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A series of chloromethylsulfonyl derivatives of amines, biguanides and amidineureas (Scheme 1) has been prepared and their antimalarial properties investigated.
OBJECTIVE: To ascertain the relative effect of antimalarial (AM) agents on fasting lipid fractions in patients with systemic lupus erythematosus (SLE). METHODS: The study was cross sectional including all patients with SLE who were seen in our lupus clinic with fasting lipid profiles measured as part of evaluation from November 1995 to March 1999. RESULTS: A total of 123 patients with a mean age of 45.3 years and mean disease duration 13.4 years were studied; 73.2% were taking prednisone with a mean +/- SD dose of 10.9 +/- 9.2 mg/day, 48.0% were taking AM, and 30.8% were taking both. In the entire group, patients taking AM had a 12.5% lower total cholesterol (TC) (5.11 +/- 1.27 vs 5.84 +/- 1.23; p = 0.002), 22.1% lower very low density lipid-cholesterol (VLDL-C) (0.66 +/- 0.40 vs 0.85 +/- 0.39; p = 0.01), and 15.7% lower LDL-C (3.01 +/- 1.14 vs 3.58 +/- 1.10; p = 0.007). For patients taking prednisone, those taking concomitant AM (n = 38) had significantly lower TC (5.26 +/- 1.30 vs 5.99 +/- 1.29; p = 0.01), VLDL-C (0.65 +/- 0.39 vs 0.85 +/- 0.41; p = 0.02), and LDL-C (3.05 +/- 1.20 vs 3.69 +/- 1.09; p = 0.01) than those without AM (n = 48). For patients taking < or = 10 mg/day prednisone, TC (4.69 +/- 0.88 vs 5.74 +/- 1.20; p < 0.001), VLDL-C (0.61 +/- 0.37 vs 0.83 +/- 0.44; p = 0.05), and LDL-C (2.57 +/- 0.76 vs 3.49 +/- 1.04; p < 0.001) were still lower in patients with concomitant AM (n = 22) than those without AM (n = 36). CONCLUSION: TC, VLDL-C, and LDL-C levels were significantly lower in patients taking AM, including patients taking concomitant prednisone. Thus AM may have beneficial effects in SLE in addition to disease suppression.
Two observations of severe neuropsychiatric reactions occurring during chemoprophylaxis with mefloquine are reported. The first case regards a 43 years old woman who developed a severe depression with visual and auditive hallucinations and a paranoid delusion. She was treated by clomipramine and risperidone. The second case concerns a 55 years old man who developed an acute psychosis with confusion. He was treated with halopridol during a short time. He presented twice an acute psychosis during a chemoprophylaxis with mefloquine. Several cases of neuropsychiatric side effects with mefloquine chemoprophylaxis or treatment have been described. Authors estimate that one of 250 therapeutic users has severe neuropsychiatric reactions, compared with one of 10,000 to 15,000 in the prophylaxis users. Disorders could last from 15 minutes to several weeks. Women and patients with personal or familial antecedents of psychiatric disorders are more frequently concerned. Alcohol and the association with other antimalarial drugs (like quinine) are two other risk factors. Therefore, some advices may be suggested regarding the use of mefloquine for malaria prophylaxis and treatment.
The effects of the antimalarial drug chloroquine on cardiac action potential and membrane currents were studied at clinically relevant concentrations. In cat Purkinje fibers, chloroquine at concentrations of 0.3 to 10 microM increased action potential duration, and reduced maximum upstroke velocity. At concentrations of 3 and 10 microM, chloroquine increased automaticity and reduced maximum diastolic potential, and after 60 min of perfusion with a concentration 10 microM, spontaneous activity was abolished. In isolated cat ventricular myocytes, chloroquine also increased action potential duration in a concentration-dependent manner, and reduced resting membrane potential at 3 and 10 microM. In voltage-clamped cat ventricular myocytes, chloroquine blocked several inward and outward membrane currents. The order of potency was inward rectifying potassium current (I(K1)) > rapid delayed rectifying potassium current (I(Kr)) > sodium current (I(Na)) > L-type calcium current (I(Ca-L)). Only tonic block of I(Na) and I(Ca-L) was observed at a stimulation frequency of 0.1 Hz and no additional blockade was observed during stimulation trains applied at 1 Hz. The effect of chloroquine on I(K1) was voltage-dependent, with less pronounced blockade at negative test potentials. In addition, unblock was achieved by hyperpolarizing pulses to potentials negative to the current reversal potential. Chloroquine blocked the rapid component of the delayed rectifying outward current, I(Kr,) but not the slow component, I(Ks). These findings provide the cellular mechanisms for the prolonged QT interval, impaired ventricular conduction, and increased automaticity induced by chloroquine, which have been suggested as responsible for the proarrhythmic effects of the drug.
The expanding foci of multiple drug resistant malaria and emergence of different strains requires the reassessment of antimalarial activity with various drugs. In vitro response of a chloroquine sensitive and a chloroquine resistant isolate of P. falciparum to a group of 6 quinine derived and 3 artemisinin derived standard drugs has been screened, to evaluate schizontocidal activity of the drugs. In a conventional test system the IC50s were derived from the log dose response curves and evaluated by a rigorous statistical interpretation. Analysis by Tukey's test was significant for the quinine related drugs (Q < or = 0.01) and excludes the statistical significance of artemisinin related drugs in these isolates. The dose-responses of these two isolates vary with quinine derivatives, with some overlap at lower doses for the sensitive isolate than for the resistant one which manifests at higher doses.
Mefloquine is a quinoline antimalarial drug that is structurally related to the antiarrhythmic agent quinidine. Mefloquine is widely used in both the treatment and prophylaxis of Plasmodium falciparum malaria. Mefloquine can prolong cardiac repolarization, especially when coadministered with halofantrine, an antagonist of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. For these reasons we examined the effects of mefloquine on the slow delayed rectifier K+ channel (KvQT1/minK) and HERG, the K+ channels that underlie the slow (I(Ks)) and rapid (I(Kr)) components of repolarization in the human myocardium, respectively. Using patch-clamp electrophysiology we found that mefloquine inhibited KvLQT1/minK channel currents with an IC50 value of approximately 1 microM. Mefloquine slowed the activation rate of KvLQT1/minK and more block was evident at lower membrane potentials compared with higher ones. When channels were held in the closed state during drug application, block was immediate and complete with the first depolarizing step. HERG channel currents were about 6-fold less sensitive to block by mefloquine (IC50 = 5.6 microM). Block of HERG displayed a positive voltage dependence with maximal inhibition obtained at more depolarized potentials. In contrast to structurally related drugs such as quinidine, mefloquine is a more effective antagonist of KvLQT1/minK compared with HERG. Block of KvLQT1/minK by mefloquine may involve an interaction with the closed state of the channel. Inhibition by mefloquine of KvLQT1/minK in the human heart may in part explain the synergistic prolongation of QT interval observed when this drug is coadministered with the HERG antagonist halofantrine.
Ten 4-methyl-5-substituted-phenoxy-6-methoxy-8-[(1-ethyl-4-amino) butylamino] quinolines (10a-j) have been synthesized and evaluated preliminarily for both suppressive and causal prophylactic antimalarial activities. The results of preliminary screening test showed that three of these compounds exhibited significant activity against Plasmodium yoelii in mice, among which 10c was 4-8 times as effective as primaquine. Moreover, 10c was superior to primaquine in suppressive test against Plasmodium berghei K173 strain in mice. On the basis of ED50 and ED90, 10c was about 2 times as active as primaquine. Most of other compounds showed similar activity and the minority of them exhibited lower activity compared with primaquine.
OBJECTIVE: To obtain the experience of selected experts in the use of antimalarial drugs (AM) in pregnancy and lactation in systemic lupus erythematosus. METHODS: Seventy-eight lupus experts identified from North America and UK were mailed a 19 question survey regarding their experience using AM in pregnancy and lactation. RESULTS: The 52 (67%) respondents with usable questionnaires treated a median of 75 lupus patients/year, including 4-5 lupus pregnancies/year. Thirty-five (69%) continued AM sometimes, often, or always during pregnancy. Continuing AM increased with the number of pregnant lupus patients seen (p < 0.01). None reported having seen any fetal toxicity with AM use, and pregnancy was never terminated because of AM, other than at patient insistence (n = 1). Postpartum, 29 (63%) continued AM and advised breast-feeding. Responses were consistent among North American and UK experts. CONCLUSION: The majority of lupus experts continue AM during pregnancy. This was particularly true for those who treated a larger number of pregnant lupus patients per year. The majority advise breast-feeding and continue AM postpartum. These practices are supported by the limited literature available.
The DELI-microtest (Double-Site Enzyme Linked LDH Immunodetection) is a colorimetric method for determination of Plasmodium falciparum in vitro sensitivity to antimalarial drugs. This method is based on the capture of the specific lactate deshydrogenase of Plasmodium falciparum (pLDH) using 2 monoclonal antibodies which recognize 2 different sites of the enzyme. The second monoclonal antibody is biotinylated and may catch a peroxidase-labelled streptavidine and develop a colorimetric reaction in the presence of peroxidase substrate. The level of pLDH released by parasite growth is determined by the measure of optical densities. An excellent correlation has been observed between the IC50's obtained using the DELI-microtest and the classical isotopic microtest, and the high sensitivity of the DELI-microtest can be used to measure the IC50's for isolates with parasitemia as low as 0.005%. It is easier and faster to process than isotopic microtest in field conditions. In addition, due to high sensitivity of the DELI-microtest, isolates with a low parasitemia may be included in the studies.
Chloroquine is a drug with over 60 years of safe clinical use in the treatment of malaria. The multiple mechanisms of chloroquine action have appeared to be useful in the therapy of many miscellaneous disorders well beyond its original antimalarial purposes. This paper is focused on the application of chloroquine for the treatment of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic rheumatism and lupus. The possibility of the use of chloroquine in the therapy of other disorders such as diabetes mellitus, AIDS, hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed. Mechanisms of action of the drug as well as side effects on metabolism are discussed in view of recent discoveries.
BACKGROUND: Limits of Wells'syndrome, a nosologically enlarged entity defined after classic eosinophilic cellulitis, are imprecise. We report on a new "frontier" case, remarkable in its clinical pattern and its high sensitivity to antimalarial drugs. CASE REPORT: A 35-year-old woman was referred for evaluation of recurrent inflammatory, figurated and often annular lesions, mainly located on the trunk and the proximal parts of the limbs, associated with significant peripheral eosinophilia and featuring dense perivascular infiltrates throughout the dermis with abundant eosinophils but without any "flame figure". These lesions responded dramatically to protracted treatment with hydroxychloroquine. DISCUSSION: The relationship of this affection to Wells' syndrome is discussed along with its possible similarities to the sparse reports of so-called eosinophilic annular erythema.
OBJECTIVE: To study the inhibition of growth of Plasmodium falciparum cultured in vitro with antisense oligodeoxyribonucleotide (AS ODN) against histidine-rich proteins (HRP). METHODS: The ODNs against HRP II and HRP III were synthesized and used to study the antimalarial activities in vitro. Plasmodium falciparum (FCC1/HN strain, China) were exposed to AS DONs for 48 h, and the growth inhibition was determined by microscopic examination. RESULTS: At 1 mumol/L, all ODNs inhibited parasite growth and development in a target-independent manner. However, when the ODN concentrations were between 0.01 and 0.5 mumol/L, the AS ODN significantly inhibited the growth and development of P. falciparum compared with ODN controls (P < 0.01). Inhibition by the sense strand ODN did not differ significantly from the control group (P > 0.05). CONCLUSION: Blockade of the expression of HRP II and HRP III AS ODN could inhibit P. falciparum cultured in vitro.
Genotyping frequently is used to distinguish recrudescent from new infections in antimalarial drug efficacy trials, but methodology and interpretation of results have not been standardized. We compared the utility of polymorphisms within 3 Plasmodium falciparum genes during a longitudinal trial in Kampala, Uganda. Merozoite surface protein-1 (msp-1) and merozoite surface protein-2 (msp-2) revealed greater diversity than glutamate-rich protein. Genotypes based on msp-1, msp-2, and all 3 genes combined were compared for 394 initial and subsequent isolates. Classification of most episodes as due to recrudescence or reinfection was straightforward. In 24% (msp-1), 16% (msp-2), and 62% (3 genes combined) of samples, subsequent episodes contained identical and new alleles, however. Our analysis suggested that such episodes should be classified as reinfections and not recrudescence. Comparing the 3 studied genes, msp-2 results were most accurate, and analysis of this single gene effectively distinguished recrudescence from reinfection in our study population.
To redefine strategy and policy to cure or to prevent malaria, there is a need to get relevant and updated data on Plasmodium sp sensitivity level to antimalarial drugs. Thus, in September 1999, the Madagascan Ministry of Health and the Institut Pasteur de Madagascar (IPM) formed a network named RER for malaria resistance surveillance. To alleviate the lack of experienced medical teams within the health centres, and due to technical and logistic matters, as part of the network activities, it was decided to give a start with the in vitro studies which are carried out at IPM. In vitro sensitivity testing is done by use of the isotopic method. Results from the study done in 2001 demonstrate that the Madagascan P. falciparum isolates are susceptible to amodiaquine (n = 215), to cycloguanil (n = 56), to pyrimethamine (n = 98) and to quinine (n = 214). One isolate (1/110 i.e. 0.9%) of mefloquine-resistant phenotype is detected from the Eastern region. P. falciparum susceptibility to chloroquine is satisfactory with 95.4% (206/216) of in vitro sensitive isolates. RER arises from the partnership and collaboration between the Madagascan Ministry of Health and the IPM. The network set-up is presented. The usefulness of the in vivo approach, and the in vitro investigations (chemosusceptibility test and screening of mutations accounting for resistance to chloroquine) to monitor the emergence and the dissemination of drug-resistant parasites in Madagascar as well as in the subregion of the Indian Ocean is discussed.
Diosgenone is a major component of the hexane extract from the plant Solanum nudum (Solanaceae). The products from degraded and acetylated diosgenone that showed in vitro antimalarial activity against the FCB-2 strain of Plasmodium falciparum and methanol, dichloromethane and ethereal extracts of Solanum nudum were tested for their mutagenic activity using the Ames test with the TA-97a, TA-98, TA-100 and TA-102 strains of Salmonella typhimurium. These compounds were not mutagenic at the tested concentrations.
The World Health Organization (WHO) has developed guidelines for in vivo antimalarial drug efficacy testing for Plasmodium falciparum and Plasmodium vivax in areas with low-to-moderate transmission, such as the Americas. These guidelines are used widely by ministries of health and national malaria control programs to assess the efficacy of their first-line and second-line drugs for the treatment of malaria and to provide the information necessary to update national malaria treatment policies. Following the WHO guidelines, we have conducted in vivo efficacy trials with a variety of drugs and drug combinations against P. falciparum and P. vivax at 13 sites in Peru, Bolivia, and Ecuador. Based on these experiences, we have identified several modifications that we believe should be made in the WHO recommendations to make them more suitable to the relatively low levels of P. falciparum transmission in the Americas and to the logistic challenges of carrying out such studies in sparsely populated areas, such as the Amazon Basin. These include changes in inclusion and exclusion criteria, in enrollment and follow-up procedures, and in the measurement of study outcomes.
Mefloquine is an important antimalarial drug for treatment and prophylaxis of chloroquine-resistant malaria. Its use has been associated with neuropsychiatric side-effects. We report a case of paranoid psychosis associated with mefloquine occurring in a remote part of Papua New Guinea. Adverse reactions and contraindications are discussed. This case underlines the importance of awareness of neuropsychiatric side-effects with mefloquine use and of taking a careful psychiatric history before prescribing mefloquine.
Oxidation and redox cycling of the hydroxylated metabolites of the antimalarial drug primaquine (i.e. 5-hydroxyprimaquine, 5-hydroxydemethylprimaquine, and 5,6-dihydroxy-8-aminoquinoline) were studied. The three metabolites readily oxidized under physiological conditions, forming hydrogen peroxide and the corresponding quinone-imine derivatives as the main products. The latter compounds were characterized by visible, NMR, and infrared spectroscopy. Concomitant formation of drug-derived radicals and hydroxyl radicals was attested by direct and spin-trapping EPR experiments, respectively. The use of the spin stabilization method indicated that the radicals derived from 5-hydroxydemethylprimaquine and 5,6-dihydroxy-8-aminoquinoline are of the o-semiquinone type. Tentative structures are proposed for the radicals based on product identification and computer simulation of the experimental EPR spectra. The quinone-imines obtained from the reduced metabolites did not react at appreciable rates with NADPH but underwent redox cycling upon addition of ferredoxin:NADP+ oxidoreductase, forming hydrogen peroxide and hydroxyl radicals. The effect of antioxidant enzymes on hydroxyl radical yield obtained during oxidation and redox cycling indicates that the main route for hydroxyl radical formation is the metal ion-catalyzed reaction between the drug-derived radicals and hydrogen peroxide. Taken together, the results indicate that hydrogen peroxide is the potential toxic product formed from the primaquine metabolites.