Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At present, in countries of tropical Africa, chemotherapy is the main and often the only operationally, administratively, and financially feasible method of malaria control. This applies particularly in rural areas. This article reviews experience with chemotherapy in Africa since the late 1940s with mepacrine, proguanil, pyrimethamine, chloroquine, amodiaquine, and sulfones and sulfonamides in combination with dihydrofolate reductase inhibitors. Chloroquine has proved to be the most effective compound and it is the drug of choice as long as malarial parasites remain susceptible to it. Because of reports from East Africa of strains of Plasmodium falciparum resistant to 4-aminoquinolines, it is essential that national and regional policies be developed for the rational use of antimalarials.In most of the countries, the scope of activities is still limited to the administration of antimalarial drugs to sick persons through a limited network of health institutions. In some countries, however, attempts have been made to extend the coverage of drug administration by involving voluntary collaborators or through the provision of suppressive treatment to vulnerable groups of the population (such as infants, young children, pregnant women, nursing mothers, and schoolchildren) but the efficacy of such methods depends on the degree of involvement of voluntary collaborators, primary health workers, and communities.
 ...
PMID:Use of drugs for malaria control in tropical Africa. 31 34

A series of 2,4-diaminoquinazolines bearing an aryl function attached to the 6 position through an acetamido or related linkage was synthesized. Each compound was evaluated as an inhibitor of rat liver dihydrofolate reductase as well as for suppressive antimalarial effects against Plasmodium berghei in mice. Significant in vivo activity was found to reside primarily with 5-chloro-6-arylacetamido derivatives. Most of these compounds were also tested for prophylactic activity against sporozoite-induced Plasmodium gallinaceum in chicks. Thirteen compounds, each of which possesses a 5-Cl or 5-CH3 group, displayed curative activity in this test system. Since several of these showed markedly greater potency against the avian infection, selective inhibitory action upon preerythrocytic forms of the malaria parasite is thus implied.
 ...
PMID:Synthesis and evaluation of 6-arylactamido-2,4-diaminoquinazolines and related compounds as folic acid antagonists. 109 14

Data are presented on the causal prophylactic action of about 100 compounds of various types against Plasmodium yoelii nigeriensis N67 in mice. Examples are given to show how action against pre-erythrocytic schizonts may be differentiated from action on emerging erythrocytic stages. In a series of 35 8-aminoquinolines, all but 10 showed definite causal prophylactic activity at tolerated doses. The data permit the compounds to be ranked in order of activity, and many are shown to be more active in this test system than primaquine. Marked causal prophylactic activity is displayed by a variety of quinone structures, several of which show a significant residual action on blood stages. A high level of activity is found in dihydrofolate reductase inhibitors within several chemical classes. Rorguanil is more effective as a causal prophylactic than a blood schizontocide in the mouse as in man. Sulphonamides and sulphones are also effective in this system. The active levels are influenced by the content of PABA in the diet of the hosts. Causal prophylactic action has been detected in a number of experimental compounds including some antibiotics (such as tetracycline and clindamycin). The pyrocatechol RC 12 shows only slight activity at the maximum tolerated dose. Chloroquine, mepacrine, quinine, quinolinemethanols and phenanthrenemethanols are inactive as causal prophylactics. It is concluded that a rodent malaria-mouse model does provide a relatively simple model for the screening of drugs for causal prophylaxis, and the data so obtained are of relevance to the detection of causal prophylactics against human malaria.
 ...
PMID:The chemotherapy of rodent malaria, XXIII Causal prophylaxis, part II: Practical experience with Plasmodium yoelii nigeriensis in drug screening. 109 90

Most antibodies directed against the Plasmodium falciparum circumsporozoite (CS) protein react with its central domain, which contains about 40 repeats of the tetrapeptide Asn-Ala-Asn-Pro (NANP). To search for new epitopes in the non-repetitive part of the CS protein, we expressed the non-repetitive regions of the protein in E. coli as fusion proteins with mouse dihydrofolate reductase linked to six adjacent histidine residues. These fusion proteins were obtained at greater than 70% purity by a single Ni-chelate affinity chromatography step. Of the new epitopes defined in the C-terminal portion of the CS protein, three are located in a stretch of 65 amino acids immediately C-terminal of the protein's central repetitive domain. Pooled sera from inhabitants of a malaria-endemic area reacted with epitopes in this region of the molecule, and four mouse monoclonal antibodies to this region also reacted with the native CS protein on sporozoites. Two of the monoclonal antibodies reacted with a peptide PNDPNRNVD derived from a conserved region of the CS protein. The other two antibodies showed different reactivities to sporozoites of the NF54 and Ro59 parasite isolates. One, which reacted with a peptide ENANANNAV, recognized Ro59 but not NF54 sporozoites, while the other reacted with a small percentage of NF54 but not Ro59 sporozoites. Antibodies which react with non-repetitive regions of the CS protein could contribute to maintaining its genetic variability.
 ...
PMID:New B cell epitopes in the Plasmodium falciparum malaria circumsporozoite protein. 169 36

Infections with parasitic protozoa have always been problems for the developing world and are becoming of greater importance to the developed world in this age of easy international travel. The major human protozoal diseases are summarised with an emphasis on their presentation in normal hosts and in immunocompromised individuals and current US drug treatment recommendations are discussed. Present antiprotozoal regimens are based either on a pharmacokinetic rationale or on clinical trial and error. Regimens based on trial and error include amphotericin B against leishmaniasis and arsenic against African trypanosomiasis. Regimens which are to some extent driven by pharmacokinetic or biochemical considerations include paromomycin and metronidazole against amoebiasis, sodium stibogluconate against leishmaniasis, halofantrine and mefloquine against malaria, dihydrofolate reductase (DHFR) inhibitors against Pneumocystis carinii and toxoplasmosis and aerosolised pentamidine against P. carinii pneumonia. The majority of pharmacokinetic studies have been performed only on agents which have some therapeutic activity against other diseases of the developed world. Despite the trend toward rational treatment regimens, no studies have been performed that permit optimisation of antiprotozoal treatment regimens on the basis of clinical conditions such as renal failure.
 ...
PMID:Pharmacokinetic justification of antiprotozoal therapy. A US perspective. 178 41

In The Gambia co-trimoxazole is used widely to treat children with an acute respiratory infection (ARI). Because malaria may sometimes be mistaken for ARI, some children with malaria are treated with co-trimoxazole. Therefore, we investigated the sensitivity of Gambian isolates of Plasmodium falciparum to this drug. Six days after the start of treatment with co-trimoxazole 3.3% of blood films of 65 asymptomatic subjects were positive, and 7.7% were positive after 21 d. One of 10 patients with ARI and malaria treated with co-trimoxazole had a positive blood film 3 d after the start of treatment but was negative thereafter. All 10 patients recovered satisfactorily. Thirty 'wild' isolates of P. falciparum were tested in vitro against co-trimoxazole at a ration of 5 parts sulphamethoxazole (SMZ) to 1 part trimethoprim (TMP). The mean EC50s, using a 36 h assay, were 1.2 x 10(-7) and 2.5 x 10(-8) M for SMZ and TMP respectively. When a [3H]hypoxanthine incorporation assay was employed, values of 5.7 x 10(-7) M for SMZ and 1.2 x 10(-7) M for TMP were obtained. These values are well below the peak plasma concentration. Our findings suggest that co-trimoxazole is effective against falciparum malaria in The Gambia. However, if it were to be used widely, the parasite would be likely to develop resistance to this and other dihydrofolate reductase inhibitor antimalarials.
 ...
PMID:Sensitivity of Plasmodium falciparum in The Gambia to co-trimoxazole. 194 36

Pyrimethamine resistance in cultivated laboratory isolates of Plasmodium falciparum is linked to the dihydrofolate reductase mutation Asn-108, a mutation that acts by interrupting drug binding within the active site of the enzyme. To determine the prevalence of this mutation in endemic regions harboring pyrimethamine-resistant malaria, we used a mutation-specific polymerase chain reaction assay to survey P. falciparum strains from a wide section of the Brazilian Amazon. Mutations were identified directly from blood samples without intervening steps of in vitro cultivation. Of 42 samples collected from four states in Brazil, 38 (90%) contained the Asn-108 codon AAC that confers pyrimethamine resistance, four samples contained only the wild-type Ser-108 codon AGC, and none contained the Thr-108 codon ACC found in cycloguanil-resistant pyrimethamine-sensitive strains. These findings indicate that a very high incidence of the Asn-108 DHFR mutation is responsible for pyrimethamine resistance in the Amazon, and they are consistent with recent failure rates reported for Fansidar (pyrimethamine-sulfadoxine). We suggest that limited use of proguanil be evaluated as an alternative to pyrimethamine.
 ...
PMID:Prevalence of the dihydrofolate reductase Asn-108 mutation as the basis for pyrimethamine-resistant falciparum malaria in the Brazilian Amazon. 195 58

Proguanil and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria. Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine, and vice versa. Analysis of the P. falciparum dihydrofolate reductase (DHFR) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs. Parasites harboring a pair of point mutations from Ala-16 to Val-16 and from Ser-108 to Thr-108 are resistant to cycloguanil (the active metabolite of proguanil) but not to pyrimethamine. A single Asn-108 mutation, on the other hand, confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil. Significant cross-resistance to both drugs occurs in parasites having mutations that include Ser-108----Asn-108 and Ile-164----Leu-164. These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of DHFR. Alternative inhibitors, used alone or in combination, may be effective against some strains of cycloguanil- or pyrimethamine-resistant malaria.
 ...
PMID:Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. 218 22

Over recent years many antimalarial drugs have been rendered useless by the development of resistance by the malaria parasite. New antimalarials are rapidly suffering the same fate as the traditional therapies and yet a biological understanding of the mechanisms of resistance has, until recently, not been described. This review describes recent work which has identified the mechanism of resistance to the dihydrofolate reductase (DHFR) inhibitors as being due to point mutations within the DHFR gene that render the enzyme less susceptible to inhibition by the drugs. The relationship between chloroquine resistance and the recently described multidrug resistance gene is explored and the possibility that this is the main cause of chloroquine resistance by the parasite is discussed. Parasites have developed resistance against many of the quinine-like antimalarials over the past three decades and the possibility that this is linked to the appearance of chloroquine resistance must be considered.
 ...
PMID:Chemotherapy and drug resistance in malaria. 221 Sep 44

Selection of the rodent malaria Plasmodium chabaudi with low levels of the antifolate drug pyrimethamine has previously been shown by us to result in duplication of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene by a duplication of chromosome 7 and subsequent rearrangements. We have selected this resultant parasite line with large doses of pyrimethamine and analysed the DHFR-TS gene and chromosomes for any changes. Increased drug pressure has resulted in reappearance of a chromosome with the same structure as chromosome 7 from DS the parent line. Sequencing of the DHFR gene from each of the chromosomes has identified a single point mutation that results in a serine to asparagine change at position 106. This is the equivalent mutation that has been identified as the key residue in the mechanism of resistance to pyrimethamine in Plasmodium falciparum. There is no apparent increase in transcription of the DHFR-TS gene and the large increase in resistance is most likely a result of the mutation in the DHFR gene.
 ...
PMID:Chromosomal rearrangements and point mutations in the DHFR-TS gene of Plasmodium chabaudi under antifolate selection. 223 98


1 2 3 4 5 6 7 8 9 10 Next >>