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PubMed1999

Comparative efficacy and safety of chloroquine and alternative antimalarial drugs: a meta-analysis from six African countries.

OBJECTIVE: To evaluate the safety and efficacy of the currently used antimalarial drugs in six African countries. DESIGN: A meta-analysis. MAIN OUTCOME MEASURES: The role of efficacy, safety and cost on the selection of antimalarial drugs. RESULTS: The comparative efficacy study showed that amodiaquine (with > 90% cure rate) was superior to chloroquine and sulphadoxine-pyrimethamine at seven days schedule. The efficacy of amodiaquine was also observed to be comparable to that of mefloquine and halofantrine. The parasite clearance time (PCT) of these drugs ranged between two days and a week and the fever clearance time (FCT) was within 48 hours. The recrudescence rate at D14-D21 was found to be 12-17% in chloroquine and amodiaquine, while sulphadoxine-pyrimethamine showed a trend similar to halofantrine and mefloquine (0-12% recrudescence rate). Similarly, a big difference was also noted in the cost of the different antimalarial drugs. The pharmacokinetic data, however, showed that they are of similar profile, except in adverse features and contraindications, and values like their half-life (t1/2) where the long (t1/2) in drugs like sulphadoxine-pyrimethamine endows them with suppressive-cure feature, especially against recrudescent strains. Nevertheless, as these data are obtained from resident population in Africa, who however naive are exposed to few malaria challenges in their life, the results should not be directly extrapolated to total non immunes such as visitors from Europe. CONCLUSION: The choice of alternative antimalarial drugs should be mainly based on their relative efficacy, safety and cost.

Africa, Eastern↗
PubMedDate not supplied

QSAR studies on antimalarial activities of 2-phenyl-4-quinoline-carbinolamines.

QSAR study on a series of 2-phenyl-4-quinoline carbinolamine antimalarials was performed using electronic parameters to correlate the electronic features with antimalarial activities. The electronic parameters used were energy of the highest occupied molecular orbitals (EH), energy of the lowest unoccupied molecular orbitals (EL), the total pi-electron energy (ET) and charge density (CD). The results have shown that the antimalarial potential can be modeled by these parameters. The study will aid in efficient designing of this class of antimalarial agents.

Antimalarials↗
PubMedDate not supplied

Synthesis and biological activity of new potential antimalarial: 1H-pyrazolo[3,4-b]pyridine derivatives.

The appearance of drug resistant Plasmodium falciparum malaria necessitates the search for novel antimalarial agents. Using the classical ring-bioisosterism concept as a strategy to develop new potential drugs, 1H-pyrazolo[3,4-b]pyridine 4-aminomethanol compounds were designed and synthesized as isosteres of the classical quinoline antimalarial mefloquine. The hydrochloride form of these compounds were tested for in vitro antimalarial activity against chloroquine-sensitive (Sierra Leone D-6) and resistant (Indochina W-2) clones of P. falciparum. The results described herein indicated that 1-H-pyrazolo[3,4-b]pyridine system represents a bioisosteric framework to quinoline system in the antimalarial activity.

Animals↗
PubMed2002

[Mechanism of action of antimalarials. Value of combined atovaquone/proguanil].

Determining the mode of action of different antimalarial drugs at the cellular level is essential to optimizing their use and to understanding the mechanisms underlying plasmodial resistance. The main targets for antimalarial drugs in Plasmodium falciparum have been the food vacuole and mitochondrial system. A new target is recently discovered organelle named the apicoplast. The apicoplast is the site of a number of metabolic pathways crucial to the survival of the parasite. It may also be involved in DNA replication and transcription. Antimalarial drugs are classified into three groups according to site of action, i.e., drugs that act on the food vacuole, drugs that block metabolic synthesis and oxidative processes, and drugs that interfere with membrane processes. Knowledge of these sites of action has enabled identification of new drugs with the most promising potential for development. Current antimalarial strategies prioritize combination therapies such as atovaquone/proguanil or artemether/lumefantrine and prolonged treatments to limit the risk of inducing drug resistant Plasmodium.

Animals↗
PubMedDate not supplied

Enhancement of antimalarial activity of chloramphenicol against Indian Plasmodium falciparum isolates in vitro by chloroquine.

The antimalarial activity of chloramphenicol, a broad-spectrum antibiotic was studied in three Indian Plasmodium falciparum isolates having high or low sensitivity to chloroquine. The antimalarial activity was evaluated in 72 hours culture in the presence of various doses of chloramphenicol alone or in combination with a fixed dose of chloroquine added at a concentration that is well tolerated by parasites in vitro. Significant growth inhibition with chloramphenicol was observed at concentrations above 10 micrograms/ml in three isolates. However, an increase in the antimalarial activity of the compound at low concentrations in the range of 0.25-2.5 micrograms/ml has also been observed in the presence of chloroquine. Parasite growth was significantly inhibited in chloroquine resistant parasites. Use of chloramphenicol with chloroquine may be useful as a combination therapy to improve efficacy of the antimalarials and to retard the development of resistance to the individual components of the combination.

Animals↗
PubMed2004

Molecular epidemiology of malaria in Cameroon. XIX. Quality of antimalarial drugs used for self-medication.

Substandard and counterfeit pharmaceutical products are increasingly circulating and distributed around the world, in particular in less developed countries. These low-quality or counterfeit products often involve drugs that are in high demand for the prevention and treatment of highly prevalent diseases, such as antimalarial drugs in endemic countries. Self-medication for presumed malarial infections with drugs purchased from unofficial drug vendors is a common practice in Africa. The aim of the study was to investigate the quality of chloroquine, quinine, and sulfadoxine-pyrimethamine obtained from illegitimate sector in urban and rural areas in Cameroon and analyze the impact of these drugs on patients. We collected 284 samples of three antimalarial drugs from 132 different sources in 16 villages and cities throughout the country. We also collected antimalarial drugs that were used for self-medication by malaria-infected patients. Drug quality was assessed by a simple color reaction test and semi-quantitative thin-layer chromatography. Fifty (38%) of 133 chloroquine, 52 (74%) of 70 quinine, and 10 (12%) of 81 antifolates had either no active ingredient, an insufficient active ingredient, the wrong ingredient, or unknown ingredient(s). Self-medication with antimalarial drugs purchased from unofficial vendors is not a reliable strategy to diminish morbidity and mortality. These counterfeit drugs contribute to the spread of drug-resistant malaria parasites and may lead to increasing therapeutic failure and medical expense.

Antimalarials↗
PubMed2004

In vitro and in vivo antimalarial studies of Striga hermonthica and Tapinanthus sessilifolius extracts.

The antimalarial activities of the methanol extracts of Striga hermonthica (whole plant) and Tapinanthus sessilifolius (leaves), commonly used in Northern Nigeria for the treatment of malaria, were evaluated. In the in vitro antiplasmodial analysis, the extracts of T. sessilifolius and S. hermonthica utilized in the study, displayed mild to weak activities with IC50 values of 200.5 and 274.8 microg/ml respectively. This was investigated, using the multidrug resistant Plasmodium falciparum, K1 strain, in the parasite lactate dehydrogenase assay. The murine model in vivo antimalarial activity of the tested extracts, using chloroquine-sensitive Plasmodium berghei (ANKA P1), in the 4-day suppressive test, showed that both plants had intrinsic antimalarial properties, that were dose-dependent. At a dose of 400mg/kg weight of mice, extract of S. hermonthica exhibited a higher intrinsic antimalarial activity (68.5 % suppression) than that of T. sessilifolius (51.3 %). Chloroquine, the standard reference drug, had an average suppression of 78.0 % at a dose of 10 mg/kg weight of mice while normal saline was used as control. Preliminary phytochemical screening of the extracts indicated the presence ofsaponins, tannins, flavonoids, volatile oils and cardiac glycosides.

Animals↗
PubMed2004

Cyquant cell proliferation assay as a fluorescence-based method for in vitro screening of antimalarial activity.

The appearance of drug resistant parasites and the absence of an effective vaccine have resulted in the need for new effective antimalarial drugs. Consequently, a convenient method for in vitro screening of large numbers of antimalarial drug candidates has become apparent. The CyQUANT cell proliferation assay is a highly sensitive fluorescence-based method for quantitation of cell number by measuring the strong fluorescence produced when green GR dye binds to nucleic acids. We have applied the CyQUANT assay method to evaluate the growth of Plasmodium falciparum D6 strain in culture. The GR-nucleic acid fluorescence linearly correlated with percent parasitemia at both 0.75 or 1 percent hematocrit with the same correlation coefficient of r2 = 0.99. The sensitivity of P. falciparum D6 strain to chloroquine and to 3,6-bis-omega-diethylaminoamyloxyxanthone, a novel antimalarial, determined by the CyQUANT assay were comparable to those obtained by the traditional [3H]-ethanolamine assay: IC50 value of chloroquine was 54 nM and 51 nM by the CyQUANT and [3H]-ethanolamine assay, respectively; IC50 value for 3,6-bis-omega-diethylaminoamyloxyxanthone was 254 nM and 223 nM by the CyQUANT and [3H]-ethanolamine assay, respectively. This procedure requires no radioisotope, uses simple equipment, and is an easy and convenient procedure, with no washing and harvesting steps. Moreover, all procedures can be set up continuously and thus, the CyQUANT assay is suitable in automatic high through-put drug screening of antimalarial drugs.

Animals↗
PubMed2005

[The future outlook of antimalarials].

Spreading of resistance to chloroquine in the early 1960's had a dramatic impact on malaria treatment worldwide. The development of new antimalarial drugs, at first driven by political interests, is now centred on the need to limit disease extension due to a strong sensibilisation by NGO and the medias. Difficulties in using antimalarial drugs are mostly the result of geographic variabilities of drug resistance of Plasmodium falciparum to existing drugs, implying a decision "à la carte" for malaria treatment in each endemic country. To fight against resistance situations, the NGO Médecins sans frontières and the World Health Organization have launched the concept of multiple antimalarial drug therapies based on artemisinin derivatives. Such strategy has been initiated in order to limit extension of drug resistance to existing antimalarial treatments, waiting for a new innovative drug able to provide a "universal" treatment worldwide which does not exist at present.

Antimalarials↗
PubMed1991

Pricing, distribution, and use of antimalarial drugs.

Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary.

Antimalarials↗
PubMed1988

Antimalarial drugs, systemic lupus erythematosus and pregnancy.

Antimalarial drugs containing the 4-amino quinoline radical are used to help control disease activity in discoid lupus erythematosus and systemic lupus erythematosus (SLE). Many patients with these complaints are young women, some of whom will become pregnant. The use of these substituted 4-amino quinoline compounds in pregnancy is controversial. We studied the full obstetric histories of 8 women with SLE who had taken either chloroquine phosphate or hydroxychloroquine sulphate (Plaquenil) throughout the entire length of at least 1 pregnancy. These 8 women had 14 pregnancies while receiving antimalarial drugs. Fetal wastage was high in these patients, regardless of antimalarial therapy, and was almost 100% in patients who were clinically active. Six normal full term spontaneous deliveries resulted from these pregnancies with clinically healthy normal babies born despite exposure to antimalarial therapy throughout the pregnancies.

Abortion, Spontaneous↗
PubMed1980

Effect of antimalarial drugs on psoriasis.

This study was undertaken to determine whether the use of antimalarial drugs is truly contraindicated in patients with psoriasis. Forty-eight patients in Vietnam were examined, treated, and tested. All had been taking prophylactic antimalarial medication, and some were given additional chloroquine in an attempt to elicit an exacerbation. Although in twenty patients (41.7 percent) the condition showed some degree of worsening from the antimalarial medication, in only three patients (6.3 percent) was there worsening without further improvement from topical therapy. The higher dosage of chloroquine caused no exacerbations. Due to the absence of severe exacerbation noted in this study, the use of antimalarial drugs is not strongly contraindicated in those with psoriasis.

Adult↗
PubMed1981

[Resistance of Plasmodium falciparum to antimalarials: practical implications and control prospects].

The author reviews the present knowledge on the resistance of P. falciciparum to various antimalarials, such as the inhibitors of the dehydrofolate reductase (proguanil, pyrimethamine, cycloguanil embonate and trimethoprim), the 4-aminoquinolines, quinine and the combination of sulfadoxine-pyrimethamine and combinations of other antimalarials and outlines the geographical distribution of P. falciparum chloroquine-resistant strains. The genetic peculiarities of resistance to antimalarials and their possible relation to the actions exerted by the drugs in some biological processes of the parasite are described in the light of present knowledge. The classification of the response of P. falciparum to 4-aminoquinolines, proposed by a working group of the World Health Organization (sensitivity, resistance at R I, R II and R III levels) and the methods at present available to define the different responses (in vivo and in vitro methods) are described in detail. Attention is then drawn to the practical implications resulting from the continuous spreading of the phenomenon of drug-resistance, both in countries already affected by the problem and in those which are exposed to the risk of the importation of drug-resistant strains. Practical advice is given: (i) for the treatment of chloroquine- or poly-resistant P. falciparum strains with a brief description of the therapeutic potentialities of new antimalarials still at the experimental stage, especially mefloquine and (ii) on the measures to be taken to prevent the spreading and to control the phenomenon of drug-resistance. The future prospects for an efficacious control of the disease and of drug-resistance are viewed with some pessimism, due to the recent discovery of chloroquine-resistant P. falciparum strains in Africa and to the scarcity of the financial resources required to implement adequate control programmes.

Antimalarials↗
PubMed1994

[Treatment of Horton disease. Value of synthetic antimalarials. Apropos of a retrospective study of 36 patients].

Thirty-six patients with giant cells arteritis were studied retrospectively. Histological examination of the temporal artery or another artery was positive in 95% of cases. Mean follow-up was five years. A synthetic antimalarial was used in every case. Two groups were differentiated. One (Group I) was composed of 21 patients who were given the antimalarial drug as part of the first-line therapy, either with a corticosteroid in a mean dose of 36 mg/d (18 patients) or with a nonsteroidal antiinflammatory agent. The other group (Group II) included 15 patients in whom the antimalarial was used after a period of corticosteroid therapy, because of steroid-dependency (n = 5) or adverse effects (n = 9), or as part of a routinely used protocol (n = 1). Withdrawal of the corticosteroid was achieved in 81% of cases, after a mean interval of 15 months. Many patients discontinued the corticosteroid after less than one year. The 18 Group I patients who were given a corticosteroid were all able to discontinue this drug. The overall recovery rate was 58%; mean time to recovery was 33 months with a mean follow-up of 52 months. There were no recurrences at discontinuation of the treatment. Adverse effects of antimalarial therapy were recorded in 30.5% of patients and required discontinuation of the drug in 19%. The most often used regimen was hydroxychloroquine (40 mg/d) for at least two years and prednisone 20 to 30 mg/d for two months, in the absence of vascular complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models.

The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.

Animals↗
PubMed1993

Antimalarial drugs, pregnancy and lactation.

Disease activity has been demonstrated to be one of the major factors contributing to fetal loss in SLE patients, and discontinuation of antimalarial therapy can precipitate a flare of disease. It is therefore important to determine whether it is safe to continue antimalarial therapy throughout pregnancy. We have previously stated that we consider lupus patients and their fetuses to be at risk for disaster if antimalarial therapy is discontinued during pregnancy, and it has been our experience that lupus patients can produce normal offspring even if they are taking daily chloroquine or hydroxychloroquine. Several other reports now support our findings that it is probably safe to continue antimalarial therapy during pregnancy, although there are no large studies published. Data on the secretion of hydroxychloroquine in the breast milk of patients on steady-state hydroxychloroquine therapy are minimal, and further studies are required to determine whether these women can safely nurse their infants while taking hydroxychloroquine daily.

Antimalarials↗
PubMed1996

Antimalarial drugs in pregnancy--the North American experience.

The use of the 4-aminoquinoline antimalarials in pregnancy is controversial. The current practice of discontinuing these medications because of pregnancy makes little sense as the half-life of these medications is so long. Patients with SLE have increased fetal wastage and one of the factors known to contribute to this fetal wastage is disease activity. It is also known that discontinuing the 4-aminoquinoline antimalarial drugs can precipitate flares of disease in lupus patients. Mothers and their potential offspring are therefore at risk for flares of disease and pregnancy failure if these medications are discontinued because of pregnancy. This review addresses the North American experience of the use of antimalarial drugs in pregnant lupus patients. Unlike most centers in North America, we continue our patients on these medications throughout pregnancy and to date have documented 16 lupus patients who have taken these drugs throughout pregnancy. Our most recent study documents nine pregnancies in eight women. All of these pregnancies resulted in live births (five pre-term deliveries and four full-term deliveries). There were no congenital abnormalities in these infants and follow-up to date has revealed no evidence of ocular or oral deficits in any of these children. One patient experienced a flare of disease when her antimalarial therapy was temporarily discontinued.

Antimalarials↗
PubMed1997

Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells.

Antimalarials are beneficial therapeutic agents in systemic lupus and rheumatoid arthritis. These autoimmune diseases have abnormally low apoptosis of inflammatory cells. Both disorders have an abnormal angiogenesis. In the present report, antimalarials were demonstrated to selectively increase apoptosis of HUVECs in vitro. A 24-h exposure to 50 or 150 microM of the drugs was associated with a significant loss of substrate-adherent cells. Chloroquine exhibited an inhibitory effect on HUVEC proliferation over 7 days. Programmed cell death in HUVECs rendered nonadherent by chloroquine was confirmed by the induction of DNA fragmentation in floating cells. Northern blot analysis revealed a rapidly increased expression of the bcl-x(s) gene without any change in the expression of the bcl-2 gene, indicating that HUVECs under chloroquine were undergoing apoptosis. The onset of the apoptotic cascade in HUVECs appeared shortly after the addition of chloroquine. The effect of chloroquine on apoptosis was distinct from acute cell lysis and was restricted to HUVECs. Antimalarials also induced IL-1alpha production. In parallel, chloroquine alone did not increase the expression of IL-6. Anti-IL-1alpha Ab or IL-1Ra only marginally reversed chloroquine-induced depression of proliferation for the low drug concentration, but not the massive cell death effect at and above 50 microM. Taken together, these data may indicate that antimalarials repress angiogenesis. The autocrine mechanism involving IL-1alpha accounts only for a minor fraction of the full antiendothelial effect of chloroquine, which is mainly dependent on apoptosis.

Antimalarials↗