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PubMed2004

[Combined antimalarial therapy using artemisinin].

The existing armamentarium of drugs for the treatment and prevention of malaria is limited primarily by resistance (and cross-resistance between closely related drugs). However, most of these drugs still have a place and their life-span could be prolonged if better deployed and used, and also by rationally combining them based on pharmacodynamic and pharmacokinetic properties. Newer compounds are also being developed. The nature of malaria disease and its prevalence in the developing world call for innovative approaches to develop new affordable drugs and to safeguard the available ones. According to WHO, the concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination. Combination therapy (CT) with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. In the context of this definition, multiple-drug therapies that include a nonantimalarial drug to enhance the antimalarial effect of a blood schizontocidal drug are not considered combination therapy. Similarly, certain antimalarial drugs that fit the criteria of synergistic fixed-dose combinations are operationally considered as single products in that neither of the individual components would be given alone for anti-malarial therapy. An example is sulfadoxine-pyrimethamine. Artemisinin-based combination therapies have been shown to improve treatment efficacy and also contain drug resistance in South-East Asia. However, major challenges exist in the deployment and use of antimalarial drug combination therapies, particularly in Africa. These include: 1) the choice of drug combinations best suited for the different epidemiological situations; 2) the cost of combination therapy; 3) the timing of the introduction of combination therapy; 4) the operational obstacles to implementation, especially compliance. As a response to increasing levels of antimalarial resistance, the World Health Organization (WHO) recommends that all countries experiencing resistance to conventional monotherapies, such as chloroquine, amodiaquine or sulfadoxine/pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs--artemisinin-based combination therapies) for malaria caused by Plasmodium falciparum. There is a promising role of such compounds in replacing or complementing current options. Since 1979, several different formulations of artemisinin and its derivatives have been produced and studied in China in several thousand patients for either P. falciparum or P. vivax malaria. To date, there is no evidence of drug resistance to these compounds. The use of artemisinin, artemether, arteether and artesunate for either uncomplicated or severe malaria is now spreading through almost all malarious areas of the world, although some of they have no patent protection, their development (with few exceptions) has not followed yet full international standards. Both artesunate, artemether and arteether are rapidly and extensively converted to their common bioactive metabolite, dihydroarte-misinin. WHO currently recommends the following therapeutic options: 1) artemether/lumefantrine; 2) artesunate plus amodiaquine; 3) artesunate plus sulfadoxine/pyrimethamine (in areas where SP efficacy remains high); 4) artesunate plus mefloquine (in areas with low to moderate transmission); and 5) amodiaquine plus sulfadoxine/pyrimethamine, in areas where efficacy of both amodiaquine and sulfadoxine/pyrimethamine remains high (mainly limited to countries in West Africa). This non artemisinin-based combination therapy is reserved as an interim option for countries, which, for whatever reason, are unable immediately to move to ACTs.

Amodiaquine↗
PubMed2004

Antimalarial drug use among caregivers in Ghana.

BACKGROUND: Chloroquine remains the first line antimalarial drug in Ghana. However, the emergence of Plasmodium falciparum resistance to chloroquine is a major obstacle to the national control strategy of case management. This study provides information on some of the reasons underlying chloroquine treatment failure in the country. METHODOLOGY: Household surveys, using multi-stage sampling, were conducted in 2 sentinel districts, Wassa West and Kassena Nankana, established to monitor chloroquine resistance in the country. Five hundred caregivers were interviewed in each district to determine patterns of antimalarial drug use among caregivers of children under 10 years. Inventory on home-kept drugs was conducted. RESULTS: Two hundred and four households in the Wassa West district kept a cumulative total of 248 drugs, whereas 228 households in the Kassena Nankana district kept a cumulative total of 410 drugs. One hundred and ninety-nine (80.2%) of the drugs kept in the Wassa West district and 181 (44.2%) of drugs kept in the Kassena Nankana district were antimalarials. The most commonly kept antimalarial drug in homes was chloroquine (88% and 96% in the Wassa West and Kassena Nankana districts respectively). Reasons given for keeping antimalarials were mainly "leftover after previous treatment". Caregivers' descriptions of the amount of chloroquine given to family members suspected to have malaria within the 2-week period preceding the survey were mostly inappropriate in the 2 districts. However, the proportion of appropriateness of doses was significantly lower in the Wassa West district (11.1% vs 36.4%; p < 0.0001). CONCLUSIONS: The significantly higher proportion of inappropriateness of chloroquine use in the Wassa West district could be a factor influencing the lower sensitivity of Plasmodium falciparum to chloroquine in the district compared to the Kassena Nankana district.

Adolescent↗
PubMed2006

In vitro potentiation of antimalarial activities by daphnetin derivatives against Plasmodium falciparum.

OBJECTIVE: To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. METHOD: Plasmodium faciparum (FCC1) was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. RESULTS: DA79 and DA78 showed potent antimalarial activity against Plasmodium falciparum cultured in vitro. CONCLUSION: Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

Animals↗
PubMed1991

The effect of N-alkyl modification on the antimalarial activity of 3-hydroxypyridin-4-one oral iron chelators.

The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3-hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

Alkylation↗
PubMed1996

The efficacy of antimalarials in systemic lupus erythematosus.

The use of antimalarial drugs to treat systemic lupus erythematosus (SLE) is receiving increased attention. A retrospective controlled study suggested that antimalarials were useful in suppressing disease activity in SLE. A randomized discontinuation trial of hydroxychloroquine sulphate supported the clinical belief that antimalarials are of benefit in SLE of mild to moderate disease activity and might have a role as adjunctive therapy to protect against more severe relapses of SLE. A randomized trial of the ability of hydroxychloroquine sulphate to suppress articular manifestations of SLE demonstrated no consistent statistically significant benefit, although the sample size was small. Anecdotal reports and the experience of expert clinicians have suggested a corticosteroid sparing role for antimalarials, although no controlled study has been conducted to specifically address this hypothesis. Thus, the evidence favors a role for antimalarials in suppressing mild to moderate disease activity in SLE and possibly in preventing severe disease exacerbations. Their role as corticosteroid sparing agents in SLE is widely believed, but unproven.

Adrenal Cortex Hormones↗
PubMed1997

Disposition of amodiaquine and related antimalarial agents in human neutrophils: implications for drug design.

The development and clinical use of 4-aminoquinoline antimalarial agents such as amodiaquine have been limited by toxicity to neutrophils. We have investigated the chemical basis of amodiaquine-induced toxicity and compared the findings with those for established antimalarial drugs proposed for human use. Amodiaquine, like chloroquine, mefloquine and halofantrine, was lysosomotropic and accumulated in human neutrophils. Amodiaquine did not lead to impairment of either cellular function or cell viability at therapeutic levels. In contrast to other antimalarial agents, amodiaquine (because it contains a 4-aminophenol function) depleted glutathione in activated neutrophils, by formation of an electrophilic quinoneimine metabolite. Bioactivation was accompanied by the expression of a drug-related antigen on the cell surface, which was recognized by drug-specific antibodies, suggesting that a type II hypersensitivity reaction is responsible for the observed toxicity. Similar bioactivation and accumulation were observed for the structurally related amopyroquine. The effects of chemical modifications at the 3'- and 5'-positions, which are known to enhance antimalarial activity, were also investigated. The introduction of a lipophilic 5'-chlorophenyl group and 3'-t-butyl group blocked bioactivation but enhanced cellular accumulation, with resultant impairment of function and neutrophil viability, whereas introduction of a second cationic dialkylamino group (bis-mannich compounds) blocked bioactivation and reduced cellular accumulation, without producing noticeable effects on cellular function and viability. These data provide a chemical rationale for the idiosyncratic agranulocytosis observed with amodiaquine, and they suggest that similar toxicity might be anticipated for amopyroquine but is less likely with bis-mannich antimalarial agents such as pyronaridine.

Amodiaquine↗
PubMed1998

Use and quality of antimalarial drugs in the private sector in Viet Nam.

This study examines the use and quality of antimalarial drugs in the growing private sector of Viet Nam. The practices of drug vendors (called alternative treatment providers (ATPs)) as well as their stocks and the quality of drugs sold by them, and the local production and distribution of antimalarials were investigated. Antimalarials were sold by the vast majority of ATPs, almost all the common antimalarials being available for sale. The practices and indications for sale, however, varied. Underdosing for malaria was frequent in all three provinces studied, and lack of knowledge of the appropriate regimen for cure was common among the drug-sellers. Samples of antimalarials were collected from ATP outlets in the three provinces, and the drugs were assessed for their contents and expiry date by the Institute of Drug Quality Control in Hanoi. Of the 218 samples of drugs examined by the Institute, over 96% met the quality requirements. However, a 10% sample of these drugs were independently assessed by WHO and revealed a different picture: 70% of them failed to meet the standard specifications required. There is therefore an urgent need to improve the capability and monitoring procedures of bodies involved in assessing and regulating drugs in Viet Nam.

Antimalarials↗
PubMed1989

Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 2. Stereospecificity of the ether side chain.

A new series of hydrolytically stable and water-soluble dihydroartemisinin derivatives with optically active side chains was prepared as potential antimalarial agents. This was an effort to prepare compounds with activity superior to that of artelinic acid and to examine the impact of the stereospecificity of the introduced alkyl side chain on biological properties. The ester derivatives (6a-d) possess superior in vitro activity to artemisinin, artemether, and arteether against two strains of Plasmodium falciparum (D-6 and W-2); however, conversion of the esters to their corresponding acids drastically reduces their antimalarial activity. None of the new acids possess in vitro antimalarial activity superior to that of artelinic acid. Although there appears to be limited stereospecificity for antimalarial activity among the acids (7a-d) tested, significant differences in antimalarial activity was seen among the esters.

Animals↗
PubMed1990

Parasite uptake of desferroxamine: a prerequisite for antimalarial activity.

Desferroxamine has been shown to exhibit potent antimalarial activity. However, it is unclear as to whether desferroxamine functions by the chelation of extracellular, intra-erythrocytic, or parasite-associated iron. In order to determine desferroxamine's site of action, we have employed a large molecular weight dextran derivative of desferroxamine (70 kDa) and a reversible osmotic lysis technique by which erythrocytes were intracellularly loaded with this chelator. The desferroxamine-dextran derivative has virtually identical iron-binding characteristics to desferroxamine but, unlike desferroxamine, it is unable to cross the erythrocyte membrane. As previously shown, desferroxamine added to culture media exhibited potent antimalarial activity (mean effective inhibitory dose (ED50) approximately 6 microM). However, extracellular desferroxamine-dextran showed antimalarial activity only at very high doses (ED50 greater than or equal to 180 microM), indicating that extracellular iron chelation is not involved in the antimalarial activity of desferroxamine. The intra-erythrocytic entrapment of the desferroxamine-dextran derivative also had no significant effect, except at very high concentrations, demonstrating that desferroxamine does not remove a non-haem iron source necessary for malarial replication. The results of this study clearly suggests that the antimalarial activity of desferroxamine is directly related to its ability to enter the parasitic compartment and not due to the chelation of extra- or intra-erythrocytic iron pools necessary for malarial growth.

Animals↗
PubMed2005

Antimalarial drugs: QT prolongation and cardiac arrhythmias.

Most available antimalarial drugs induce cardiac side effects. These side effects include various mild heart rate changes (amodiaquine) to excessive prolongation of the QT interval (halofantrine) which may lead to lethal arrhythmias such as Torsade de Pointes (TdP). The cellular mechanism of such events during antimalarial therapy is principally related to ion channel inhibition (e.g., human ether-a-go-go related gene channel) which may slow the repolarisation process and create a good substrate for arrhythmia (when dispersion of repolarisation is present). However, other antimalarial drugs do not show as potent cardiac side effects, like co-arthemeter and sulfadoxine-pyrimethamine. Considering that TdP are favoured by a complex combination of electrophysiological changes, a predictive cardiosafety strategy for new antimalarial drugs should comprise assays with an increasing level of information from ion channel level, cellular and organ level, to the whole organism. In this review, the actual knowledge on underlying mechanisms of QT prolongation and TdP is described, followed by the cardiac safety profiles of present antimalarial drugs.

Amodiaquine↗
PubMed1991

Antimalarial antibody in relation to seroreactivity for HIV infection in sera from blood donors.

A total of 74 specimens from blood donors showing evidence of HIV infection comprising of 40 positive by both ELISA and Western Blot (true positive), 16 positive by ELISA but negative by Western Blot (false positive) and 18 specimens positive by ELISA but showing indeterminate bands in Western Blot were screened for anti-malarial antibody. The prevalence of antimalarial antibody was noted as 62.5%, 56.3% and 66.6% respectively in these groups. None of these groups had any difference in the prevalence of antimalarial antibody with the group of 60 specimens negative for HIV infection by both ELISA as well as Western Blot (true negative) which had a prevalence of antimalarial antibody as 53.3%. The mean titre of antimalarial antibody in the above categories of specimens positive for HIV infection also did not show any difference with that of true negative group. These findings point out that antimalarial antibody does not influence the serological positivity for HIV infection.

Animals↗
PubMed1998

Antimalarial work in China: a historical perspective.

Systematic scientific studies of malaria in China did not begin until the 1920s. The persistence of misconceptions about the disease and the absence of political stability, funds and trained personnel were obstacles to any large scale antimalarial campaigns. In the 1920s and 30s, antimalarial efforts involved epidemiologic studies, environmental alterations, and treatment of patients. During the Sino-Japanese War when the Chinese government relocated inland, China's antimalarial work focused on the control of the disease, especially in the western and southwestern provinces. After the founding of the People's Republic of China in 1949, nationwide antimalarial campaigns were initiated and enforced by the central government which also promoted intersectoral and interregional cooperation. Together with the building of a preventive and anti-epidemic infrastructure and health care system as well as the training of personnel, the government used techniques of mass mobilization to launch programs of vector control and mass therapy. Provinces were also organized into antimalarial regional alliances to facilitate malaria control and surveillance.

China↗
PubMed2003

The efficacy of antimalarial monotherapies, sulphadoxine-pyrimethamine and amodiaquine in East Africa: implications for sub-regional policy.

Between 1998 and 2001, Kenya, Uganda, Tanzania, Zanzibar, Rwanda and Burundi changed antimalarial drug policy, in the face of widespread chloroquine resistance. The new first-line treatment is either sulphadoxine-pyrimethamine (SP) monotherapy, or a combination of SP with either chloroquine or amodiaquine. Two national malaria control programmes, Burundi and Zanzibar, have decided upon amodiaquine-artesunate as their first-line treatment, although SP will continue to fill this role until the new policy can be implemented. Given the broad uniformity of parasite chemoresistance in the six countries, The East African Network for Monitoring Antimalarial Treatment (EANMAT) has focused attention on, and worked towards, a sub-regional antimalarial drug policy, where the evidence base would be the entire portfolio of network in vivo test results. Currently, there are several different antimalarial drug policies within the EANMAT area: the intention is to eventually replace this plethora of policies with a single, sub-regional policy based upon combination therapy. Currently, successful malaria treatment depends primarily upon the efficacy of SP, and of amodiaquine, which is either a component of first-line treatment, or the second line drug. This report addresses the results of WHO in vivo tests on these two monotherapies within the network. Results are analysed to assess the evidence for change in parasite susceptibility over time; the range of susceptibility to each drug within countries, and the implications of test results on policy.

Africa, Eastern↗
PubMed2000

Antimalarial activity of four plants used in traditional medicine in Mali.

Mitragyna inermis (De Willd.) O. Kuntze Rubiaceae, Nauclea latifolia (Sm.) Rubiaceae, Glinus oppositofolius (Linn) Molluginaceae and Trichilia roka (Forsk.) Chiv. Meliaceae were investigated for their in vitro antimalarial activity. Leaves, roots and stem barks were submitted to aqueous, hydromethano and chloroform extractions and antimalarial activity was evaluated by microscopic and flow cytometric analysis. The results present evidence that the alkaloids contained in chloroform extracts and ursolic acid, purified from the hydromethanol extract of M. inermis induced a significant decrease of parasite proliferation. However, aqueous extracts, traditionally used for medication did not show high antimalarial activity. Statistical comparison between microscopic and cytometric analysis demonstrated the validity of this new technique for the screening of active antimalarial compounds isolated from plants.

Animals↗
PubMed2005

Antimalarial compounds from Kniphofia foliosa roots.

During the course of screening Ethiopian medicinal plants for their antimalarial properties, it was found that the dichloromethane extract of the roots of Kniphofia foliosa Hochst. (Asphodelaceae), which have long been used in the traditional medicine of Ethiopia for the treatment of abdominal cramps and wound healing, displayed strong in vitro antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum with an ED50 value of 3.8 microg/mL and weak cytotoxic activity against KB cells with an ED50 value of 35.2 microg/mL. Five compounds were isolated from the roots and evaluated for their in vitro antimalarial activity. Among the compounds tested, 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin, showed a high inhibition of the growth of the malaria parasite, P. falciparum with ED50 values of 0.260 and 0.537 microg/mL, respectively, while the naphthalene derivative, 2-acetyl-1-hydroxy-8-methoxy-3-methylnaphthalene, exhibited a less significant antimalarial activity with an ED50 value of 15.4 microg/mL. To compare the effect on the parasite with toxicity to mammalian cells, the cytotoxic activities of the isolated compounds against the KB cell line were evaluated and 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin displayed very low toxicity with ED50 values of 104 and 90 microg/mL, respectively. This is the first report of the inhibition of the growth of P. falciparum by anthraquinone-anthrone dimers and establishes them as a new class of potential antimalarial compounds with very little host cell toxicity.

Animals↗
PubMed1993

Antimalarial drugs inhibit calcium-dependent backward swimming and calcium currents in Paramecium calkinsi.

The antimalarial drugs, quinacrine, chloroquine, quinine, primaquine, and mefloquine, share structural similarities with W-7, a compound that inhibits calcium-dependent backward swimming and calcium currents in Paramecium. Therefore, we tested whether antimalarial drugs also inhibit backward swimming and calcium currents in P. calkinsi. When the Paramecium is depolarized in high potassium medium, voltage-dependent calcium channels in the ciliary membrane open causing the cell to swim backward for 30 to 70 s. Application of calcium channel inhibitors, such as W-7, reduce the duration of backward swimming. In 0.05 mM calcium, quinacrine, mefloquine, quinine, chloroquine, primaquine and W-7 all reduced the duration of backward swimming. These effects were seen in sodium-containing and sodium-free high potassium solutions as well as sodium-free depolarizing solutions containing potassium channel blockers. In these low calcium solutions, backward swimming was inhibited by 50% at concentrations ranging from 100 nM to 30 microM. At higher calcium concentrations (1 mM or 15 mM), the effects of the antimalarials and W-7 were reduced. The effects of quinacrine and W-7 were tested directly on calcium currents using the two microelectrode voltage clamp technique. In 15 mM calcium, 100 microM quinacrine and 100 microM W-7 reduced the peak calcium current by 51% and 42%, respectively. Thus, antimalarial drugs reduce calcium currents in Paramecium calkinsi.

Animals↗
PubMed1991

Studies on the antimalarial mode of action of quinoline-containing drugs: time-dependence and irreversibility of drug action, and interactions with compounds that alter the function of the parasite's food vacuole.

The quinoline-containing antimalarial drugs chloroquine, quinine and mefloquine exert an irreversible inhibitory effect on erythrocytic stages of Plasmodium falciparum grown in culture. Inhibition is time- and concentration-dependent and the full effect is observed after 2-6 hours of exposure to the drug. Washing of infected cells after drug exposure in the presence of NH4Cl to accelerate drug efflux, intensifies the inhibitory effect of chloroquine, probably due to the pH-dependent release of highly concentrated drug from the acidic food vacuole of the parasite. When both antimalarials and NH4Cl are present in the culture, drug effect is reduced, as expected from the demonstrable alkalinization of the food vacuole and the consequent reduction in drug accumulation. The protease inhibitor leupeptin inhibits digestion of ingested host cell cytosol, and thus inhibits parasite growth, though reversibly so (Rosenthal et al, J. Clin. Invest. 82 1560-1566 (1988)). Thus, although the antimalarials also inhibit the feeding process, this is not the cause of their irreversible action. Leupeptin is found to be antagonistic to antimalarials' action, suggesting that the drugs form complexes with products of host cell digestion that are responsible for irreversible inhibition of parasite growth.

Ammonium Chloride↗
PubMed1987

Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes.

Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic levels suppressed the lymphocytes' proliferation, but not their IL-2 production. All three quinolines suppressed the proliferation of lymphocytes, but not equally, with mefloquine having the strongest effect. Quinine suppressed the growth at therapeutic concentrations. The IL-2 production was suppressed at concentrations twice as high as those required to suppress lymphocyte proliferation. Addition of exogenous IL-2 only partially reversed the suppressive effect on lymphocyte proliferation. Delayed addition of the quinolines decreased their suppressive effect, but not completely. The mechanisms of action on human mononuclear cells of the various antimalarial drugs and the potential adverse effects of antimalarial chemotherapy are discussed.

Antimalarials↗