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At least 1,315 records · Page 73Linked to original sources
PubMed2004

The quality of essential antimicrobial and antimalarial drugs marketed in Rwanda and Tanzania: influence of tropical storage conditions on in vitro dissolution.

OBJECTIVE: The quality of 33 formulations of essential antimicrobial and antimalarial drugs (amoxicillin capsules, metronidazole tablets, sulfamethoxazole/trimethoprim tablets, quinine tablets and sulphadoxine/pyrimethamine tablets) marketed in Rwanda and Tanzania was assessed and the influence of tropical storage conditions on potency and in vitro dissolution investigated. METHODS: Drug content and in vitro dissolution were determined immediately after purchase and during 6-month storage under simulated tropical conditions (75% relative humidity, 40 degrees C) using the methods described in the USP 24 monographs on the drugs concerned. RESULTS AND DISCUSSION: At the time of purchase, the drug content of all the formulations was within the limits recommended by the USP 24, but after 6-month storage, the drug content of one sulfamethoxazole/trimethoprim and one quinine formulation were found to be substandard. Immediately after purchase, four formulations (three sulfamethoxazole/trimethoprim and one sulphadoxine/pyrimethamine combination) failed the USP 24 dissolution test. Except for three metronidazole and one quinine formulations, dissolution tests performed after 6 months of storage under simulated tropical conditions showed that drug release remained within the USP 24 recommended values. CONCLUSION: In both countries, essential drug formulations met pharmacopoeial potency requirements, but some had a poor in vitro drug release profiles. Some of the formulations tested were not stable upon storage under simulated tropical conditions.

Anti-Infective Agents↗
PubMed2005

Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers.

BACKGROUND: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. OBJECTIVE: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. RESULTS: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone. CONCLUSIONS: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.

Adolescent↗
PubMed2004

The difference between effectiveness and efficacy of antimalarial drugs in Kenya.

OBJECTIVE: To demonstrate the difference between effectiveness and efficacy of antimalarial (AM) drugs in Kenya. METHODS: We undertook a series of linked surveys in four districts of Kenya between 2001 and 2002 on (i) community usage of nationally recommended first- and second-line AM drugs; (ii) commonly stocked AM products in the retail and wholesale sectors; and (iii) quality of the most commonly available first- and second-line AM products. These were combined with estimates of adherence and clinical efficacy to derive overall drug effectiveness. RESULTS: The overall modelled effectiveness for sulphadoxine-pyrimethamine (SP) was estimated to be 62% compared with 85% for reported SP clinical efficacy. For amodiaquine the modelled effectiveness was 48% compared with 99% reported efficacy during the same time period. CONCLUSIONS: The quality of AM products and patient adherence to dosage regimens are important determinants of drug effectiveness, and should be measured alongside clinical efficacy. Post-registration measures to regulate drug quality and improve patient adherence would contribute significantly to AM drug performance.

Antimalarials↗
PubMed1982

Antimalarials in rheumatic diseases.

The use of antimalarials in rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) has declined over recent years due to concern over retinal toxicity and the impression that this class of drugs is relatively ineffective in rheumatic diseases. Recent reviews suggest that this position should be changed. Firstly, there is now good evidence for the efficacy of these drugs in RA and secondly strict control of the daily dosage and careful ophthalmological surveillance can almost eliminate the risk of serious retinal toxicity.

Antimalarials↗
PubMed1994

Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics.

In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4-aminoquinolines, empirically used up to now. The mechanism of action of 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine-resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are extensively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4-aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse-effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine-resistant malaria.

Aminoquinolines↗
PubMed1974

The selection of arylamidinourea antimalarials by their predicted physicochemical properties.

1 A small group of arylamidinoureas for which the predicted physicochemical properties were widely spaced and uncorrelated was selected for study.2 The antimalarial activity of each compound was measured against three species of plasmodium. Three corresponding regression equations were calculated relating the potency of each compound to its predicted physicochemical properties.3 The potency of further test compounds was forecast for each species, by using the corresponding regression equation. These forecasts were compared with the measured activity of the test compounds, and were better than would be expected by chance.4 It is suggested that only a few compounds in a series need be studied initially in order to derive regression equations with worthwhile predictive properties, if the compounds are selected according to appropriate criteria.

Amidines↗
PubMedDate not supplied

Combined action of inhibitors of S-adenosylmethionine decarboxylase with an antimalarial drug, chloroquine, on Plasmodium falciparum.

Methylglyoxal bis (guanylhydrazone), (MGBG) a potent competitive inhibitor of S-adenosyl-L-methionine decarboxylase activity, Berenil, a trypanocidal agent and chloroquine, the commonly used antimalarial resulted in a dose dependent inhibition of Plasmodium falciparum in vitro. The IC50 values of MGBG, Berenil and chloroquine were 224 microM, 40 microM and 42 nM respectively. Parasites treated with different concentrations of MGBG or Berenil were arrested at the trophozoite stage of the erythrocytic cycle. The combined action of chloroquine (10 nM) with either Berenil (0.1 mM) or MGBG (0.1 mM) on P. falciparum growth showed an additive inhibitory effect. The effect of these inhibitors alone and in combination on polyamine biosynthesis is also reported.

Adenosylmethionine Decarboxylase↗
PubMed2006

Adaptive response to the antimalarial drug artesunate in yeast involves Pdr1p/Pdr3p-mediated transcriptional activation of the resistance determinants TPO1 and PDR5.

The expression of the transcription regulator Pdr1p and its target genes PDR5 and TPO1 is required for Saccharomyces cerevisiae adaptation and resistance to artesunate, a promising antimalarial drug, also active against tumour cells and viruses. PDR5 and TPO1 encode plasma membrane multidrug transporters of the ATP-binding cassette and the major facilitator superfamilies, respectively. The transcriptional activation of TPO1 (10-fold) and PDR5 (13-fold) was registered after 30 min of exposure of the unadapted yeast population to acute artesunate-induced stress, being significantly reduced in the absence of Pdr1p and abolished in the absence of Pdr1p and Pdr3p. Maximum TPO1 mRNA levels were rapidly reduced to basal values following adaptation of the yeast population to artesunate, while high PDR5 levels were maintained during drug-stressed exponential growth.

ATP-Binding Cassette Transporters↗
PubMed1993

Antimelanoma activity of chloroquine, an antimalarial agent with high affinity for melanin.

The antimalarial agent chloroquine is known for high affinity for melanin. This 4-aminoquinoline derivative was examined for anti-melanoma activity and uptake into melanoma cells. Chloroquine inhibited growth of cultured melanoma cells; the effect was much greater to a moderately pigmented cell line HMV-II than to a nonpigmented HMV-I. Treatment with chloroquine at a dose of 62 mg/kg i.p. for 12 days prolonged by 71% the life span of mice bearing B16 melanoma, while 24-day treatment at 31 mg/kg resulted in a 81% increase in life span. HMV-II cells showed a two-fold increase in uptake of chloroquine as compared with HMV-I cells. Chloroquine, 24 hr after administration to mice implanted s.c. with B16 melanoma, was selectively accumulated in the pigmented tissues, melanoma and eyes. Other nonpigmented tissues such as the liver, lung, and kidney showed rapid uptake (within 1 hr) and release. These results suggest that chloroquine is toxic to pigmented melanoma cells, the process being partly mediated by binding to melanin.

Animals↗
PubMed1987

Photosensitized lysis of red blood cells by phototoxic antimalarial compounds.

A family of 12 phototoxic quinolinemethanol antimalarials and three other non-phototoxic clinically used compounds were irradiated in the presence of red blood cells to determine if the resulting hemolysis would be a reliable predictor of phototoxicity. The most phototoxic compounds from in vivo tests were also the most phototoxic in this study. Quinine caused little RBC lysis, paralleling its non-phototoxicity in humans. The quinolinemethanol-induced photohemolysis occurs both in the presence and absence of oxygen. Enriching the RBC with BHA and cholesterol was particularly effective at protecting the cells from photohemolysis. Other compounds offered some measure of protection, while superoxide dismutase and sodium azide, among others, afforded no protection.

Antimalarials↗
PubMed1984

Effect of chloroquine and some other antimalarials on the immune mechanism in experimental animals.

The effects of chloroquine and some other antimalarials on the immune responses in experimental animals have been examined. Chloroquine and quinine caused significant decrease of serum anti-SRBC haemagglutination titre. Chloroquine lowered the serum IgM level and also reduced plaque-forming cells in the spleen of mice. The delayed-type hypersensitivity responses to SRBC and the passive cutaneous anaphylaxis were also diminished in rats treated with chloroquine. Thus, the immunosuppressant activity of chloroquine may explain its efficacy in various types of immune disorders.

Adrenal Glands↗
PubMed1992

The binding of the antimalarial arteether to human plasma proteins in-vitro.

The binding of the novel antimalarial drug, arteether, to human plasma, pure albumin and alpha 1-acid glycoprotein has been investigated by ultrafiltration, using [14C]arteether. The protein binding in plasma obtained from 11 healthy male subjects ranged from 73.4 to 81.8% bound, with a mean of 78.7 +/- 2.1%. The binding of drug in plasma was mainly accounted for by binding to albumin and alpha 1-acid glycoprotein. Scatchard analysis of the binding data revealed that the binding affinity of arteether to alpha 1-acid glycoprotein is much greater (20-fold) than that to albumin. This suggests that alpha 1-acid glycoprotein is the more important binding protein in plasma. This may have clinical importance due to alterations in plasma protein binding in patients with malaria, as the concentration of alpha 1-acid glycoprotein is markedly increased during malarial infection.

Adult↗
PubMed1996

Reaction between ferriprotoporphyrin IX and the antimalarial endoperoxide artesunate gives an intermediate species with enhanced redox catalytic activity.

The kinetics of the reaction between ferri(Fe(III) protoporphyrin IX (haemin) and the potent sesquiterpene endoperoxide antimalarial artesunate are shown to be consistent with a three-step, two-intermediate mechanism, with the final product possessing a degraded tetrapyrrole ring system. Microscopic rate constants for the mechanism have been evaluated. The redox catalytic capability of the haem artesunate complex is shown to be approximately fourfold that of haemin alone, suggesting a possible mechanism of action of the drug.

Antimalarials↗
PubMed2006

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.

Aminoquinolines↗
PubMed2006

Characterization of human urinary metabolites of the antimalarial piperaquine.

Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin-piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously.

Antimalarials↗
PubMed2005

Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor.

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Binding of dihydroartemisinin to hemoglobin H: role in drug accumulation and host-induced antimalarial ineffectiveness of alpha-thalassemic erythrocytes.

Dihydroartemisinin and other artemisinin derivatives are relatively ineffective against Plasmodium falciparum infecting alpha-thalassemic erythrocytes, namely hemoglobin (Hb) H or HbH/Hb Constant Spring erythrocytes, as compared with those infecting genetically normal erythrocytes. The variant erythrocytes accumulate radiolabeled dihydroartemisinin to a much higher extent than the normal ones, and the accumulated drug was retained after extensive washing, in contrast to the drug in normal erythrocytes which was mostly removed. At initial drug concentration of 1 mM, most (82-88%) of the drug was found in the cytosol fraction of both variant and normal erythrocytes. Binding of the drug to hemoglobins accounted for 40-70% of the total uptake. Hb H accounted for 10.9 +/- 2.7% and 12.4 +/- 6.2% of total protein in HbH and HbH/Hb Constant Spring erythrocytes. HbH bound with 28.7 +/- 6.7% of the drug, whereas HbH/Hb Constant Spring erythrocytes bound with 21.8 +/- 8.3% of the drug. Binding experiments showed that Hb H had 5-7 times the drug-binding capacity of Hb A. For Hb H, the maximum binding capacity (Bmax) = 1.67 +/- 0.17 mol/mol Hb, and the dissociation constant (Kd) = 66 +/- 17 microM, and for Hb A, Bmax = 0.74 +/- 0.18 mol/mol Hb and Kd = 224 +/- 15 microM. It is concluded that preferential binding of dihydroartemisinin to Hb H over Hb A accounts partly for the higher accumulation capacity of the alpha-thalassemic erythrocytes, which leads to its antimalarial ineffectiveness.

Animals↗
PubMed2002

A class of potent antimalarials and their specific accumulation in infected erythrocytes.

During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and P. cynomolgi.

Animals↗