Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Antimalarials”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 955 records · Page 53Linked to original sources
PubMed2005

Antimalarial multi-drug resistance in Asia: mechanisms and assessment.

The emergence and spread of drug-resistant parasites poses a major problem for management of Plasmodium falciparum malaria in endemic areas. Nowhere is this more apparent than in southeast Asia, where multi-drug resistance to chloroquine and sulfadoxine-pyrimethamine was exacerbated when mefloquine monotherapy began failing in the 1980s. A better understanding of mechanisms of (multi-) drug resistance is urgently warranted to monitor and guide antimalarial chemotherapy regimens more efficiently. Here we review recent advances on identification of molecular markers that can be employed in predicting in vitro and in vivo resistance in southeast Asia. Examples include amplification of PfMDR1 (P. falciparum multi-drug resistant gene 1) and mefloquine, K76T PfCRT and chloroquine, as well as mutations in the dihydroperoate synthase and dihydrofolate reductase genes and the antifolate class of drugs.

ATP-Binding Cassette Transporters↗
PubMed1989

Antimalarial activity of new floxacrine-related acridinedione derivatives: studies on blood schizontocidal action of potential candidates against P. berghei in mice and P. falciparum in vivo and in vitro.

Deoxyfloxacrine derivatives (1-hydrazone: S 83 0083; 1-imine: S 84 7277) and floxacrine derivatives (10-methoxy-floxacrine: L 84 7667; 1-imine: L 84 7693) selected from a series of newly synthesized 3-aryl-7-chloro-3,4-dihydro-1,9(2H,10H)-acridinediones were evaluated for blood schizontocidal activities in mice infected with asexual stages of various drug-resistant lines of P. berghei and in New World monkeys infected with blood schizonts of different chloroquine-resistant strains of P. falciparum. All compounds tested showed high activity against drug-resistant lines of P. berghei (ED50: 1.0-4.4 mg/kg x 5, per os) and were distinctly superior in their antimalarial potency to floxacrine. Compounds L 84 7667 and L 84 7693 proved to be highly active against the FCBR strain of P. falciparum in vitro (IC50: 0.73-1.78 nmol); they effected temporary clearance of parasitemias due to the Palo Alto strain of P. falciparum in squirrel monkeys at oral doses of 15 mg/kg given daily for 5 consecutive days. Compounds S 83 0083 and S 84 7277, showing moderate in vitro effects (12.9-24.8 nmol), cleared parasitemias of the FCBR strain of P. falciparum in owl monkeys at oral doses of 20 mg/kg (S 84 7277) given daily for 5 or 7 consecutive days (follow-up period, 17 and 30 days, respectively) or at doses of 20 mg/kg (x 4) (S 83 0083) followed by doses of 40 mg/kg (x 3) within a follow-up period of 30 days. These observations suggest that the range of doses required for the cure of established P. falciparum infections is probably too large to cover infections with strains of the least susceptibility and might evoke toxic reactions by the potential candidates tested.

Acridines↗
PubMed1986

Microscopic and flow cytophotometric analysis of parasitemia in cultures of Plasmodium falciparum vitally stained with Hoechst 33342--application to studies of antimalarial agents.

Conditions for rapid vital staining of Plasmodium falciparum infected human erythrocytes were 1 microgram/ml of the dye Hoechst 33342 for 15 min in the standard culture medium at 37 degrees C. Fixed and stained cultures were analyzed by fluorescence microscopy and flow cytophotometry. The usefulness of this type of analysis for in vitro studies of antimalarial agents was demonstrated using three such agents--cyclosporin A, chloroquine, and pyrimethamine.

Antimalarials↗
PubMed1983

Interaction of antimalarial drugs with hemin.

Hemin (ferriprotoporphyrin IX) is shown to form complexes with the chloroquine class of antimalarial drugs. The Soret band of hemin becomes optically active upon the addition of chiral drugs. Results on the hemin-induced quenching of the fluorescence of chloroquine are consistent with the formation of a 2:1 hemin:drug complex with a formation constant of 1.4 x 10(7) at 298 K. Also a direct comparison of the drug-treated and drug-free parasites themselves, by the noninvasive photoacoustic spectroscopic method, reveals an in vivo interaction between endogenous hemin and the added drug.

Animals↗
PubMed1980

Inhibition of diamine oxidase by antimalarial drugs.

The antimalarial drugs amodiaquine, quinacrine and chloroquine inhibit the catabolism of putrescine by the rat. Amodiaquine, the most potent of the three, does so in a dose-dependent fashion. This is attributed to the action in vivo of the drugs on diamine oxidase, an enzyme that is inhibited by them in vitro.

Amine Oxidase (Copper-Containing)↗
PubMedDate not supplied

Absence of significant pharmacokinetic and pharmacodynamic interactions between artemether and quinoline antimalarials.

The study was carried out to investigate the pharmacokinetic and pharmacodynamic interactions between artemether (ARTEM) and quinoline antimalarials namely mefloquine (MQ), quinine (QN) and primaquine (PQ) when given concurrently. A randomised comparative, seven way cross-over design was performed in eight healthy male Thais following the administrations of seven drug regimens on seven occasions i.e. a single oral dose of ARTEM (300 mg), or MQ (750 mg), or QN (600 mg), or PQ (45 mg) alone, or the combination of ARTEM (300 mg) with MQ (750 mg), or QN (600 mg), or PQ (45 mg). All clinical and laboratory parameters were normal in all subjects, before, during and after the study. The eight subject experienced no adverse effect after ARTEM, QN, PQ alone regimens, or combination of ARTEM with QN and PQ. After administration of MQ in either occasion, 3 subjects had weakness, nausea, abdominal pain, and diarrhoea; one subject complained of dizziness. All symptoms were mild and occurred during the first day of MQ administration. The fitting of the concentration-time curves of ARTEM, QN and PQ, to a one-compartment model with first order absorption yielded satisfactory results in all subjects. The best fit model for MQ was two-compartment model with first order absorption. The pharmacokinetics of all investigated drug, when given alone or in combination were not significantly different.

Adult↗
PubMed2006

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance.

Molecular determinants of antimalarial drug resistance are useful and informative tools that complement phenotypic assays for drug resistance. They also guide the design of strategies to circumvent such resistance once it has reached levels of clinical significance. Established resistance to arylaminoalcohols such as mefloquine and lumefantrine in SE Asia is mediated primarily by gene amplification of the P. falciparum drug transporter, pfmdr1. Single nucleotide polymorphisms in pfmdr1, whether assessed in field isolates or transfection experiments, are associated with changes in IC(50) values (to arylaminoalcohols and chloroquine), but not of such magnitude as to influence clinical treatment outcomes. Recently described emerging in vitro resistance to artemisinins in certain areas correlates with mutations in the SERCA-like sequence PfATP6 and supports PfATP6 as a key target for artemisinins.

Africa↗
PubMed2000

[Combination of antimalarial drugs mepacrine and chloroquine in therapy refractory cutaneous lupus erythematosus].

Antimalarials represent the first line in treatment of cutaneous lupus erythematosus (LE). However, some patients show no improvement on monotherapy with chloroquine or hydroxychloroquine. A 30-year-old female patient had treatment-resistant cutaneous LE exhibiting features of both LE tumidus and subacute cutaneous LE. Previously, the patient had been unsuccessfully treated with chloroquine, hydroxychloroquine, dapsone, and azathioprine, each in combination with variable doses of prednisolone. However, the LE lesions increased during these therapeutic regimens. A combination of chloroquine and mepacrine therapy led to improvement and then total clearing after 4 months of treatment.

Adult↗
PubMed2006

Raman spectroscopic investigation of the antimalarial agent mefloquine.

The antimalarial agent mefloquine was investigated using Fourier transform near-infrared (FT NIR) Raman and FT IR spectroscopy. The IR and Raman spectra were calculated with the help of density functional theory (DFT) and a very good agreement with the experimental spectra was achieved. These DFT calculations were applied to unambiguously assign the prominent features in the experimental vibrational spectra. The calculation of the potential energy distribution (PED) and the atomic displacements provide further valuable insight into the molecular vibrations. The most prominent NIR Raman bands at 1,363 cm(-1) and 1,434 cm(-1) are due to C=C stretching (in the quinoline part of mefloquine) and CH(2) wagging vibrations, while the most intense IR peaks at 1,314 cm(-1); 1,147 cm(-1); and 1,109 cm(-1) mainly consist of ring breathings and deltaCH (quinoline); C-F stretchings; and asymmetric ring breathings, C-O stretching as well as CH(2) twisting/rockings located at the piperidine moiety. Since the active agent (mefloquine) is usually present in very low concentrations within the biological samples, UV resonance Raman spectra of physiological solutions of mefloquine were recorded. By employing the detailed non-resonant mode assignment it was also possible to unambiguously identify the resonantly enhanced modes at 1,619 cm(-1), 1,603 cm(-1) and 1,586 cm(-1) in the UV Raman spectra as high symmetric C=C stretching vibrations in the quinoline part of mefloquine. These spectroscopic results are important for the interpretation of upcoming in vitro and in vivo mefloquine target interaction experiments.

Antimalarials↗
PubMed2006

Combined Fourier-transform infrared imaging and desorption electrospray-ionization linear ion-trap mass spectrometry for analysis of counterfeit antimalarial tablets.

This paper reports use of a combination of Fourier-transform infrared (FTIR) spectroscopic imaging and desorption electrospray ionization linear ion-trap mass spectrometry (DESI MS) for characterization of counterfeit pharmaceutical tablets. The counterfeit artesunate antimalarial tablets were analyzed by both techniques. The results obtained revealed the ability of FTIR imaging in non-destructive micro-attenuated total reflection (ATR) mode to detect the distribution of all components in the tablet, the identities of which were confirmed by DESI MS. Chemical images of the tablets were obtained with high spatial resolution. The FTIR spectroscopic imaging method affords inherent chemical specificity with rapid acquisition of data. DESI MS enables high-sensitivity detection of trace organic compounds. Combination of these two orthogonal surface-characterization methods has great potential for detection and analysis of counterfeit tablets in the open air and without sample preparation.

Antimalarials↗
PubMed2006

Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects.

OBJECTIVE: To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects. METHODS: Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM. RESULTS: A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V(ss)/F and t(1/2)(z) were found to be 56.4 (29-84) l/h, 6,000 (3,500-8,500) l and 11.7 (8.3-15.7) days, respectively. CONCLUSION: Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.

Administration, Oral↗
PubMed2006

Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug.

Artemisinin isolated from the aerial parts of Artemisia annua L. is a promising and potent antimalarial drug which has a remarkable activity against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum, and is useful in treatment of cerebral malaria. Because the low content (0.01-1 %) of artemisinin in A. annua is a limitation to the commercial production of the drug, many research groups have been focusing their researches on enhancing the production of artemisinin in tissue culture or in the whole plant of A. annua. This review mainly focuses on the progresses made in the production of artemisinin from A. annua by biotechnological strategies including in vitro tissue culture, metabolic regulation of artemisinin biosynthesis, genetic engineering, and bioreactor technology.

Antimalarials↗
PubMed2004

Antimalarial dihydroartemisinin also inhibits angiogenesis.

Dihydroartemisinin, a more water-soluble metabolite of artemisinin derivatives, is a safe and most effective antimalarial analog of artemisinin. In the present study, we investigated the antiangiogenic activity of dihydroartemisinin in vitro and in vivo, and investigated dihydroartemisinin-induced apoptosis in human umbilical vein endothelial cells (HUVEC). Dihydroartemisinin markedly reduced VEGF binding to its receptors on the surface of HUVEC. The expression levels of two major VEGF receptors, Flt-1 and KDR/flk-1, on HUVEC were lower following dihydroartemisinin treatment as shown by an immunocytochemical staining assay. The in vivo antiangiogenic activity was evaluated in the model of chicken chorioallantoic membrane (CAM) neovascularization. Dihydroartemisinin significantly inhibited CAM angiogenesis at low concentrations (5-30 nmol/100 microl per egg). We also investigated both qualitatively and quantitatively the induction of HUVEC apoptosis by dihydroartemisinin. A dose-related (5-80 microM) and time-dependent (6-36 h) increase in dihydroartemisinin-induced HUVEC apoptosis was observed by flow cytometry. Our results suggest that the antiangiogenic effect induced by dihydroartemisinin might occur by induction of cellular apoptosis and inhibition of expression of VEGF receptors. These findings and the known low toxicity of dihydroartemisinin indicate that it might be a promising candidate angiogenesis inhibitor.

Angiogenesis Inhibitors↗
PubMed2001

Amorpha-4,11-diene synthase: cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin.

The sesquiterpenoid artemisinin, isolated these from the plant Artemisia annua L., and its semi-synthetic derivatives are a new and very effective group of antimalarial drugs. A branch point in the biosynthesis of this compound is the cyclisation of the ubiquitous precursor farnesyl diphosphate into the first specific precursor of artemisinin, namely amorpha-4,11-diene. Here we describe the isolation of a cDNA clone encoding amorpha-4,11-diene synthase. The deduced amino acid sequence exhibits the highest identity (50%) with a putative sesquiterpene cyclase of A. annua. When expressed in Escherichia coli, the recombinant enzyme catalyses the formation of amorpha-4,11-diene from farnesyl diphosphate. Introduction of the gene into tobacco (Nicotiana tabacum L.) resulted in the expression of an active enzyme and the accumulation of amorpha-4,11-diene ranging from 0.2 to 1.7 ng per g fresh weight.

Alkyl and Aryl Transferases↗
PubMed2003

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum.

The in vitro antimalarial activity against Plasmodium falciparum and heme polymerization were evaluated for ten metalloporphyrins: gallium protoporphyrin IX (GaPPIX), sodium salt of gallium protoporphyrin IX, silver protoporphyrin IX, palladium protoporphyrin IX, cobalt protoporphyrin IX, manganese protoporphyrin IX, tin protoporphyrin IX (SnPPIX), chromium protoporphyrin IX, gallium deuteroporphyrin IX (GaDPIX) and gallium hematoporphyrin IX. Metalloporphyrins inhibited parasite growth with 50% inhibitory concentrations (IC(50)) ranging from 15.5 microM to 190 microM. In trophozoite lysate-mediated heme polymerization assays, SnPPIX, GaPPIX and GaDPIX exerted potent inhibitory activity similar to that of artemisinin and chloroquine.

Animals↗
PubMed2004

Evaluation of cysteine proteases of Plasmodium vivax as antimalarial drug targets: sequence analysis and sensitivity to cysteine protease inhibitors.

Cysteine proteases perform critical roles in the life cycles of malaria parasites. In Plasmodium falciparum, treatment of cysteine protease inhibitors inhibits hemoglobin hydrolysis and blocks the parasite development in vitro and in vivo, suggesting that plasmodial cysteine proteases may be interesting targets for new chemotherapeutics. To determine whether sequence diversity may limit chemotherapy against Plasmodium vivax, we analyzed sequence variations in the genes encoding three cysteine proteases, vivapain-1, -2 and -3, in 22 wild isolates of P. vivax. The sequences were highly conserved among wild isolates. A small number of substitutions leading to amino acid changes were found, while they did not modify essential residues for the function or structure of the enzymes. The substrate specificities and sensitivities to synthetic cysteine protease inhibitors of vivapain-2 and -3 from wild isolates were also very similar. These results support the suggestion that cysteine proteases of P. vivax are promising antimalarial chemotherapeutic targets.

Amino Acid Sequence↗
PubMed1997

Potentiation of the antimalarial activity of atovaquone by doxycycline against Plasmodium falciparum in vitro.

The effect of doxycycline, obtained from human volunteers administered doxycycline, on the minimum inhibitory concentration (MIC) of atovaquone was determined against the K1 and FC27 isolates of Plasmodium falciparum in vitro. Doxycycline concentrations ranging from 0.10-1.18 microg/ml added to atovaquone produced MIC ratios [atovaquone + doxycycline/atovaquone alone] ranging from 0.38 to 0.70. These results suggest that the antimalarial activity of atovaquone is potentiated by doxycycline. Additionally, these drugs may be rational partners for the treatment and prophylaxis of falciparum malaria.

Animals↗
PubMed2006

Pharmacodynamic interaction between atovaquone and other antimalarial compounds against Plasmodium falciparum in vitro.

Atovaquone, a 2-hydroxy-1,4-naphthoquinone, was first introduced as a drug against opportunistic infections in immuno-compromised patients. Early clinical-parasitological experiences in the treatment of malaria were disappointing due to highly variable and poor absorption, a phenomenon typical for naphthoquinones. Proguanil was found to potentiate the activity of atovaquone and the combination of the two drugs was introduced as an antimalarial drug with blood schizontocidal and causal prophylactic activity. It is now widely used in therapy and prophylaxis. Despite the enhanced activity, the combination does not always overcome the problem of poor absorption of atovaquone, especially in the presence of gastro-intestinal disorders. Therefore, further combination with a fast-acting blood schizontocide, e.g. one of the artemisinins, could accelerate clinical improvement and normalization of absorption. The interaction between artemisinin and atovaquone and that of artemisinin and atovaquone + proguanil has been investigated in 37 fresh isolates of Plasmodium falciparum from northwestern Thailand, an area with high prevalence of multi-drug resistance. Interaction between atovaquone and artemisinin was synergistic above the EC(30), with mean SigmaFIC (Berenbaum) values of 0.9679 at the EC(50), 0.4014 at the EC(90) and 0.2214 at the EC(99). Synergism was more pronounced with the triple combination, i.e. atovaquone + proguanil and artemisinin, starting at the EC(10) level. The mean SigmaFIC values were 0.7626 at the EC(50), 0.2939 at the EC(90), and 0.1527 at the EC(99). The strong synergism at the therapeutically relevant effective concentrations suggests that the therapeutic efficacy of atovaquone-proguanil can be considerably enhanced by the additional administration of a suitable artemisinin derivative, e.g. artesunate.

Animals↗