Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
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One hundred and two children aged 0-10 years with cerebral malaria (Blantyre coma score of 2 or less) were randomly treated either with intramuscular arteether (3.2 mg/kg on Day 0, followed by 1.6 mg/kg on Days 1 to 4) or intravenous (i.v.) quinine dihydrochloride (20 mg of the salt/kg, followed by 10 mg of the salt/kg every 8 hr up to Day 6). Treatment with oral quinine sulfate (10 mg/kg every 8 hr) was substituted for i.v. quinine when the patient was able to take oral medicine. All patients were followed up in the hospital for 7 days; thereafter, they were treated as outpatients on Days 14, 21, and 28. Mortality rate, the main efficacy parameter, was 11.8% lower in the arteether treatment group than in the quinine group (15.7% versus 27.4%); however, the difference was not significant (P = 0.25). Means for fever clearance time, coma resolution time, and parasite clearance time were similar in the 2 treatment groups (42.2 +/- 34.9 hr; 34.8 +/- 18.8 hr, and 46.3 +/- 28.5 hr, respectively for arteether, versus 45.0 +/- 26.7 hr; 30.3 +/- 18.9 hr, and 40.7 +/- 18.9 hr, respectively, for quinine). At 28 days, the cure rates were 73.2% and 64.9% for the arteether and quinine treatment groups, respectively. Arteether is safe and therapeutically at least as effective as quinine for the treatment of cerebral malaria in children in Cameroon. Because of its ease of administration, arteether appears to be suited for use in the rural zones where monitoring facilities do not exist.
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PMID:Clinical trial of beta-arteether versus quinine for the treatment of cerebral malaria in children in Yaounde, Cameroon. 1146 8

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.
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PMID:History and importance of antimalarial drug resistance. 1170 37

P30P2MSP1(19) is a recombinant subunit vaccine derived from merozoite surface protein 1 (MSP1) of Plasmodium falciparum, the causative agent of malaria. P30P2MSP1(19) consists of two universal T-cell epitopes fused to the most C-terminal 19-kDa portion of MSP1, and this protein has previously shown promising potential as a vaccine for malaria. However, previous attempts at producing this molecule in Saccharomyces cerevisiae resulted in the production of a truncated form of the molecule missing most of the universal T-cell epitopes. Here, we report the production of full-length P30P2MSP1(19) in Pichia pastoris. As salt precipitation is a common problem during P. pastoris high-density fermentation, we utilized an alternative low-salt, fully defined medium that did not reduce growth rates or biomass yields to avoid precipitation. A total of 500 mg/L of secreted purified protein was produced in high cell density fermentation and the protein was purified in one step utilizing nickel-chelate chromatography. P30P2MSP1(19) produced in Pichia was reactive with monoclonal antibodies that recognize only conformational epitopes on correctly folded MSP1. Rabbits immunized with this molecule generated higher and more uniform antibody titers than rabbits immunized with the protein produced in Saccharomyces. P30P2MSP1(19) produced in Pichia may prove to be a more efficacious vaccine than that produced in Saccharomyces and Pichia would provide a system for the cost-effective production of such a vaccine.
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PMID:High-level production and purification of P30P2MSP1(19), an important vaccine antigen for malaria, expressed in the methylotropic yeast Pichia pastoris. 1172 85

In areas where multidrug-resistant Plasmodium falciparum (MDR-Pf) is prevalent, only quinine is known to be safe and effective in pregnant women. On the western border of Thailand, 7 days of supervised quinine (30 mg/kg daily) cures two-thirds of P. falciparum-infected women in the 2nd and 3rd trimesters of pregnancy. Artesunate is effective against MDR-Pf and the limited data on its use in pregnancy suggest it is safe. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) in combination with clindamycin (5 mg/kg every 8 h) for 7 days (QC7) versus artesunate 2 mg/kg per day for 7 days (A7) was conducted in 1997-2000 in 129 Karen women with acute uncomplicated falciparum malaria in the 2nd or 3rd trimesters of pregnancy. There was no difference in the day-42 cure rates between the QC7 (n = 65) and A7 (n = 64) regimens with an efficacy of 100% in both, confirmed by parasite genotyping. The A7 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for A7 was 3 (95% CI 0-19) and for QC7 was 39 (95% CI 21-66) per 1000 person-weeks, respectively (P < 0.01). There was no difference in gastrointestinal symptoms between the groups but there was significantly more tinnitus in the QC7 group compared to the A7 group (44.9% vs 8.9%; RR 5.1; 95% CI 1.9-13.5; P < 0.001). The favourable results with quinine-clindamycin mean that there is a useful back-up treatment for women with falciparum malaria who experience quinine and artesunate failures in pregnancy. Adherence to the 7-day regimen and cost (US$18.50 per treatment) are likely to be the main obstacles to this regimen.
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PMID:Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. 1181 39

We have earlier obtained good results in falciparum malaria by treating children with low doses of quinine for 7 days in Guinea-Bissau. In order to further simplify treatment, we compared outcome in 100 children with falciparum malaria treated in 1999/2000 for 7 days with 15 mg quinine salt/kg/dose twice daily (group I), 100 children treated with 7.5 mg quinine salt/kg/dose twice daily (group II), and 100 children treated with one single daily dose of 15 mg/kg. One day 28, parasites had reappeared in 12%, 15%, and 9%, respectively. These results are similar to what has been found after previous successful treatment regimens. Apart from a higher incidence of vomiting during the first 24 h of treatment in the groups treated with 15 mg/kg/dose no significant differences in symptoms or side-effects were found between the groups. In patients suffering from uncomplicated malaria, treatment with quinine can be simplified to one single dose of 15 mg/kg bodyweight whenever logistics make 2 daily doses less feasible.
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PMID:Treatment of Plasmodium falciparum malaria with quinine in children in Guinea-Bissau: one daily dose is sufficient. 1205 11

5-Fluoroorotic acid (H(3)FOro) is a potent inhibitor for some metalloproteins such as dihydroorotase and dihydroorotate dehydrogenase and for thymidylate synthase (nonmetalloprotein) in the human malaria parasite Plasmodium falciparum. To study the coordination chemistry of H(3)Foro, the ammonium salt [NH(4)(+)][H(2)FOro(-)].1H(2)O (1) and the first coordination compounds of H(3)FOro with transition metals [Ni(HFOro(2-))(H(2)O)(4)].1H(2)O (2), [Cu(HFOro(2-))(NH(3))(H(2)O)](n) (3) and [Cu(3)(FOro(3-))(2)(NH(3))(6)(H(2)O)(2)] (4) have been synthesised and characterised by single-crystal X-ray diffraction, IR spectroscopy and by thermogravimetry. Three different coordination modes of 5-fluoroorotic acid have been established. In all cases the ligand is chelated to the metal via an amido-nitrogen and a carboxylate-oxygen but for (3), there is also a carboxylate oxygen from another HFOro(2-) ligand resulting in a polymeric structure and for (4), the second amido-nitrogen in the ororotic acid ring coordinates to give a trinuclear complex. The metal coordination polyhedra are octahedral in (2), square-pyramidal in (3) and square-planar and approximately square-pyramidal in (4). An octahedral coordination geometry including a N(1)/O(61)-chelating HFOro(2-) ligand with four aqua ligands is proposed for the Zn complex [Zn(HFOro(2-)) (H(2)O)(4)].0.5H(2)O (5), based on IR and thermogravimetric data. Extensive hydrogen bonded networks and some ring-ring stacking interactions are observed in each of the structures.
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PMID:The interaction of 5-fluoroorotic acid with transition metals: synthesis and characterisation of Ni(II), Cu(II) and Zn(II) complexes. 1206 27

From 1980 through 1984 the same communication and social marketing strategy was applied to teaching oral rehydration therapy (ORT) and related child survival practices in both the Gambia and Honduras. Within that strategy, each country developed campaigns that had their own character, peculiarities, and challenges. Data bridging 3 years and the 2 cultures show almost identical results, including sustained adoption of ORT and significant improvement in nutritional practices. This discussion reports on the most interesting similarities, differences, and data from the 2 countries, based on recently published longitudinal studies conducted by Stanford University and Applied Communication Technology. Highly specific objectives were pursued and multiple channels -- radio, print materials, and direct contact -- were coordinated to support these objectives in the campaigns of Honduras and Gambia to teach ORT and related practices. Although emphasis shifted among topics for limited periods of time during the interventions, the key communication methods and procedures for conducting the interventions would not end abruptly but become an ongoing part of the public health education process and the health care delivery system. The interventions in Honduras and Gambia adapted lessons learned from past experiences. The methodological sequence is outlined. Stratified, random panels of approximately 750-1000 households with posttest controls were surveyed in each country in repeated waves over a 3 year period. The overall evaluation plan examined a sequential model of changes, recognizing that changes in any individual do not necessarily follow the same pattern. 1 technique used with strong impact in Gambia was the "Happy Baby Lottery." This was a contest of skill rather than chance and proved successful in overcoming the difficulty many Gambian women expeience in interpreting 2-dimensional graphs. The "lottery" in Gambia marked the beginning of a 2-year effort to teach a water/sugar/salt (WSS) home-mix solution and related diarrheal control and infant feeding practices. The evaluation shows that the mothers learned about ORT and changed their behavior accordingly. An overview of the 2-year data set indicates sustained adoption of WSS solution to treat diarrhea. The campaign in Health Region I of Honduras emphasizing ORT and related diarrheal control and infant feeding practices lasted 2 years and then expanded to the national level and to other topics during the 3rd year -- immunizations, malaria control, and compliance with tuberculosis treatment. The same method of village investigation, behavioral analysis, pretesting, integrated use of multiple channels, and monitoring were applied in developing and implementing a sustained, phased, public health communications intervention. Honduran mothers also learned and changed their practices significantly. At the beginning of the campaign none of the Health Region I mothers had used Litrosol, a newly introduced product, but within 6 months 37% of all surveyed mothers had tried it. By the end of the campaign over 60% of mothers had used Litrosol.
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PMID:Communication works across cultures: hard data on ORT. 1234 May 40

The resistance of Plasmodium falciparum to the chloroquine-proguanil association (C/P) as antimalarial chemoprophylaxis is becoming increasingly common in Africa. Daily oral doxycycline hyclate 100 mg is effective as malaria prophylaxis. But the hyclate salt's adverse effects combined with the capsule's galenic form are incompatible with good chemoprophylaxis compliance. We conducted a randomized group study of 522 French soldiers deployed in Gabon and Chad for 4 months to determine the tolerability of short-term malaria chemoprophylaxis with a 100-mg daily tablet of a monohydrate doxycycline salt compared with a daily C/P capsule. At days 7 and 120, compliance was better in the doxycycline group [respectively 98.5%vs. 73.9% (P < 0.001) and 90.5%vs. 74% (P < 0.001)]. No major event (evacuation, hospitalization) was related to the medications. Epigastralgia, diarrhoea, urticaria, mouth ulcers, sun sensitization and desquamation were significantly more frequent in the C/P group (P < 0.05). There was no statistical difference for malaria incidence, vertigo, nausea and hair loss. These results suggest that doxycycline monohydrate may be safely used in short-term malaria chemoprophylaxis. With the same efficacy as a hyclate doxycycline, doxycycline monohydrate could be a good chemoprophylaxis for short-term travellers at particular risk of C/P resistant P. falciparum malaria.
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PMID:Tolerability of doxycycline monohydrate salt vs. chloroquine-proguanil in malaria chemoprophylaxis. 1239 May 96

The Neotropical malaria vector Anopheles aquasalis Curry is distributed predominantly along the Atlantic and Pacific Coasts because of its tolerance for breeding in salt water. We tested the hypothesis that the freshwater Amazon River acts as a barrier to gene flow in northeastern Brazil, by examining variation at a 588-nucleotide fragment of the mitochondrial cytochrome oxidase Igene from five populations. We identified 15 haplotypes of which 5 were shared both (1) between sample localities and (2) across the Amazon River Delta. Sequence divergence ranged from 0.0017-0.0272 (average = 0.0137). Estimates of genetic subdivision based on the presence of the Amazon Riverwere greatest within localities (phi = 0.029) and among regions (phi = 0.018), followed by among localities (phi = 0.011), but none were significant. Parsimony, neighbor-joining, and Nested Clade Analyses were used to estimate relationships among populations and infer evolutionary processes. Two phylogenetically distinct clusters of populations were moderately supported by parsimony. Neighbor-joining trees were poorly resolved, thus providing no geographical resolution and no support for the Amazon River as a barrier to migration. Phylogeographic structure as detected by the Nested Clade Analysis was consistent with restricted gene flow coupled with isolation by distance. Taken together, these analyses suggest that the localities within this region of northeastern Brazil constitute a single large population of An. aquasalis that spans the Amazon Delta.
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PMID:Evaluation of the Amazon River delta as a barrier to gene flow for the regional malaria vector, Anopheles aquasalis (Diptera: Culicidae) in northeastern Brazil. 1249 84

The authors present the results of a study carried out to determine the efficacy of chloroquine- and pyrimethamine-salt mixtures as a suppressive against sporozoite-induced vivax malaria (Chesson strain). The test subjects used in this study were volunteers of military age in the US Penitentiary at Atlanta, Ga. The subjects chosen were all in good physical condition and had no previous history of malaria.Both drug-salt mixtures were entirely acceptable to the volunteers, were indistinguishable in taste and appearance from ordinary salt, and remained stable under the conditions of food preparation. The weekly dosage of the drugs (300 mg of chloroquine base or 25 mg of pyrimethamine per 50 g of salt) had in each case been adjusted to the average salt consumption. Suppression of malaria was found to be complete throughout the salt-drug regimen and for 28-43 days thereafter, even though the subjects were exposed to repeated heavy doses of sporozoites. In contrast, the control subjects, exposed to the same infective doses, all exhibited parasitaemia 13-15 days after exposure.The procedures for preparing the drug-salt mixtures are described in detail and a simple method for determining the salt consumption by measurement of the urinary chloride excretion is outlined.
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PMID:Chloroquine or pyrimethamine in salt as a supressive against sporozoite-induced vivax malaria (Chesson strain). 1358 60


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