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PubMed1996

Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.

We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.

Animals↗
PubMed1996

Chemical Determinants of antimalarial activity of reversed siderophores.

Reversed siderophores (RSFs) are artificial hydroxamate-based iron chelators designed after the natural siderophore ferrichrome. The modular molecular design of RSF derivatives allowed the synthesis of various congeners with controlled iron-binding capacities and partition coefficients. These two physicochemical properties were assessed by a novel fluorescent method and were found to be the major determinants of RSF permeation across erythrocyte membranes and scavenging of compartmentalized iron. The partition coefficient apparently conferred upon RSFs two major features: (i) the ability to rapidly access iron pools of in vitro-grown Plasmodium falciparum at all developmental stages and to mobilize intracellular iron and transfer it to the medium and (ii) the ability to suppress parasite growth at all developmental stages. These features of RSFs were assessed by quantitative determination of the structure-activity relationships of the biological activities and partition coefficients spanning a wide range of values. The most effective RSF containing the aromatic group of phenylalanine (RSFm2phe) showed 50% inhibitory concentration of 0.60 +/- 0.03 nmol/ml in a 48-h test and a 2-h onset of inhibition of ring development at 5 nmol/ml. The lipophilic compound RSFm2phe and the lipophilic and esterase-cleavable compound RSFm2pee inhibited parasite growth at all developmental stages whether inhibition was assessed in a continuous mode or after discontinuing drug administration. The antimalarial effects of RSFm2phe and cleavable RSFm2pee were potentiated in the presence of desferrioxamine (DFO) at concentrations at which DFO alone had no effect on parasite growth. These studies provide experimental evidence indicating that the effective and persistent antimalarial actions of RSFs are associated with drug access to infected cells and scavenging of iron from intracellular parasites. Moreover, the optimal antimalarial actions of RSFs are apparently also determined by improved accessibility to critical iron pools or by specific interactions with critical parasite targets.

Animals↗
PubMed1998

Antimalarial synergy of cysteine and aspartic protease inhibitors.

It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.

Animals↗
PubMed1999

Synergistic in vitro antimalarial activity of omeprazole and quinine.

Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.

Animals↗
PubMed2000

Gametocytocidal activity and synergistic interactions of riboflavin with standard antimalarial drugs against growth of Plasmodium falciparum in vitro.

Our previous studies have shown that riboflavin has activity against Plasmodium falciparum asexual-stage parasites in vitro. In the present study we examine the gametocytocidal activity of riboflavin and the interaction of riboflavin with some commonly used antimalarial drugs against the asexual forms of P. falciparum in vitro. The addition of riboflavin to P. falciparum cultures killed gametocytes at all stages, even those at late stages (III to V), which are not affected by many of the commonly used antimalarials. Combinations of riboflavin with mefloquine, pyrimethamine, and quinine showed a marked potentiation of the activities of these drugs against asexual-stage parasites in vitro. The combination of riboflavin with artemisinin was additive, while that with chloroquine was mildly antagonistic. High doses of riboflavin are used clinically to treat several inborn errors of metabolism with no adverse side effects. Its efficacy in combination with standard antimalarial drugs in treating and preventing the transmission of P. falciparum malaria can therefore be evaluated in humans.

Animals↗
PubMed2000

Therapeutic responses to different antimalarial drugs in vivax malaria.

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for > or =28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed >28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.

Adult↗
PubMed2002

Optimization of xanthones for antimalarial activity: the 3,6-bis-omega-diethylaminoalkoxyxanthone series.

Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-omega-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R(2) = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 x 10(5) and 9.02 x 10(5) M(-1), respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.

Alkanes↗
PubMed2003

Simple in vitro assay for determining the sensitivity of Plasmodium vivax isolates from fresh human blood to antimalarials in areas where P. vivax is endemic.

The aim of this study was to develop a simple, field-practical, and effective in vitro method for determining the sensitivity of fresh erythrocytic Plasmodium vivax isolates to a range of antimalarials. The method used is a modification of the standard World Health Organization (WHO) microtest for determination of P. falciparum drug sensitivity. The WHO method was modified by removing leukocytes and using a growth medium supplemented with AB(+) serum. We successfully carried out 34 in vitro drug assays on 39 P. vivax isolates collected from the Mae Sod malaria clinic, Tak Province, Thailand. The mean percentage of parasites maturing to schizonts (six or more merozoites) in control wells was 66.5% +/- 5.9% (standard deviation). This level of growth in the control wells enabled rapid microscopic determination (5 min per isolate per drug) of the MICs of chloroquine, dihydroartemisinin, WR238605 (tafenoquine), and sulfadoxine. P. vivax was relatively sensitive to chloroquine (MIC = 160 ng/ml, 50% inhibitory concentration [IC(50)] = 49.8 ng/ml) and dihydroartemisinin (MIC = 0.5 ng/ml, IC(50) = 0.47 ng/ml). The poor response of P. vivax to both tafenoquine (MIC = 14,000 ng/ml, IC(50) = 9,739 ng/ml) and sulfadoxine (MIC = 500,000 ng/ml, IC(50) = 249,000 ng/ml) was due to the slow action of these drugs and the innate resistance of P. vivax to sulfadoxine. The in vitro assay developed in our study should be useful both for assessing the antimalarial sensitivity of P. vivax populations and for screening new antimalarials in the absence of long-term P. vivax cultures.

Animals↗
PubMed2003

Antimalarial activities of novel synthetic cysteine protease inhibitors.

Among promising new targets for antimalarial chemotherapy are the cysteine protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the activities of synthetic peptidyl aldehyde and alpha-ketoamide cysteine protease inhibitors against these proteases, against cultured Plasmodium falciparum parasites, and in a murine malaria model. Optimized compounds inhibited falcipain-2 and falcipain-3, blocked hemoglobin hydrolysis, and prevented the development of P. falciparum at nanomolar concentrations. The compounds were equally active against multiple strains of P. falciparum with varied sensitivities to standard antimalarial agents. The peptidyl inhibitors were consistently less active against vinckepain-2, the putative falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite Plasmodium vinckei. The lead compound morpholinocarbonyl-leucine-homophenylalanine aldehyde, which blocked P. falciparum development at low nanomolar concentrations, was tested in a murine P. vinckei model. When infused continuously at a rate of 30 mg/kg of body weight/day, the compound delayed the progression of malaria but did not eradicate infections. Our data demonstrate the potent antimalarial activities of novel cysteine protease inhibitors. Additionally, they highlight the importance of consideration of the specific enzyme targets of animal model parasites. In the case of falcipains, differences between P. falciparum and rodent parasites complicate the use of the rodent malaria model in the drug discovery process.

Aldehydes↗
PubMed2004

Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening.

Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC(50)) after 48 h of parasite growth in the presence of each drug. The EC(50)s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-epsilon-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.

Animals↗
PubMed2004

The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains.

The clinical potential of mefloquine has been compromised by reports of adverse neurological effects. A series of 4-quinolinecarbinolamines were compared in terms of neurotoxicity and antimalarial activity in an attempt to identify replacement drugs. Neurotoxicity (MTT [thiazolyl blue reduction] assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC(50)) of mefloquine was 25 microM, while those of the analogs were 19 to 200 microM. The relative (to mefloquine) therapeutic indices of the analogs were determined after using the tritiated hypoxanthine assay for assessment of the antimalarial activity of the analogs against mefloquine-sensitive (W2) and -resistant (D6 and TM91C235) Plasmodium falciparum strains. Five analogs, WR157801, WR073892, WR007930, WR007333, and WR226253, were less neurotoxic than mefloquine and exhibited higher relative therapeutic indices (RTIs) against TM91C235 (2.9 to 12.2). Conventional quinoline antimalarials were generally less neurotoxic (IC(50)s of 400, 600, and 900 for amodiaquine, chloroquine, and quinine) or had higher RTIs (e.g., 30 for halofantrine against TM91C235). The neurotoxicity data for the 4-quinolinecarbinolamines were used to develop a three-dimensional (3D), function-based pharmacophore. The crucial molecular features correlated with neurotoxicity were a hydrogen bond acceptor (lipid) function, an aliphatic hydrophobic function, and a ring aromatic function specifically distributed in the 3D surface of the molecule. Mapping of the 3D structures of a series of structurally diverse quinolines to the pharmacophore allowed accurate qualitative predictions of neurotoxicity (or not) to be made. Extension of this in silico screening approach may aid in the identification of less-neurotoxic quinoline analogs.

Animals↗
PubMed2005

Antimalarial activities and therapeutic properties of febrifugine analogs.

Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.

Animals↗
PubMed1998

Long-term effectiveness of antimalarial drugs in rheumatic diseases.

OBJECTIVE: The purpose of this study was to compare the long-term effectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ). METHODS: Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or inefficacy, or both. Bivariate analysis including t tests and chi 2 tests were used to assess differences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders. RESULTS: After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The proportion of patients with side effects taking HCQ and CQ was 15% and 28% respectively (p = 0.001). Using Cox regression model to adjust for age at the onset of antimalarial treatment, physician differences, sex, disease type, disease duration before treatment, and rank selection, there were no differences in the hazard ratio (HR) for overall discontinuations between CQ and HCQ. While the HR for discontinuations because of toxicity was lower for HCQ (HR = 0.6, 95% CI 0.4, 0.9), the HR for discontinuations because of inefficacy was significantly higher for HCQ (HR = 1.4, 95% CI 1.1, 1.9). CONCLUSIONS: After adjusting for time and several confounders HCQ was less toxic but less effective than CQ. Only one case of probable/possible retinopathy was found. Therefore, we propose a careful baseline ophthalmological evaluation by an expert and then one or every two years if proper doses are used.

Adult↗
PubMed1985

Screening for antimalarial maculopathy in rheumatology clinics.

Ophthalmoscopy and three tests of visual function were undertaken in 39 patients with rheumatoid arthritis receiving treatment with antimalarial drugs and in a control group of 16 patients with rheumatoid arthritis who were not receiving such treatment. Visual contrast sensitivity, macular threshold to red light, and central visual fields to red targets were not significantly different in treated patients and controls. There were no abnormalities in visual acuity, but 11 of 76 eyes of treated patients showed minor macular abnormalities on ophthalmoscopy that were not seen in control patients, suggesting that ophthalmoscopy may be the most sensitive measure of early drug toxicity. Five rheumatologists were able to identify 52 of 65 minor changes detected by an ophthalmologist. These studies, and a critical review of published reports, suggest that in clinical practice antimalarial drugs can be administered safely to patients with rheumatoid arthritis without the need for repetitive routine examination by an ophthalmologist or the use of complicated physiological tests. Recording of visual acuity in each eye and ophthalmoscopy by the prescribing doctor may be all that are required to detect early antimalarial maculopathy.

Adult↗
PubMed2025

Strategies for mitigating emerging artemisinin-based antimalarial drug resistance in Rwanda: a promising approach for managing therapies in malaria-endemic countries.

Malaria treatment failures associated with reduced efficacy of chloroquine (CQ) and amodiaquine (AQ) antimalarial drugs emerged in Rwanda during the 1980s, prompting the policy shift towards adopting artemisinin-based combination therapies in 2006 as an alternative. However, recent findings from malaria surveillance and therapeutic efficacy studies have revealed a countrywide increase in antimalarial drug resistance. Particularly, artemether-lumefantrine (AL) efficacy has significantly decreased, probably due to the emergence of Plasmodium falciparum (Pf) genomic mutations. To mitigate the current drug resistance, Rwanda has adopted targeted multiple first-line therapies. Through the national malaria control program, antimalarial drugs were deployed in accordance with the reported resistance profile. A significant rise in Pfkelch13 mutations, particularly A675V associated with AL resistance, was mainly reported in the western region; therefore, artesunate-pyronaridine was recommended. Dihydroartemisinin-piperaquine was considered in eastern and central regions, where R561H mutations were predominant. On the contrary, AL was maintained in the southern region, where the prevalence of the R561H mutation was low. Insights from this data-driven model will inform its extension to other malaria-endemic countries facing emerging Pf genetic diversity.

Antimalarials↗
PubMedDate not supplied

Antimalarial prescribing practices: a challenge to malaria control in Ghana.

OBJECTIVE: The study was conducted to determine antimalarial prescribing practices among prescribers in 2 of the 6 sentinel sites established to document antimalarial drug efficacy in Ghana in order to provide some explanation underlying chloroquine treatment failures in the country. SUBJECTS AND METHODS: The study was descriptive combining both qualitative and quantitative designs. The qualitative design involved in-depth interviews of general prescribers in the Wassa West and Kassena Nankana districts using an interview guide. The quantitative design involved a review of Outpatient Department prescriptions of 100 patients clinically diagnosed as having malaria within the year 2000 in each of the 7 selected health care facilities. RESULTS: The overall number of drugs prescribed per patient encounter was 4.3 in the Wassa West district and 3.0 in the Kassena Nankana district. The number of drugs per patient encounter was 5.4 and 3.7 in private and government health care facilities, respectively. The commonly prescribed antimalarial drug in all the health care facilities visited was chloroquine. However, only 9.8% of prescriptions in private health care facilities contained correct doses of chloroquine compared to 54% in government health care facilities (p = 0.000). Prescriptions containing chloroquine injections were least likely to have correct doses of chloroquine. CONCLUSION: The findings indicate that although chloroquine remained the first-line drug in the treatment of uncomplicated malaria in the two districts, the level of appropriateness of doses prescribed was generally low. Inappropriate doses of chloroquine prescribed were more prevalent in private than government health care facilities, and among prescriptions containing injections.

Amodiaquine↗
PubMed2006

The use of genotyping in antimalarial clinical trials: a systematic review of published studies from 1995-2005.

BACKGROUND: The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied. METHODS: A systematic review of all clinical antimalarial efficacy trials published from 1995-2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy. RESULTS: In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections. CONCLUSION: Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed.

Africa↗
PubMed2006

Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria.

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%).

Animals↗