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Antimalarial effects of rifampin in Plasmodium vivax malaria.

The antimalarial effects of rifampin in 60 adults with Plasmodium vivax malaria were assessed. There were three treatment groups: rifampin (20 and 15 mg/kg of body weight per day for 1 and 4 days, respectively; n = 5); rifampin followed by primaquine (15 mg of base per day for 14 days; n = 25), and chloroquine (25 mg of base per kg over 3 days) followed by primaquine (n = 30). All patients were hospitalized till clearance of fever and parasites, and 45 patients stayed in the hospital for 1 month. Despite initial clearance of fever in all patients and a > or = 6-fold reduction in parasitemia per 48-h life cycle, rifampin alone was not effective: all five patients had subsequent R2-like parasitological responses. All patients treated with rifampin-primaquine cleared both fever and parasitemia, but the therapeutic responses were slower than those following treatment with chloroquine-primaquine. Final fever clearance times were significantly longer (mean [standard deviation] = 43 [35] versus 27 [19] h; P = 0.046), and the parasite clearance times (to 50 and 90% of admission parasite counts and to a level undetectable in a peripheral blood smear) were also significantly greater (P = 0.053 to < 0.001). However, reappearance of infection occurred in only one patient treated with rifampin-primaquine. The results of this study suggest that rifampin at the usual therapeutic doses has partial activity against blood stages of P. vivax in humans but that used alone it is insufficient for cure. Rifampin might therefore be of value in combination antimalarial therapy.

Adolescent↗

Antimalarial antibodies of the immunoglobulin G2a isotype modulate parasitemias in mice infected with Plasmodium yoelii.

Previous studies have demonstrated the importance of antibodies in mediating immunity to malaria, but the relative contribution of the different immunoglobulin isotypes has not been assessed. In this study, hyperimmune plasma was generated against Plasmodium yoelii and separated by protein A-Sepharose chromatography into fractions containing immunoglobulin G1 (IgG1), IgG2a, IgG2b, or IgG3 antibodies and the remaining nonbinding plasma proteins, including IgM. Following concentration, the antimalarial titer of each isotypic fraction was approximately equivalent to the corresponding isotype in hyperimmune plasma. The isotypic fractions were passively transferred to BALB/c and outbred ICR mice prior to challenge with virulent P. yoelii 17XL and to CBA/CaJ mice challenged with avirulent P. yoelii 17XNL. Only mice receiving IgG2a antibodies experienced an altered course of infection. Immunoprecipitation studies showed that all four IgG isotypes appear to recognize a similar set of antigens. These results suggest that antimalarial antibodies of the IgG2a isotype play a dominant role in modulating P. yoelii parasitemias.

Animals↗

Congenital exposure to Plasmodium falciparum antigens: prevalence and antigenic specificity of in utero-produced antimalarial immunoglobulin M antibodies.

Congenital Plasmodium falciparum malaria in newborns is uncommon in sub-Saharan Africa. A significant number of infants, however, become infected or exposed to malarial antigens either in utero or at delivery and have the potential to produce antimalarial antibodies and memory cells before their first natural infection. In Yaounde, Cameroon, parasite-specific immunoglobulin M (IgM) was detected in 14% of cord blood samples. The IgM antibodies reacted with a wide range of asexual-stage antigens, with each newborn having its own unique pattern of IgM reactivity. PCR-based detection and genotyping of cord blood parasites found that the prevalence, total number of parasite genotypes, and complexity of infection were higher in newborns who had produced antimalarial IgM than those who had not. Maternal placental malaria and anemia were associated with the production of P. falciparum-specific IgM by the fetus. The effect of early immune priming on acquisition of immunity by infants is unknown and merits further investigation, since a significant proportion of Cameroonian newborns developed a humoral response to malaria before birth.

Adult↗

Malaria and antimalarial plants in Roraima, Brazil.

One of the numerous problems created by the gold rush which took place in northern Brazil (Roraima State) at the end of the 1980s was a severe epidemic of malaria amongst the indigenous peoples of the region. Worst hit were the Yanomami Indians, who had lived in almost total isolation prior to this event. The problem has been exacerbated by the development of chloroquine-resistant strains of Plasmodium falciparum. In an effort to identify viable alternatives to dependence on western medicine for malaria treatment, a survey was carried out on the local plant species (wild and cultivated) used for this purpose in Roraima. Fieldwork was carried out amongst seven indigenous peoples, as well as with the non-indigenous settlers. Over 90 species were collected, many of which have been cited as used for treatment of malaria and fevers elsewhere. Knowledge of antimalarial plants was found to vary greatly between the communities, and in some cases there was evidence of recent experimentation. Initial screening of plant extracts has shown a high incidence of significant antimalarial activity amongst the species collected.

Brazil↗

[Historical overview of antimalarials used in Venezuela].

A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs.

Communicable Disease Control↗

[Iron chelation in antimalarial therapy].

Rapid development of significant resistance to antimalarial drugs has been a major force driving research to identify and develop new compounds. A number of iron(III)-chelating compounds designed for purposes other than treating malaria have in vitro antimalarial activity stemming from iron deprivation or toxic effects related to free radical release. Several of the iron(III) chelators have been effective in animal models of plasmodial infection. Desferrioxamine has been used successfully against both uncomplicated and severe malaria in humans. Iron-chelating agents seem to be promising therapeutic adjuvants for treatment of severe Plasmodium falciparum malaria infection.

Animals↗

Long-term course of antimalarial maculopathy after cessation of treatment.

Since 1980 I have examined some 1650 patients for the presence or absence of antimalarial maculopathy. Bilateral, irreversible visual field defects have been diagnosed is 62 patients, 37 of whom have been followed for at least 4 years. The 22 patients who presented with relative scotomas did not lose central visual acuity; over a median follow-up period of 6.0 years 33 (75%) of the eyes maintained their visual field, 5 (11%) showed some improvement in visual field, 4 (9%) lost some visual field, and 2 (4%) manifested small absolute scotomas. Nine (60%) of the 15 patients who presented with absolute scotomas were symptomatic. Over a median follow-up period of 8.8 years 19 (63%) of the eyes in this group lost one or more lines of visual acuity, including 4 (13%) that became legally blind; 19 (63%) lost field owing to an increase in the size of the absolute scotomas (13 eyes) or the development of new absolute scotomas (6 eyes). The results suggest that the visual prognosis is excellent if antimalarial therapy is stopped at an early stage of the disease.

Chloroquine↗

A radioimmunoassay for the antimalarial drug chloroquine.

We describe a 3H-based RIA for the antimalarial drug chloroquine (CLQ), the most commonly used antimalarial drug. In the assay a monoclonal antibody is used that is directed against 4-amino-7-chloroquinoline conjugated to keyhole limpet hemocyanin by the glutaraldehyde method. Besides CLQ, this antibody also recognizes with good affinity the 4-aminoquinoline homologs, hydroxychloroquine and amodiaquine. No extraction step or sample preparation is required, and the method can detect as little as 10 micrograms/L, the lower concentration in plasma of humans who are taking CLQ as a preventive measure. The between-assay CV is less than or equal to 10%, the within-assay CV less than or equal to 3%. Results correlate with those by liquid chromatography (r2 = 0.96). The speed and simplicity of the RIA method make it useful in evaluating the CLQ concentrations in acutely toxic patients.

Antibodies, Monoclonal↗

Malaria in urban and rural areas of southern Ghana: a survey of parasitaemia, antibodies, and antimalarial practices.

A comparative cross-sectional survey was undertaken in two populations, urban and rural, in southern Ghana to assess the impact of urbanization on the prevalence of malaria parasitaemia and antibodies. At the same time, a survey of antimalarial practices was conducted on sample populations in the two communities. The results showed a low parasite rate (1.6%) and correspondingly low titres of malaria antibodies in a significant proportion of the urban community, particularly in children less than 10 years old. This was associated with widespread use in the urban community of antimalarial drugs, particularly chloroquine, as prophylaxis. The parasite rate in the rural community was 22%, and 97% of the sample population over 1 year of age had antibodies against Plasmodium falciparum. These results demonstrate that a substantial proportion of urban children are growing up with little exposure to malaria, even in a region considered endemic for malaria. The implications of these findings are discussed.

Adolescent↗

Antimalarial psychosis revisited.

Drug-induced psychosis resulted from the administration of quinacrine hydrochloride at a dosage of 100 mg twice daily for the treatment of discoid lupus. After two weeks of drug treatment, the patient exhibited symptoms similar to those seen in the manic phase of bipolar affective disorder. Although the incidence of antimalarial psychosis is unclear and perhaps small, we recommend close observation of patients for behavioral changes suggesting the development of antimalarial psychosis. Astute observation, leading to the early detection of behavioral changes, may help avert the development of a costly and disabling complication of drug therapy.

Female↗

Gingival pigmentation associated with antimalarial drugs.

Two cases of pigmentary changes in the gingivae as well as other oral sites are described. The bluish pigmentation is related to the oral administration of the antimalarial drug Camoquin. The literature is inconclusive as to the nature of the pigment and the pathogenic mechanisms involved. Some authors believe the pigment to be hemosiderin but there seems to be growing evidence that the pigmentary changes result from increased melanin formation. The pigment fades away gradually after the use of the drug is discontinued. The pigmentary changes described assume an increased importance in the differential diagnosis of oral pigmentary lesions as the antimalarial drugs are becoming more popular in the treatment of various dermatologic disorders.

Adult↗

[Mother-transmitted antimalarial immunity. its evolution in child (author's transl)].

The authors report the results of a survey and a longitudinal study of mother-transmitted antimalarial antibodies, conducted through indirect immunofluorescence tests. The data indicate that 16 p. 100 of the new-born and 25 p. 100 of the considered age group get maternal antibodies either through transplacental way of through breast-feeding. Among 99 mothers having a positive antimalarial serology at their delivery, 30 have transmitted their antibodies to their infant. But whatever the way of transmission may be, these antibodies do not last longer, as a rule, than one month. If this passive immunity is either lacking or insufficient to protect the child, it seems that HbF has a great protective role, as indicated by the concordance between its decrease and the raise of malaria morbidity in children. As a consequence of the existence of a natural protection by HbF during the first three months of life, malarial prophylaxis does not seem necessary during this period.

Antibodies↗

Antimalarial measures--type, sources of advice and compliance among tourists to Natal/KwaZulu.

Typical advice on antimalarial measures provided by pharmacies as well as actual behaviour in this regard and sources of advice accessed by tourists to northern Natal/KwaZulu were canvassed by telephonic interviews with 70 pharmacies and 53 'care providers' (members of travel parties). Doctors (26%) and pharmacists (40%) were the most commonly approached sources of antimalarial advice. Professional recommendations frequently involved chloroquine-based drugs (80% of recommended drugs), despite the chloroquine-resistant status of the study area. Drug choice reflected the limited availability of new alternatives to chloroquine at the time the study was conducted, as well as ignorance of drug resistance in the area. Possible reasons for the inappropriate nature of many of the reported recommendations, as well as an approach to the dissemination of future prophylactic policy documents, are discussed.

Adult↗

Epileptogenic potential of antimalarial drugs.

Available clinical reports suggest that antimalarial drugs may cause epileptic seizures as an adverse reaction in susceptible individuals. Epileptic patients and others with a low seizure threshold appear particularly prone. Antimalarial drugs, particularly chloroquine and mefloquine, should be used with caution by patients with epilepsy.

Adult↗

[Malaria in infants in a rural area of maritime Guinea (Guinea Conakry). II. Development of antimalarial antibodies and malaria during the first year of life].

A transversal investigation carried out on 551 children and a longitudinal study of 55 infants showed the disappearance of maternal anti-plasmodium antibodies during the first year of life. Out of 212 new-borns surveyed for one year, 59 (28%) were infested by Plasmodium, but never during the first two months of life. This infestation was not related to the age of the infant nor to the season. For 46% of cases, infestation was completely asymptomatic, for 18% of cases respiratory signs were present and for 20% digestive signs not specific to malaria. Fever was present in 14 cases (24%) and isolated in 6 cases. Only 7 infants received a specific antimalarial treatment. Evolution under medical surveillance was favourable in all cases. These findings prove the difficulties inherent to the diagnosis of malaria, especially in the absence of laboratories for diagnosing other infections--such as typhoid--which do not appear in sanitary statistics. The findings also raise the question as to the efficiency of systematic antimalarial treatment in case of fever in the infant or child. Asymptomatic parasitemia can be explained by the existence of antitoxic immunity different from antiplasmodia immunity.

Aging↗

Genome-Guided Discovery of Antimalarial 4-Amino-2,4-Pentadienoate-Containing Cyclolipodepsipeptides.

4-Amino-2,4-pentadienoate-containing cyclolipodepsipeptides (APD-CLDs) represent a structurally distinctive family of natural products known for their selective activity against hypoxic cancer cells. To explore the structural diversity of APD-CLDs, we have identified and prioritized cryptic APD-CLD biosynthetic gene clusters (BGCs) for compound discovery. Using a combination of genetic and chemical methods, we successfully activated three dormant BGCs, leading to the discovery of 12 new APD-CLDs. These newly discovered metabolites significantly expanded the diversity of the APD-CLD family, with chloromalamides and arabimalamides representing the first halogenated and glycosylated members, respectively. Unexpectedly, chloromalamides and arabimalamides exhibited potent antiplasmodial activity, with IC50 values in the 25-161&#xa0;nM range against drug-sensitive and multidrug-resistant Plasmodium falciparum strains. Phenotypic studies revealed arabimalamide B halted parasite development during the asexual blood stage life cycle, resulting in enlarged digestive vacuoles, dispersed hemozoin, and ultimately reduced reinvasion efficiency. These phenotypes are reminiscent of the effect of chloroquine and other 4-aminoquinoline drugs, suggesting that arabimalamides may disrupt the parasite's heme detoxification mechanism. Biosynthetic studies identified key scaffold-forming and modifying enzymes, including a rare membrane glycosyltransferase in arabimalamide biosynthesis. Together, these findings unveil APD-CLDs as new antimalarial lead scaffolds and set the stage for structural diversification and optimization.

Antimalarials↗

Antimalarial activity of hydroxy-substituted naphthalene compounds.

A new series of mono- and di-hydroxy substituted naphthalene compounds was synthesized and found to possess antimalarial activity against P. gallinaceum infection of young chicks. A representative compound with a high degree of activity was chosen for extensive testing against other malarial species and for pharmacological investigation. The formula of this compound, number 377C54, was 1:6-dihydroxy-2:5-bis(cyclohexylaminomethyl)naphthalene dihydrochloride. Effective doses against P. gallinaceum in chicks, P. berghei in mice and P. cathemerium in canaries were 2.3, 4.0, and about 6 mg./kg. respectively. Compound 377C54 acted rapidly against the parasitaemia of P. gallinaceum in chicks and P. knowlesi in a rhesus monkey. Parasiticidal activity remained in the blood of chicks for a long time after a single oral dose. The drug can be estimated by the production of colour on coupling with diazotized p-nitroaniline. Drug concentrations in blood from chicks and humans rose rapidly after oral administration. In tissues from chicks, particularly liver and lung, the drug persisted for a long period. An unsuccessful attempt was made to induce resistance to 377C54 in a strain of P. gallinaceum. Extensive pharmacological investigation showed that 377C54 possessed no special pharmacological properties.

Administration, Oral↗

Dialysis studies in rats on the long-acting antimalarial CI-501.

Through the use of dialysis sacks, containing the repository antimalarial CI-501, implanted intraperitoneally into rats, evidence has been obtained indicating a local rather than a systemic reservoir of the drug. These results suggest that the repository activity of CI-501 is due to drug release from the injection site and that the probability of toxic effects resulting from storage or accumulation of the drug in vital organs is remote.

Animals↗