal choice is applied to estimate the relative availabilities of humans, cattle and other host populations to malaria vectors in African communities, using published human blood indices and ratios of cattle to humans. Cattle were bitten < 0.01, 0.021 +/- 0.11, 1.61 +/- 0.16 and 1.61 +/- 0.46 times as often as humans by Anopheles funestus, An. gambiae sensu stricto and An. arabiensis in Segera, Tanzania, and An. gambiae sensu lato in The Gambia, respectively. No significant feeding upon host species other than cattle or humans was detected. Even though An. gambiae s.l. in The Gambia were mostly An. gambiae s.s., they were 77 times more likely to choose cattle over humans than An. gambiae s.s. in Tanzania. The model accurately predicted cattle blood indices for the An. arabiensis population in Tanzania (predicted = 0.99 +/- 0.21 x observed + 0.00 +/- 0.10; r2 = 0.66). The potential effect of increased cattle abundance upon malaria transmission intensity was simulated using fitted relative availability parameters and assuming vector emergence rate, feeding cycle length and survivorship were unaffected. The model predicted that increased cattle populations would not affect malaria transmission in Tanzania but could drastically reduce transmission in The Gambia or where An. arabiensis is the dominant vector. We define the availability of a host as the rate at which a typical individual host-seeking vector encounters and feeds upon that host in a single feeding cycle. Mathematical models based on this definition also represent promising tools for quantifying the dependence of vector longevity, feeding cycle length and dispersal upon host availability.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):463-8

Malaria morbidity, mortality and pregnancy outcome in areas with different levels of malaria transmission in Uganda: a hospital record-based study.

Ndyomugyenyi R, Magnussen P.

Vector Borne Diseases Control, Ministry of Health, P.O. Box 1661, Kampala, Uganda.

A retrospective hospital record-based study for Uganda was conducted in Hoima district (an area of stable malaria transmission) and in Kabale district (an area of unstable malaria transmission). In-patient and maternity ward registers for January 1997-December 1998 were reviewed and malaria admissions, mortality, abortions, stillbirths and birthweights were recorded. Data were analysed in relation to rainfall patterns. Admissions due to malaria were significantly higher at Hoima compared to Kabale hospital in 1997 (P < 0.0001). However, the situation reversed in 1998 with significantly more malaria cases registered at Kabale compared to Hoima hospital (P < 0.0001). The increase at Kabale hospital in 1998 was attributed to increased and prolonged rains during 1997 (E1 Nino). Pregnancy was a risk factor for admission with malaria at Kabale, but not at Hoima. Anaemia was significantly more common among patients admitted to hospital at Hoima compared to Kabale in 1997 and 1998 (P < 0.0001 and P = 0.02, respectively). The rate of low birthweight (birthweight < 2.5 kg) was significantly higher among primigravidae and multigravidae at Hoima hospital compared to Kabale hospital (P < 0.0001). There were significantly more stillbirths at Kabale compared to Hoima hospital (P < 0.0001). Routine hospital data such as birthweight and number of malaria cases can provide information on the level of malaria transmission useful for the health services to target appropriate malaria interventions and allocate resources to control outbreaks of malaria epidemics.

Trans R Soc Trop Med Hyg 2001 Sep-Oct;95(5):457-62

Do untreated bednets protect against malaria?

Clarke SE, Bogh C, Brown RC, Pinder M, Walraven GE, Lindsay SW.

Danish Bilharziasis Laboratory, Jaegersborg Alle 1D, DK-2920 Charlottenlund, Denmark. 
[email protected]

Bednets are thought to offer little, if any, protection against malaria, unless treated with insecticide. There is also concern that the use of untreated nets will cause people sleeping without nets to receive more mosquito bites, and thus increase the malaria risk for other community members. Regular retreatment of nets is therefore viewed as critical for malaria control. However, despite good uptake of nets, many control programmes in Africa have reported low re-treatment rates. We investigated whether untreated bednets had any protective benefit (in October and November 1996) in The Gambia where nets, although widely used, are mostly untreated. Cross-sectional prevalence surveys were carried out in 48 villages and the risk of malaria parasitaemia was compared in young children sleeping with or without nets. Use of an untreated bednet in good condition was associated with a significantly lower prevalence of Plasmodium falciparum infection (51% protection [95% CI 34-64%], P < 0.001). This finding was only partly explained by differences in wealth between households, and children in the poorest households benefited most from sleeping under an untreated net (62% protection [14-83%], P = 0.018). There was no evidence that mosquitoes were diverted to feed on children sleeping without nets. These findings suggest that an untreated net, provided it is in relatively good condition, can protect against malaria. Control programmes should target the poorest households as they may have the most to gain from using nets.

J Biol Chem 2001 Nov 12; Full-text article at: http://www.jbc.org

Purine-less death in Plasmodium falciparum induced by Immucillin-H, a transition state analogue of purine nucleoside phosphorylase.

Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, Kim K.

Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.

Plasmodium falciparum is responsible for the majority of life-threatening cases of malaria. Plasmodia species cannot synthesize purines de novo while mammalian cells obtain purines from de novo synthesis or by purine salvage. Hypoxanthine is proposed to be the major source of purines for P. falciparum growth. It is produced from inosine phosphorolysis by purine nucleoside phosphorylase (PNP). Immucillins are powerful transition-state analogue inhibitors of mammalian PNP and also inhibit P. falciparum PNP as illustrated in the accompanying paper (Kicska, G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Kim, K., and Schramm, V. L. (2001) J. Biol. Chem. 276, In Press). This work tests the hypothesis that erythrocyte and P. falciparum PNP are essential elements for growth and survival of the parasite in culture. Immucillin-H reduces the incorporation of inosine but not hypoxanthine into nucleic acids of P. falciparum and kills P. falciparum cultured in human erythrocytes with an IC-50 of 35 nM. Growth inhibition by Imm-H is reversed by the addition of hypoxanthine but not inosine, demonstrating the metabolic block at PNP. The concentration of Imm-H required for inhibition of parasite growth varies as a function of culture hematocrit, reflecting stoichiometric titration of human erythrocyte PNP by the inhibitor. Human and P. falciparum PNPs demonstrate different specificity for inhibition by immucillins, with the 2'-deoxy analogues showing marked preference for the human enzyme. The IC-50 values for immucillin analogue toxicity to P. falciparum cultures indicate that inhibition of PNP in both the erythrocytes and the parasite are necessary to induce a purine-less death.

Infect Immun 2001 Dec;69(12):7783-7792

Plasmodium falciparum Genotypes, Low Complexity of Infection, and Resistance to Subsequent Malaria in Participants in the Asembo Bay Cohort Project.

Branch OH, Takala S, Kariuki S, Nahlen BL, Kolczak M, Hawley W, Lal AA.

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

To assess the relationship between the within-host diversity of malaria infections and the susceptibility of the host to subsequent infection, we genotyped 60 children's successive infections from birth through 3 years of life. MSP-1 Block2 genotypes were used to estimate the complexity of infection (COI). Malaria transmission and age were positively associated with the number of K1 and Mad20 alleles detected (COI(KM)) (P < 0.003). Controlling for previous parasitemia, transmission, drug treatment, parasite density, sickle cell, and age, COI(KM) was negatively correlated with resistance to parasitemia of >500/&mgr;l (P < 0.0001). Parasitemias with the RO-genotype were more resistant than those without this genotype (P < 0.0000). The resistance in low COI(KM) infections was not genotype specific. We discuss the impact of genotype-transcending immunity to conserved antigenic determinants. We also propose a diversity-driven immunomodulation hypothesis that may explain the delayed development of natural immunity in the first few years of life and suggest that interventions that decrease the COI(KM) could facilitate the development of protective immunity.

Infect Immun 2001 Dec;69(12):7487-92

Gravidity-Dependent Production of Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Placental Chondroitin Sulfate Proteoglycan during Pregnancy.

O'Neil-Dunne I, Achur RN, Agbor-Enoh ST, Valiyaveettil M, Naik RS, Ockenhouse CF, Zhou A, Megnekou R, Leke R, Taylor DW, Gowda DC.

Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007.

During pregnancy, Plasmodium falciparum-infected erythrocytes sequester in the placenta by adhering to chondroitin 4-sulfate, creating a risk factor for both the mother and the fetus. The primigravidae are at higher risk for placental malaria than the multigravidae. This difference in susceptibility has been attributed to the lack of antibodies that block the adhesion of infected erythrocytes to placental chondroitin 4-sulfate in primigravid women. However, recent results show that many primigravidae at term have antibody levels similar to those of multigravidae, and thus the significance of antiadhesion antibodies in providing protection against malaria during pregnancy remains unclear. In this study, we analyzed plasma samples from women of various gravidities at different gestational stages for antiadhesion antibodies. The majority of women, regardless of gravidity, had similar levels of antibodies at term. Most primigravidae had low levels of or no antiadhesion antibodies prior to ~20 weeks of pregnancy and then produced antibodies. Multigravidae also lacked antibodies until ~12 weeks of pregnancy, but thereafter they efficiently produced antibodies. In pregnant women who had placental infection at term, higher levels of antiadhesion antibodies correlated with lower levels of placental parasitemia. The difference in kinetics of antibody production between primigravidae and multigravidae correlated with the prevalence of malaria in these groups, suggesting that antibodies are produced during pregnancy in response to placental infection. The early onset of efficient antibody response in multigravidae and the delayed production to antibodies in primigravidae appear to account for the gravidity-dependent differential susceptibilities of pregnant women to placental malaria.

Infect Immun 2001 Dec;69(12):7341-8

CD8(+)-T-Cell Depletion Ameliorates Circulatory Shock in Plasmodium berghei-Infected Mice.

Chang WL, Jones SP, Lefer DJ, Welbourne T, Sun G, Yin L, Suzuki H, Huang J, Granger DN, van Der Heyde HC.

Departments of Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130.

The Plasmodium berghei-infected mouse model is a well-recognized model for human cerebral malaria. Mice infected with P. berghei exhibit (i) metabolic acidosis (pH < 7.3) associated with elevated plasma lactate concentrations, (ii) significant (P < 0.05) vascular leakage in their lungs, hearts, kidneys, and brains, (ii) significantly (P < 0.05) higher cell and serum glutamate concentrations, and (iv) significantly (P < 0.05) lower mean arterial blood pressures. Because these complications are similar to those of septic shock, the simplest interpretation of these findings is that the mice develop shock brought on by the P. berghei infection. To determine whether the immune system and specifically CD8(+) T cells mediate the key features of shock during P. berghei malaria, we depleted CD8(+) T cells by monoclonal antibody (mAb) treatment and assessed the complications of malarial shock. P. berghei-infected mice depleted of CD8(+) T cells by mAb treatment had significantly reduced vascular leakage in their hearts, brains, lungs, and kidneys compared with infected controls treated with rat immunoglobulin G. CD8-depleted mice were significantly (P < 0.05) protected from lactic acidosis, glutamate buildup, and diminished HCO(3)(-) levels. Although the blood pressure decreased in anti-CD8 mAb-treated mice infected with P. berghei, the cardiac output, as assessed by echocardiography, was similar to that of uninfected control mice. Collectively, our results indicate that (i) pathogenesis similar to septic shock occurs during experimental P. berghei malaria, (ii) respiratory distress with lactic acidosis occurs during P. berghei malaria, and (iii) most components of circulatory shock are ameliorated by depletion of CD8(+) T cells.

Proc R Soc Lond B Biol Sci 2001 Nov 22;268(1483):2325-30

The effect of partial host immunity on the transmission of malaria parasites.

Buckling A, Read AF.

Institute of Cell, Animal and Population Biology, Division of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK.

Experiments were carried out to determine the effect of partial host immunity against the rodent malaria parasite Plasmodium chabaudi on the transmission success of the parasite. There was a fourfold reduction in both the blood-stage, asexually replicating parasite density and the gametocyte (transmissable stage) density in immunized hosts. Some of the reduction in asexual parasite densities was due to strain-specific immunity, but there was no evidence that strain-specific immunity affected gametocyte densities. However, immunity did affect transmission in a strain-specific manner, with a fivefold reduction in gametocyte infectivity to mosquitoes in homologous challenges compared with heterologous challenges or non-immunized controls. This implies the existence of a mechanism of strain-specific infectivity-reducing immunity that does not affect the density of gametocytes circulating in peripheral blood. The proportion of asexual parasites that produced gametocytes increased during the course of infection in both non-immunized and in immunized hosts, but immunity increased gametocyte production early in the infection.

Trop Med Int Health 2001 Nov;6(11):952-4

Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria.

Winstanley P.

Department of Pharmacology and Therapeutics, University of Liverpool, UK.

The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues.

Trop Med Int Health 2001 Nov;6(11):891-8

Monitoring antimalarial drug resistance within National Malaria Control Programmes: the EANMAT experience.

The East African Network for Monitoring Antimalarial Treatment (EANMAT).

The National Malaria Control Programme (NMCP), organized within the Ministry of Health (MoH), is an essential component for the planning, execution and coordination of malaria control activities. As effective case management remains the mainstay of malaria control in almost every African country, antimalarial drug resistance is a major barrier to the implementation of effective malaria control policies. In order to function effectively, these units must have an efficient surveillance system which can provide reliable and current estimates of the severity of drug resistance. Without this information, it is impossible for the MoH to design and promote a rational antimalarial policy, but because of limited resources, especially of people and expertise, most NMCPs have been unable to initiate and manage such a system. The need for collaborative partnerships between the MoH and the research community prompted the establishment of the East Africa Network for Monitoring Antimalarial Treatment (EANMAT). EANMAT has attempted to bring together the complimentary skills of malaria researchers and MoH staff in four east African countries. After 3 years of operation, data generated by EANMAT have been used to review and modify national malaria treatment policies in Kenya, Uganda, Rwanda and Tanzania. This new approach, which forges a closer working relationship between the research and policy communities, has effectively built capacity around the complex of surveillance, interpretation and use of evidence within a policy environment. The added-value of this approach is that the research community has learned to appreciate the constraints of policy development, and that the control community has established the need to build capacity and ownership of research evidence. Networks similar to EANMAT should be encouraged elsewhere in Africa to engender similar partnerships: to assist the development of rational treatment policies, and thus more effective malaria chemotherapy leading to significant lowering of malaria morbidity and mortality.

Trop Med Int Health 2001 Nov;6(11):845-8

History and importance of antimalarial drug resistance.

D'Alessandro U, Buttiens H.

Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium.

The emergence of Plasmodium falciparum resistance to widely used antimalarial drugs such as chloroquine (CQ) has made malaria control and treatment much more difficult. This is particularly dramatic for Africa, as few affordable alternatives are available. Drug pressure has been identified as one of the key factors for the emergence and spread of resistance. The contribution of the extensive use and misuse of antimalarial drugs to the selection of resistant parasites became particularly evident during the Global Malaria Eradication campaign, launched by World Health Organization (WHO) in 1955. The first reports confirming P. falciparum resistance to CQ came almost simultaneously in the early 1960s from South America and South-East Asia, where direct or indirect (through use of medicated cooking salt) mass drug administration (MDA) had been implemented. Similar approaches were very limited in Africa, where P. falciparum resistance to CQ was first reported from the eastern region in the late 1970s and spread progressively west. Most African countries still rely heavily on CQ as first-line treatment despite various levels of resistance, although some states have changed to sulphadoxine-pyrimethamine (SP) as the first-line drug. Unfortunately, the predicted SP useful therapeutic life might be very short, probably because of its prolonged half-life, causing a higher probability of selecting resistant strains and a consequent fast development of resistance. CQ resistance is not evenly distributed and important differences can be found within and between countries. It seems to have spread more rapidly in East than in West Africa. Considering the high level of CQ use in West Africa, other factors such as intensity of transmission, population immunity or population movements should be considered when explaining the different levels of resistance. Understanding such factors may help us in devising strategies to contain the spread of drug resistance.

Parasite Immunol 2001 Nov;23(11):587-97

Susceptibility of the different developmental stages of the asexual (schizogonic) erythrocyte cycle of Plasmodium chabaudi chabaudi to hyperimmune serum, immunoglobulin (Ig)G1, IgG2a and F(ab')2 fragments.

Cavinato RA, Bastos KR, Sardinha LR, Elias RM, Alvarez JM, D'Imperio Lima MR.

Departments of Parasitology and Immunology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

The mechanisms by which antibodies interfere with Plasmodium growth are still under debate. Characterizing the asexual erythrocyte stages susceptible to antibodies from hyperimmune individuals is therefore a relevant contribution to vaccine research. In this study, using a virulent and synchronous murine malaria parasite, Plasmodium chabaudi chabaudi AJ, we have shown that trophozoites and circulating schizonts are not the main targets for antibodies from hyperimmune serum. In drug-cured mice challenged with a high inoculum of ring-infected erythrocytes, parasitemias do not decline until the moment of erythrocyte rupture, suggesting that effector mechanisms operate immediately prior to reinvasion. Confirming these findings, treatment of primary-infected mice with hyperimmune serum inhibited the generation of new ring forms, but did not alter the numbers of schizont-infected erythrocytes, despite the fact that these cells were recognized by immunoglobulin (Ig)G antibodies. When these mice were treated with IgG1 or IgG2a purified from hyperimmune serum, both subclasses limited reinvasion, but IgG2a showed a stronger protective activity. The fact that Fc digestion decreases but does not abrogate protection suggests that both Fc-dependent and independent mechanisms participate in this process. Treatment with cobra venom factor did not interfere with the antibody-mediated protection, ruling out the participation of the complement system in both lysis and phagocytosis of merozoites or infected erythrocytes. Therefore, in mice suffering from P. c. chabaudi AJ malaria, merozoite neutralization seems to be a major mechanism of protection conferred by hyperimmune serum antibodies. However, FcgammaR-mediated interactions, or other mechanisms not yet defined, may also contribute to inhibit erythrocyte reinvasion.

Mol Microbiol 2001 Oct;42(2):553-60

The gametocyte-activating factor xanthurenic acid stimulates an increase in membrane-associated guanylyl cyclase activity in the human malaria parasite Plasmodium falciparum.

Muhia DK, Swales CA, Deng W, Kelly JM, Baker DA.

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

Sex is an obligate step in the life cycle of the malaria parasite and occurs in the midgut of the mosquito vector. With both Plasmodium falciparum and Plasmodium berghei, the tryptophan metabolite xanthurenic acid induces the release of motile male gametes from red blood cells (exflagellation), a prerequisite for fertilization. The addition of cGMP or phosphodiesterase inhibitors to cultures of mature gametocytes has also been shown to stimulate exflagellation. Here, we demonstrate that there is a guanylyl cyclase activity associated with mature P. falciparum gametocyte membrane preparations, which is dependent on the presence of Mg2+/Mn2+ but is inhibited by Ca2+. Significantly, this activity is increased on addition of xanthurenic acid. In contrast, a xanthurenic acid precursor (3-hydroxykynurenine), which is not an inducer of exflagellation, does not induce this guanylyl cyclase activity. These results therefore suggest that xanthurenic acid-induced exflagellation may be mediated by activation of the parasite cGMP signalling pathway.

Clin Infect Dis 2001 Nov 7;33(12)

A New Primaquine Analogue, Tafenoquine (WR 238605), for Prophylaxis against Plasmodium falciparum Malaria.

Shanks GD, Oloo AJ, Aleman GM, Ohrt C, Klotz FW, Braitman D, Horton J, Brueckner R.

US Army Medical Research Unit, Nairobi. 
[email protected]

We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for </=13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.

Acta Trop 2001 Dec 21;80(3):265-76

Control of malaria vectors with the insect growth regulator pyriproxyfen in a gem-mining area in Sri Lanka.

Yapabandara AM, Curtis CF, Wickramasinghe MB, Fernando WP.

Regional Office, Anti-Malaria Campaign, Matale, Sri Lanka

The study was conducted in eight adjacent villages in central Sri Lanka where there are many shallow pits dug by gem miners that fill with water. These become breeding places of the main malarial vector Anopheles culicifacies, and of the second most important vector Anopheles subpictus, but not of Anopheles varuna, the third most important vector. With the help of local volunteers, data on the adult populations of these three species was collected by various standard methods, and data on the incidence of malaria cases was collected by two clinics set up for the project and through the existing hospitals. Prevalence of malaria infection in symptom-less people was investigated by mass blood surveys. On the basis of a year's pre-intervention data the villages were stratified into four with high levels of malaria transmission and four with lower transmission. Within each stratum two villages were randomly assigned for mosquito control by treating all the gem pits, as well as river bed pools, with a granular formulation of the insect growth regulator pyriproxyfen at a target dose of 0.01 mg a.i./litre. The intervention caused significant reductions in the adult populations of An. culicifacies and An. subpictus. Similarly, incidence of malaria was reduced in the intervention villages to about 24% (95% c.l. 20-29%) of that in the controls. Prevalence of parasitaemia also declined significantly. It is concluded that in this situation where, with active community participation, the breeding sites of the main vectors could be located; vector control by a highly active and persistent insect growth regulator can be a very effective means of malaria control.

J Immunol 2001 Nov 15;167(10):5928-5934

Plasmodium berghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism.

Adachi K, Tsutsui H, Kashiwamura SI, Seki E, Nakano H, Takeuchi O, Takeda K, Okumura K, Van Kaer L, Okamura H, Akira S, Nakanishi K.

Department of Immunology and Medical Zoology and Laboratory of Host Defenses, Institute for Advanced Medical Science, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Department of Immunology, Juntendo University, Tokyo, Japan. Howard Hughes Medical Institute, Department of Microbiology and Immunology, School of Medicine, Vanderbilt University, Nashville, TN 37232. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan.

Malaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.

J Biomol Struct Dyn 2001 Oct;19(2):201-13

Computer modeling of small heat-shock metalloprotease of the human malaria parasite Plasmodium vivax.

Kothekar V, Shankar S, Lomash S, Sharma YD.

Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi. 
[email protected]

We present here computer generated model of N-terminal fragment, amino acids (aa) 36-245, of a Plasmodium vivax heat shock metalloprotease called PVHSP28, whose gene was cloned and characterised earlier. The fragment showed homology with HSPs from many organisms, including Escherichia coli and Haemophilus influenzae. PVHSP28 had the signature sequence 'HEXXH' and 'EXXXD' of Zinc metalloproteases. Being the first malarial HSP possessing metalloprotease activity, PVHSP28 is an ideal target for the design of new anti-malarial drugs. However, except for a small region (aa 62-132) which had 24.6% sequence similarity with 1TAQ (a DNA polymerase), it did not show sequence similarity with any published structures in protein data bank. Hence it could not be modelled using any automated modeling programs. We modelled 36-245 aa of PVHSP28 using predicted secondary structure as well as experimentally determined and predicted properties of the protein on the basis of its amino acid sequence, using various Internet tools and in-house package MODEL. The model was energy minimised using Sander's module of AMBER 5.0, working on a Silicon Graphics machine, with all atom force field.

J Trop Pediatr 2001 Oct;47(5):271-5

Anemia of persistent malarial parasitemia in Nigerian children.

Okafor HU, Nwaiwu O.

Department of Paediatrics, College of Medicine, University of Nigeria Teaching Hospital, Enugu.

One hundred children aged 0-60 months, 63 males and 47 females, were studied prospectively over a period of 9 months to determine the effect of persistent malaria parasitemia on their packed cell volume (PCV) levels. Thick and thin blood films for parasite identification and counts were done. Patients were randomly assigned to two treatment groups: 62 patients received chloroquine, while 38 patients received fansidar. Mean parasite count (2789.2+/-1809.6) and mean temperature (36.83 (0.66 degrees C) in the fansidar group at day 7 were found to be significantly lower than at enrollment (p < 0.05). This also corresponded with significantly higher mean PCV values of 33.85+/-4.72 (p < 0.05). In the chloroquine group it was only by day 21 that a significant reduction in parasite count and associated increase in PCV levels were noted. A negative correlation between mean parasite counts and PCV levels was observed (r = -0.9512). The hematological recovery time for chloroquine was longer at 21 days compared to fansidar which was 7 days. RII level of parasite resistance was found in 81 patients, 32 in the fansidar group, and 49 in the chloroquine group. The level of resistance to the used first-line antimalarials was found to be rather high in Enugu, south-east Nigeria. This calls for more extensive community-based studies and probable changes in drug policies.

Am J Trop Med Hyg 2001 Oct;65(4):355-61

Development and optimization of polymerase chain reaction-based malaria diagnostic methods and their comparison with quantitative buffy coat assay.

Schindler HC, Montenegro L, Montenegro R, Carvalho AB, Abath FG, Jaureguiberry G.

Departamento de Imunologia, Centro de Pesquisas Aggeu Magalhaes, Fundacao Oswaldo Cruz, Recife, Pernambuco, Brazil.

Polymerase chain reaction (PCR)-based assays targeting the small-subunit rRNA were developed and evaluated, allowing for the simultaneous diagnosis of Plasmodium falciparum and Plasmodium vivax DNA in human blood samples. The PCR methods and quantitative buffy coat (QBC) were compared in 402 patients. The heminested PCR method showed a sensitivity of 97.4%, which was superior to the sensitivity of the QBC method (91.7%, P < 0.05), to simple PCR (84.6%, P < 0.001), and to PCR with digoxigenin labeling (PCR-DIG) (88.5%, P < 0.001). The PCR-DIG and QBC analyses were more sensitive than simple PCR (P < 0.003 and P < 0.05, respectively). There was no significant difference between the sensitivities of the QBC assay and the PCR-DIG assay. The specificity for the 3 PCR-based methods was 100%, superior to the specificity calculated for the QBC assay (88.95%, P < 0.009). The frequency of a positive result in groups from endemic areas but without detectable parasitemia increased, in order, from simple PCR, QBC test, PCR-DIG, to heminested PCR. An association between a positive PCR result and a history of malaria was also found. Taken together, these data suggest that this technology could be further developed to screen people with oligoparasitemia and to monitor malaria treatment.

Am J Trop Med Hyg 2001 Oct;65(4):335-7

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Nacher M, Singhasivanon P, Gay F, Phumratanaprapin W, Silachamroon U, Looareesuwan S.

Unite INSERM 511: Immunobiologie Cellulaire et Moleculaire des Infections Parasitaires, Faculte de medecine Pitie-Salpetriere, Paris, France. [email protected]

Following a study showing an association between Ascaris and protection from cerebral malaria, we conducted a cross-sectional study comparing admission hemoglobin concentrations in relation to exposure to helminth infection in 2 separate groups of patients: 111 cerebral malaria cases and 180 mild Plasmodium falciparum malaria cases. Hookworm infections were excluded. Mean hemoglobin concentrations were significantly lower in helminth-infected patients compared to those without helminths, both in the cerebral malaria group (10.1+/-3 [n = 47] versus 11.2+/-2.4 g/dl [n = 64], P = 0.04) and the mild malaria group (11+/-2.5 [n = 89] vs 12.2+/-2.7 g/dl [n = 91], P = 0.004). Median reticulocyte counts, only available in the cerebral malaria group, were lower in helminth-infected patients compared to those without helminths (15,340/23,760 per microl, P = 0.03). Adjustments for confounders such as body mass index did not alter these associations. These data are consistent with a mechanism causing anemia linked to differences in the immune response of helminth-infected patients during malaria.

Am J Trop Med Hyg 2001 Oct;65(4):309-17


Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia.

Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM.

National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia.

Combining artesunate with existing antimalarial drugs may improve cure rates, delay emergence of resistance, and reduce transmission. We performed a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalarial drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally, 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine-pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0, and 52 patients received sulfadoxine-pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0% in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P = 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P = 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] = 0.1-1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxine-pyrimethamine group than in the sulfadoxine-pyrimethamine group (P = 0.08 and P < 0.0001, respectively). Only 20 (39.2%) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86.5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P = 0.000001, relative risk [RR] = 0.4, 95% CI = 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR = 0.5, 95% CI = 0.2-1.0 on day 7 and RR = 0.5, 95% CI = 0.2-1.1 on day 14). Mild diarrhea, rash, and itching resolved without treatment. Combined artesunate plus sulfadoxine-pyrimethamine resulted in more rapid fever and parasiteclearance, was well tolerated, reduced risk of treatment failure, and lowered gametocyte carriage.

Am J Trop Med Hyg 2001 Oct;65(4):304-8

In vitro antimalarial activity of extracts of three plants used in the traditional medicine of India.

Bhat GP, Surolia N.

Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore, Karnataka State, India.

In an attempt to search for new antimalarial drugs, we studied plants used by traditional healers of southwest India to treat malaria. Aqueous and organic solvent extracts obtained from specific parts of the plants Swertia chirata, Carica papaya, and Citrus sinensis were tested on malaria strain Plasmodium falciparum FCK 2 in vitro. The temperatures of extraction were the same as that used by the traditional healers in their plant preparations. Visual evaluation of the antimalarial activity of the plant extracts on thin blood smears was followed by quantification of the activity by use of [35S]-methionine incorporation into parasite proteins to determine the value that inhibits 50% (IC50). Among the 3 plants tested, 2 had significant inhibitory effect on P. falciparum in vitro.

Am J Trop Med Hyg 2001 Oct;65(4):285-9

Safety of the insect repellent N,N-diethyl-M-toluamide (DEET) in pregnancy.

McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsay SW.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

The safety of daily application of N, N-diethyl-m-toluamide (DEET) (1.7 g of DEET/day) in the second and third trimesters of pregnancy was assessed as part of a double-blind, randomized, therapeutic trial of insect repellents for the prevention of malaria in pregnancy (n = 897). No adverse neurologic, gastrointestinal, or dermatologic effects were observed for women who applied a median total dose of 214.2 g of DEET per pregnancy (range = 0-345.1 g). DEET crossed the placenta and was detected in 8% (95% confidence interval = 2.6-18.2) of cord blood samples from a randomly selected subgroup of DEET users (n = 50). No adverse effects on survival, growth, or development at birth, or at one year, were found. This is the first study to document the safety of DEET applied regularly in the second and third trimesters of pregnancy. The results suggest that the risk of DEET accumulating in the fetus is low and that DEET is safe to use in later pregnancy.

Bangladesh Med Res Counc Bull 2001 Apr;27(1):1-8

Prognostic factors relating to outcome of severe malaria among children in Bangladesh.

Rahman ME, Samad R, Rahman MR, Alam AK, Ferdous A.

Deptt. of Paediatrics, Mymensingh Medical College, Mymensingh.

This study was done in the Paediatric in-patient department of Chittagong Medical College Hospital (CMCH), Chittagong, Bangladesh to identify and quantify the prognostic factors associated with increased mortality in severe malaria (SM) cases. All the patients with parasitologically confirmed clinical syndromes of SM, admitted between June 1997 and May 1998, were included. A total of 53 consecutive cases were studied. Cerebral malaria (CM) was the commonest type of SM, observed in 36(68%) cases, second commonest type was severe anaemia 13(25%). More than one type of severe manifestations were present in 23(44%) cases. Overall case fatality rate (CFR) was 17% and it was 30% among those who had multi-organ manifestations. Important poor prognostic clinical variables were Blantrye coma score (BCS) score of 0 and 1 on day 1 (OR = 7.78) and day 2(OR = 40.0), multi-organ manifestations (OR = 6.8) and in-hospital complications (OR = 5.18). Important poor prognostic laboratory variables were day 2 parasite count > 50,000/cmm (OR = 5.5), blood glucose < 2.2 mmol/l (OR = 21.5) and raised CSF protein > 50 mg/dl (OR = 7.0). It can be concluded that certain clinical variables e.g. low BCS on day 1 & 2, multi-organ manifestations, in-hospital complications; and laboratory variables e.g. high parasite count, low blood glucose level, raised CSF protein levels are associated with increased mortality rate in SM cases.

Parasitol Res 2001 Oct;87(10):795-803

A comparison of the stage-specific efficacy of chloroquine, artemether and dioncophylline B against the rodent malaria parasite Plasmodium chabaudi chabaudi in vivo.

Chimanuka B, Francois G, Timperman G, Heyden YV, Holenz J, Plaizier-Vercammen J, Bringmann G.

Vakgroep Farmaceutische Technologie en Fysische Farmacie, Vrije Universiteit Brussel, Brussels, Belgium. 
[email protected]

Chloroquine, artemether and dioncophylline B efficacy against Plasmodium chabaudi was compared. One intraperitoneal injection (10 mg/kg body weight) was given daily over 3 consecutive days to OF1 mice when they were predominantly bearing ring, trophozoite and schizont forms. The parasitaemia was monitored every 2 h during two schizogonic cycles and daily thereafter until parasites were cleared. Chloroquine was more efficient at the trophozoite stage, while artemether was effective against all erythrocytic stages, with a marked efficacy against the trophozoite stage. Chloroquine-treated and artemether-treated parasites displayed a pigment-clumping morphology and lowered the parasitaemia faster than dioncophylline B. Dioncophylline B was effective at trophozoite and schizont stages, but completely ineffective at the ring stage. These results demonstrate that a better timing of drug administration increases the efficacy of common and new antimalarial drugs and provides a model for antimalarial-action monitoring.

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Last modified November 16, 2001