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At least 1,477 records · Page 82Linked to original sources
PubMed2005

Distinguishing recrudescences from new infections in antimalarial clinical trials: major impact of interpretation of genotyping results on estimates of drug efficacy.

The use of molecular genotyping to distinguish recrudescence from new infections has become common in antimalarial clinical trials. However, methods used to interpret genotyping results have not been standardized. We analyzed data from 3,000 patients enrolled in clinical trials at seven sites in Uganda. Late treatment failure requiring genotyping occurred in 51% of the patients. Among samples successfully genotyped, 21% were definitive new infections (no recrudescent strains present on day of failure), 35% were definitive recrudescences (only recrudescent strains present), and 44% were mixed (new and recrudescent strains present). The probability of having a mixed genotyping result increased as transmission intensity increased. At the highest transmission site, the estimated risk of treatment failure increased from 34% to 84% for chloroquine plus sulfadoxine-pyrimethamine, from 18% to 45% for amodiaquine plus sulfadoxine-pyrimethamine, and from 12% to 57% for amodiaquine plus artesunate, depending on whether mixed genotyping results were classified as new infections or recrudescences, respectively. The method used to classify treatment outcomes can have a major impact on estimates of drug efficacy, especially in areas of high transmission intensity.

Adolescent↗
PubMed2005

2-(aminoacylamino)benzophenones: farnesyltransferase inhibition and antimalarial activity.

The use of amino acids as acyl substitutents at the 2-amino group of our benzophenone core structure yielded compounds with mainly good to moderate farnesyltransferase inhibitory and moderate antimalarial activity. However, these farnesyltransferase inhibitors display some degree of selectivity towards malarial parasites since there was no cytotoxic activity observed at 70-80 microM.

Amino Acids↗
PubMed2005

Prevalence of Plasmodium falciparum mutations associated with antimalarial drug resistance during an epidemic in Kuna Yala, Panama, Central America.

A molecular epidemiology study was conducted to determine the distribution of antimalarial drug resistance alleles among field isolates of Plasmodium falciparum. Samples were obtained during an epidemic affecting Kuna Amerindians in Panama. A high prevalence of mutations associated with chloroquine, pyrimethamine, and sulfadoxine was observed. Genotype analysis of msp2 revealed a low genetic diversity of P. falciparum parasites circulating in the studied area. The public health implications of these findings for the Central American region are discussed.

Animals↗
PubMed1992

Development of the new antimalarial drug pyronaridine: a review.

This report outlines the structure scheme and development of a new antimalarial drug pyronaridine, which was synthesized from either 2-aminopyridine or pyridine. A series of in vivo and in vitro experimental studies and the assessment of toxicity revealed pyronaridine to be a promising agent against erythrocytic stage of malaria parasites. It exhibited low toxicity and had no cross-resistance to chloroquine. Clinical administration in malaria cases showed high efficacy and mild side-effects. In order to retard the development of resistance of Plasmodium falciparum to pyronaridine, a combination of pyronaridine/sulfadoxine/pyrimethamine was used in the treatment of chloroquine-resistant falciparum malaria in Hainan Province. Further in vivo test was carried out to monitor the sensitivity of P. falciparum to this combined formula for 5 years (1986-1990) in Diaoluo area where chloquine-resistant falciparum malaria was prevalent. Drug resistance was not demonstrated in this field study.

Administration, Oral↗
PubMed2005

In vitro evaluation of marketed antimalarial chloroquine phosphate tablets.

BACKGROUND & OBJECTIVES: The aim of the present study is to investigate the physicochemical equivalence of seven brands of tablets containing chloroquine phosphate, an antimalarial purchased from different retail pharmacy outlets. METHODS: The quality and physicochemical equivalence of seven different brands of chloroquine phosphate tablets were assessed. The assessment included the evaluation of uniformity of weight, friability, crushing strength, disintegration and dissolution tests as well as chemical assay of the tablets. RESULTS: All the seven brands of the tablets passed the British Pharmacopoeia (BP) standards for uniformity of weight, disintegration and crushing strength. One of seven brands failed the friability test. One of the brands did not comply with the standard assay of content of active ingredients. Dissolution test passes the pharmacopoeial standards for chloroquine phosphate tablets. There were no significant differences in the amounts of chloroquine phosphate released from the different brands. INTERPRETATION & CONCLUSION: Out of the seven brands of anti-malarial chloroquine phosphate tablets only one brand fails to meet BP quality specifications which shows constant market monitoring of new products to ascertain their equivalency to pharmacopoeial standards.

Animals↗
PubMed2006

Frequency distribution of antimalarial drug-resistant alleles among isolates of Plasmodium falciparum in Bangui, Central African Republic.

We determined the baseline frequency distribution of mutant alleles of genes associated with resistance to chloroquine and sulfadoxine-pyrimethamine in Plasmodium falciparum isolates in Bangui, Central African Republic. Mutant alleles of the P. falciparum chloroquine resistance transporter (pfcrt) gene were found in all samples and the frequency of the deduced CIET pfcrt haplotype was high (45%). The most common allele of the P. falciparum multidrug resistance 1 (pfmdr1) gene among the field isolates of P. falciparum was 86Y (21.9%). The 1246Y allele was also common (18.0%). Of the 167 P. falciparum isolates in which the dihydrofolate reductase gene was studied, only 11 carried the wild-type allele (6.6%) whereas many (50.3%) were quadruple mutants (50R, 51I, 59R, 108N). The frequency of the 436A mutant allele of the dihydropteroate synthase gene was high (74.3%), but the frequencies of the 437G (18.6%) and 540E (5.2%) mutant alleles were low. Molecular analyses of antimalarial drug-resistant alleles of P. falciparum isolates in Bangui strongly suggest the widespread distribution of chloroquine and pyrimethamine resistance and to a lesser extent sulfadoxine resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Determination of the physicochemical properties of pyronaridine - a new antimalarial drug.

The physicochemical properties of pyronaridine, a new antimalarial drug, have been determined for the first time in this study, since these parameters are comprehensively not available in literature. UV-Vis spectral analysis of both pyronaridine and its tetraphosphate salt were carried out in various solvents, in addition to solubility of the two drugs in these solvents. Partition coefficient was done in n-octanol-water mixture using the Leo-Hansch method as well hydrophobicity index determination. pKa determination was carried out on the tetraphosphate. UV-Vis spectral characteristics showed that both the base and the tetraphosphate salt have significant light absorption in the range 190-380 nm. Solubility in different solvents revealed that pyronaridine base is sparingly soluble in chloroform (1.34%) while it is slightly soluble in methanol (0.29%) and ethanol (0.42%) and very slightly soluble in octanol and distilled water. The tetraphosphate salt was sparingly soluble in water (1.46%) while it is only very slightly soluble in other solvents. The higher aqueous solubility of the salt was further revealed by a greater Rm value on extrapolation to 100% water concentration in hydrophobicity index determination. Log P value determination showed that the base {log P of 0.26+/-0.02} is more liposoluble than the salt {log P of - (1.240.21)}. Four prominent pKa values were obtained for the tetraphosphate titrated which when extrapolated to the base gave values of 7.08+/-0.05, 7.39+/-0.05, 9.88+/-0.05 and 10.30+/-0.10. The results should guide in formulation of appropriate dosage forms to improve bioavailability of the drug especially from oral routes.

1-Octanol↗
PubMed2005

Some compaction characteristics of the hot water leaf extract og Nauclea latifiola: a potential antimalarial agent.

This study aims to develop a suitable tablet dosage form of Nauclea latifolia, a potential antimalarial agent. The compaction characteristics of the oven dried water extract were studied using the Heckel equation. The mechanical properties of the compacts were also determined. This preliminary information will be useful in developing a suitable dosage form of the extract for use in the management of malaria. The results showed that N. latifolia extract exhibited high densification due to dye filling while the subsequent rearrangement of the granules did not contribute, significantly, to their densification. The granules had enhanced plasticity as shown by the low yield point, Py. The tablets produced from the extract had good mechanical properties, with hardness increasing via compression pressure while the friability decreased. However, the tablets had poor disintegration properties; it is concluded that while tablets of suitable physical properties can be produced from the extract, a disintegrant would need to be included in the formulation to ensure adequate drug release.

Antimalarials↗
PubMed2006

[A quantum chemistry investigation on antimalarial mechanism of Qinghaosu based on cleavage of the peroxide bridge].

AIM: To investigate antimalarial mechanism of Qinghaosu ( QHS) and its derivatives. METHODS: The electronic structure of QHS and its derivatives were completely optimized and calculated at B3LYP/6-31G * level, while the route was at HF/STO-3G level. RESULTS: The peroxide bridge is the active center of QHS and induced by ferrous iron to produce cyclic product. CONCLUSION: Heme can link with QHS derivatives.

Antimalarials↗
PubMed2006

Polymorphisms in pfcrt, pfmdr1, dhfr genes and in vitro responses to antimalarials in Plasmodium falciparum isolates from Bangui, Central African Republic.

Drug resistance is probably the greatest challenge to most malaria-control programs. Given the limited resources for other malarial-control measures, rational drug used is crucial. Molecular markers for parasite resistance such as pfcrt, pfmdr-1, and dhfr have the potential to be used in an integrated fashion to provide timely information that is useful to policy makers. Therefore, we evaluated polymorphisms in these genes from Plasmodium falciparum and their association with in vitro antimalarial drug resistance to 135 parasites samples collected in Bangui in 2004. For the dhfr gene, we found a strong association between the dhfr genotype and chemosensitivity to pyrimethamine. For the pfcrt gene, we found that haplotypes with mutant-type alleles led to significant changes in the IC50 values for chloroquine, monodesethylamodiaquine, and quinine. We found no correlations for the pfmdr1 gene. These findings suggest that a regular monitoring and screening for resistance markers for antifolates and for chloroquine could act as an adjunct to in vivo trials.

Animals↗
PubMed2006

Characterization of counterfeit artesunate antimalarial tablets from southeast Asia.

In southeast Asia, the widespread high prevalence of counterfeits tablets of the vital antimalarial artesunate is of great public health concern. To assess the seriousness of this problem, we quantified the amount of active ingredient present in artesunate tablets by liquid chromatography coupled to mass spectrometry. This method, in conjunction with analysis of the packaging, classified tablets as genuine, substandard, or fake and validated results of the colorimetric Fast Red TR test. Eight (35%) of 23 fake artesunate samples contained the wrong active ingredients, which were identified as different erythromycins and paracetamol. Raman spectroscopy identified calcium carbonate as an excipient in 9 (39%) of 23 fake samples. Multivariate unsupervised pattern recognition results indicated two major clusters of artesunate counterfeits, those with counterfeit foil stickers and containing calcium carbonate, erythromycin, and paracetamol, and those with counterfeit holograms and containing starch but without evidence of erythromycin or paracetamol.

Antimalarials↗
PubMedDate not supplied

566C80, an antimalarial hydroxynaphthoquinone with broad spectrum: experimental activity against opportunistic parasitic infections of AIDS patients.

Hydroxynaphthoquinone 566C80 was synthesised and initially developed as an antimalarial with potent activity against drug-resistant strains of the human malaria parasite, Plasmodium falciparum. Subsequent studies have revealed that in addition, this compound has experimental activity, both in vitro and in vivo, against Pneumocystis carinii and Toxoplasma gondii; the data obtained thus far for Cryptosporidium parvum are equivocal. Currently 566C80 is being assessed clinically not only against malaria, but also against P. carinii pneumonia, toxoplasmosis and cryptosporidiosis.

Acquired Immunodeficiency Syndrome↗
PubMed1991

[Antimalarial activity of deoxoqinghaosu].

Compound 3 (deoxoqinghaosu) and compound 4 (deoxocarbaqinghaosu) were synthesized from arteannuic acid (2). Primary exploration of their antimalarial effect against K173 strain of Plasmodium berghei shows that compound 3 is somewhat more effective than the natural compound--qinghaosu. However, the carba-analogue compound 4 is almost ineffective. The enhanced activity of compound 3 is supposedly ascribed to its higher lipophilicity and, hence, higher affinity for plasmodial membrane. Further studies are in progress.

Animals↗
PubMedDate not supplied

Evaluation of the antimalarial activity of new compounds against Plasmodium falciparum in vitro, and Plasmodium berghei in vivo.

Various hydrazones of thiophene carboxaldehyde were tested in vitro on two Plasmodium falciparum strains and in vivo on mice experimentally infected with Plasmodium berghei. These hydrazones were obtained by condensation of appropriate hydrazines with thiophene-2-carboxaldehyde (series 1), thiophene-3- carboxaldehyde (series 2) and 5-Nitrothiophene-2-carboxaldehyde (series 3). Compounds of series 3, 5-Nitrothiophene-2-carboxaldehyde presented significant effects in vitro. In vivo tests confirmed the antimalarial activity observed in vitro with two compounds of this series.

Animals↗
PubMed1990

[In vitro assay for detecting hemolytic toxicity of antimalarials incorporated with microsomal metabolic system].

The in vitro metabolic system comprised NADP co-factors and liver microsomes isolated from male rats pre-treated with phenobarbital, 60 mg/kg, i.p. for 3d combined with a single i.p. dose of 80 mg/kg of naphtholflavone. The 1% RBC suspension was made up from G6PD-deficient rabbit blood. Primaquine, chloroquine and M 8506 at various dosages were incubated at 37 degrees C with the microsomal metabolic system in vitro respectively. The supernatants were incubated with 1% RBC suspension. The OD635nm values of the supernatants were detected after incubation and centrifugation. The results showed that both primaquine and M 8506 exhibited potent hemolytic toxicity at the dose-range of 1.5-3 x (10(1)-10(3) mumol/L, with certain dose-effect relationship, while chloroquine exhibited no hemolytic toxicity. It is suggested that the in vitro assay incorporated with microsomal metabolic system might be a useful preliminary screening method for testing hemolytic toxicity of various antimalarials.

Aminoquinolines↗
PubMed1990

In vitro sensitivity of multiresistant Plasmodium falciparum to new candidate antimalarial drugs in western Thailand.

The present study, carried out in 1987 in Thailand, has been designed to validate the in vitro microtest system, standardized by the World Health Organization (WHO), for the new antimalarials pyronaridine and halofantrine. The sensitivity of naturally acquired, multiresistant populations of Plasmodium falciparum has been assessed in order to develop a data base for further longitudinal investigations. For both drugs the in vitro microtest system seems to be suitable. The concentration range of plates can be considered as almost ideal for pyronaridine (0.1-6.40 mumol/l) while for halofantrine (0.002-0.128 mumol/l) an upward extension of the concentration range would be appropriate. Validation studies with artemisinin demonstrated the need for revising the protocol for the production of the dosing solutions. In the light of current knowledge about therapeutic concentration levels it would probably be appropriate to adopt a range of 0.2-12.8 mumol/l. All tested isolates, except possibly three, showed sensitive responses to pyronaridine. The high EC99 value of halofantrine could be indicative of some resistance to this drug. Rank correlation analysis suggested cross-resistance of pyronaridine and chloroquine which could be of consequence for the future introduction of pyronaridine.

Animals↗