Antimalarial chemoprophylaxis in infants and children

The evolving patterns of drug resistance in malaria parasites and changes in recommendations for malaria prevention present a challenge to physicians who advise travellers on chemoprophylaxis. Because compliance with personal protection measures is usually low, children should receive appropriate chemoprophylaxis, including breast-fed infants who are not protected through maternal chemoprophylaxis. For travel to areas where chloroquine resistance has not yet been reported (i.e. parts of Central America, the Caribbean and parts of the Middle East), chloroquine alone is sufficient for antimalarial prophylaxis. Mefloquine is the drug of choice for chemoprophylaxis in areas with chloroquine-resistant Plasmodium falciparum, and can be given to infants and young children. The combination of chloroquine and proguanil is well tolerated in children but is much less effective against drug-resistant malaria. Further research is needed to determine the best dosage regimen for antimalarial drugs used for chemoprophylaxis in children.     

Inhibition of efflux of quinolines as new therapeutic strategy in malaria

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.     

Quinine: the rediscovered anti-malarial agent.

This work summarises the clinical pharmacology of quinine, a cinchona alkaloid, whose use in chloroquine resistant Plasmodium falciparum malaria is of great value considering the staggering effects the infection and its morbidity have upon social and economic development of malaria endemic areas of the world. Quinine is very effective and consistent in the treatment of falciparum malaria at all grades of severity. The effectiveness of quinine in severe malaria can be maintained and the possibility of development of resistant strains to the drug reduced by combined therapy with other drugs to which the infecting strains of P. falciparum are still sensitive.     

Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria.

Patients with falciparum malaria were studied in Thailand, an area of known chloroquine resistance. The patients were unselected and some had severe malaria, and they were randomly assigned to one of two sequential regimes. A short course of quinine (average 4 doses, equivalent to 2 g base) followed by a single dose of pyrimethamine-sulfadoxine (Fansidar) cured 92% of patients (36 out of 39), while a short course of quinine followed by a single 1-5-dose of mefloquine cured all of the 35 patients who could be followed up. Gastrointestinal side effects were minimal if at least 12 hours elapsed between the last dose of quinine and the mefloquine. Sequential quinine and mefloquine is the most effective treatment for patients with chloroquine-resistant falciparum malaria, including those with severe or complicated disease. Mefloquine, however, is not commercially available, and the similar regimen using Fansidar is almost as effective.     

Arylpiperazines displaying preferential potency against chloroquine-resistant strains of the malaria parasite Plasmodium falciparum

Arylpiperazines in which the terminal secondary amino group is unsubstituted were found to display a mefloquine-type antimalarial behavior in being significantly more potent against the chloroquine-resistant (W2 and FCR3) strains of Plasmodium falciparum than against the chloroquine-sensitive (D10 and NF54) strains. Substitution of the aforementioned amino group led to a dramatic drop in activity across all strains as well as abolition of the preferential potency against resistant strains that was observed for the unsubstituted counterparts. The data suggest that unsubstituted arylpiperazines are not well-recognized by the chloroquine resistance mechanism and may imply that they act mechanistically differently from chloroquine. On the other hand, 4-aminoquinoline-based heteroarylpiperazines in which the terminal secondary amino group is also unsubstituted, were found to be equally active against the chloroquine-resistant and chloroquine-sensitive strains, suggesting that chloroquine cross-resistance is not observed with these two 4-aminoquinolines. In contrast, two 4-aminoquinoline-based heteroarylpiperazines are positively recognized by the chloroquine resistance mechanism. These studies provide structural features that determine the antimalarial activity of arylpiperazines for further development, particularly against chloroquine-resistant strains.     

Treatment of malaria--1990

Malaria has become an increasingly common health problem in the 1970s and 1980s, both in areas where infection is endemic and in travellers returning to non-endemic areas. The severity of infection varies widely, depending on the plasmodial species involved, and there is an extensive chemotherapeutic armamentarium currently available to combat malarial infection. Drug chemistry, pharmacokinetics, mechanism of drug action and resistance, and toxicities are outlined for the cinchona alkaloids (quinine and quinidine), chloroquine, amodiaquine, pyrimethamine, the sulphonamides, pyrimethamine/sulfadoxine, mefloquine, pyrimethamine/sulfadoxine/mefloquine, the sesquiterpene lactones, primaquine, and other drugs. A knowledge of the distribution of drug resistance is vital for the provision of effective antimalarial therapy, and current information in this area is outlined. Chloroquine remains the mainstay of treatment for the erythrocytic stages of Plasmodium vivax, P. ovale, P. malariae, and chloroquine-sensitive P. falciparum malaria. The dormant hepatic stages of P. vivax and P. ovale also require further treatment with primaquine. Quinine, alone or in combination with other drugs, is the primary agent used to treat chloroquine-resistant falciparum malaria. Falciparum infection can rapidly become fatal, therefore its complications of multiple organ failure, heavy parasitaemias, cerebral malaria, and hypoglycaemia must be recognised and managed promptly. Because these protozoal parasitic infections are now encountered throughout the world and can become life-threatening, a wide variety of practitioners must become more familiar with their correct treatment.     

Ineffectiveness of continuous quinidine gluconate infusion in the treatment of severe chloroquine-resistant Plasmodium falciparum malaria

The drug of choice in the treatment of chloroquine-resistant Plasmodium falciparum malaria is parenteral quinine dihydrochloride. Due to limited use, the drug is not commercially available in the U.S. and must be obtained through the Centers for Disease Control (CDC) in Atlanta, Georgia. As an alternative, the CDC has developed a protocol to treat P. falciparum malaria with parenteral quinidine gluconate. Following this protocol, a 10 mg/kg loading dose of quinidine gluconate followed by a 0.02 mg/kg/min continuous infusion was administered to a 53-year-old man with severe life-threatening chloroquine-resistant P. falciparum malaria. Although the patient described did not survive, the use of parenteral quinidine gluconate still appears to be a viable alternative to parenteral quinine dihydrochloride in the treatment of severe chloroquine-resistant P. falciparum malaria.     

Recent patent reviews on small molecule-based antimalarial drugs

Malaria is the number one disease in the world responsible for 1-3 million deaths each year. The world wide number of malaria patients is estimated at 400 to 900 million. Approximately one third of the world's population lives in malaria-endemic areas, including Central and South America, Asia, and Africa. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae are malaria parasites responsible for infecting humans. Mosquitoes that carry malaria parasites have become resistant to insecticides, and the deadliest parasites have become resistant to previously effective antimalarial drugs such as chloroquine, quinine and other clinically used agents. Because of the widespread incidence of malaria in certain parts of the world and because of the increasing parasite resistance to standard anti-malarial agents, there is an urgent need for introducing new effective drugs. This review presents the recent patents that reveal development of novel antimalarial drugs.     

Artemisinin drugs: novel antimalarial agents

Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum. Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined. In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance. In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use. The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease. All of the artemisinin drugs have comparable efficacy; the choice of derivative should be based upon availability, cost and quality of the preparation. Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity.     

Artemisinin drugs: novel antimalarial agents

Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum. Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined. In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance. In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use. The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease. All of the artemisinin drugs have comparable efficacy; the choice of derivative should be based upon availability, cost and quality of the preparation. Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity.     

Primaquine synergises the activity of chloroquine against chloroquine-resistant P. falciparum

In recent years, resistance to the antimalarial drug, chloroquine, has become widespread. It is, therefore, imperative to find compounds that could replace chloroquine or work synergistically with this drug to overcome chloroquine resistance. We have examined the interaction between chloroquine, a 4-aminoquinoline, and a number of 8-aminoquinolines, including primaquine, a drug that is widely used to treat Plasmodium vivax infections. We find that primaquine is a potent synergiser of the activity of chloroquine against chloroquine-resistant Plasmodium falciparum. Analysis of matched transfectants expressing mutant and wild-type alleles of the P. falciparum chloroquine resistance transporter (PfCRT) indicate that primaquine exerts its activity by blocking PfCRT, and thus enhancing chloroquine accumulation. Our data suggest that a novel formulation of two antimalarial drugs already licensed for use in humans could be used to treat chloroquine-resistant parasites.     

Novel phenothiazine antimalarials: synthesis, antimalarial activity, and inhibition of the formation of beta-haematin

We report the synthesis of a series of novel phenothiazine compounds that inhibit the growth of both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. We found that the antimalarial activity of these phenothiazines increased with an increase in the number of basic groups in the alkylamino side chain, which may reflect increased uptake into the parasite food vacuole or differences in the toxicities of individual FP-drug complexes. We have examined the ability of the parent phenothiazine, chlorpromazine, and some novel phenothiazines to inhibit the formation of beta-haematin. The degree of antimalarial potency was loosely correlated with the efficacy of inhibition of beta-haematin formation, suggesting that these phenothiazines exert their antimalarial activities in a manner similar to that of chloroquine, i.e. by antagonizing the sequestration of toxic haem (ferriprotoporphyrin IX) moieties within the malaria parasite. Chlorpromazine is an effective modulator of chloroquine resistance; however, the more potent phenothiazine derivatives were more active against chloroquine-sensitive parasites than against chloroquine-resistant parasites and showed little synergy of action when used in combination with chloroquine. These studies point to structural features that may determine the antimalarial activity and resistance modulating potential of weakly basic amphipaths.     

Pharmacodynamics of antimalarial chemotherapy

Malaria chemotherapy is under constant threat from the emergence and spread of multidrug resistance of Plasmodium falciparum. Resistance has been observed to almost all currently used antimalarials. Some drugs are also limited by toxicity. A fundamental component of the strategy for malaria chemotherapy is based on prompt, effective and safe antimalarial drugs. To counter the threat of resistance of P. falciparum to existing monotherapeutic regimens, current malaria treatment is based principally on the artemisinin group of compounds, either as monotherapy or artemisinin-based combination therapies for treatment of both uncomplicated and severe falciparum malaria. Key advantages of artemisinins over the conventional antimalarials include their rapid and potent action, with good tolerability profiles. Their action also covers transmissible gametocytes, resulting in decreased disease transmission. Up to now there has been no prominent report of drug resistance to this group of compounds. Treatment of malaria in pregnant women requires special attention in light of limited treatment options caused by potential teratogenicity coupled with a paucity of safety data for the mother and fetus. Treatment of other malaria species is less problematic and chloroquine is still the drug of choice, although resistance of P. vivax to chloroquine has been reported. Multiple approaches to the identification of new antimalarial targets and promising antimalarial drugs are being pursued in order to cope with drug resistance.     

Prevention of malaria

With the increased spread of chloroquine-resistant Plasmodium falciparum malaria and mounting evidence of lack of efficacy and toxicity of alternative drugs, it has become extremely difficult to propose simple, widely applicable and uniformly acceptable recommendations for malaria chemoprophylaxis. With regard to specific drugs, it is clear that because of its toxicity amodiaquine should no longer be used for chemoprophylaxis, and that pyrimethamine/sulfadoxine should, for the most part, be used only as a presumptive therapy. The pyrimethamine/dapsone combination is promising, but data on its efficacy are limited. Although proguanil (chloroguanide) is recommended by several sources because of its safety, disturbing reports of chemoprophylaxis failure in Africa and a well-documented lack of efficacy in South East Asia would suggest that its usefulness may be limited. However, a recent study has documented the efficacy of a proguanil-sulphonamide combination in Thailand, an area of high grade chloroquine resistance. Although long term studies of drug safety are not yet available, doxycycline and mefloquine appear to be the drugs of choice in areas where P. falciparum shows multidrug resistance. Regardless of the drug regimen recommended for chemoprophylaxis, travellers must be informed that no present-day antimalarial agent guarantees protection against malaria.     

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

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

Differential effects of 4-aminoquinoline-containing antimalarial drugs on hemoglobin digestion in Plasmodium falciparum-infected erythrocytes

Several reports suggest that the antimalarial mode of action of quinoline drugs may differ in their mechanistic details. The malaria parasite Plasmodium falciparum was treated in culture with chloroquine, amodiaquine, quinine and mefloquine in a dose- and time-dependent fashion. After removal of the drug, the viability of the parasites and their hemoglobin content were determined. Whereas in the presence of chloroquine and amodiaquine, there was a correlation between parasite killing and accumulation of hemoglobin, with quinine and mefloquine parasite killing was not associated with the accumulation of hemoglobin. Mefloquine inhibited the chloroquine-dependent accumulation of hemoglobin. It is suggested that whereas chloroquine and amodiaquine inhibit the digestion of hemoglobin, mefloquine and possibly quinine inhibit the ingestion of host cell hemoglobin by interfering with the ingestion process. These results may explain the demonstrable antagonism between chloroquine and mefloquine and their antipodal sensitivity to these drugs.     

Chemosensitivity of Plasmodium falciparum in Sainte Marie island,east coast of Madagascar: in vivo and in vitro studies

In order to document the evolution of the chemoresistance of Plasmodium falciparum to chloroquine in Madagascar, a study was carried out in Sainte-Marie island located at 6 km on the eastern border of the country. Symptomatic malaria patients who satisfied criteria for resistance testing, were recruited by a process of passive case detection at two clinics. These patients were enrolled in a sensitivity 14-day in vivo test for uncomplicated P. falciparum malaria attacks. All subjects received a supervised therapeutic regimen of chloroquine (25 mg base/kg over 3 days). Parasitemia and symptoms were monitored for 14 days. 62 (93.9%) out of the 66 enrolled patients completed the 14-day follow-up. A total of 50 of 62 patients (80.6%) presented an adequate clinical response. Early and late treatment failures were observed in 3 (4.8%) and 9 (14.5%) patients respectively. Failure therapeutic treatments treated with sulfadoxine-pyrimethamine were successful. Chloroquine remains effective in the treatment of malaria due to P. falciparum and therefore its choice as a first line drug remains justified. Likewise, guidelines for the use of sulfadoxine-pyrimethamine as second line drug are adequate. In vitro, 4 resistances out of 27 successful tests to chloroquine (14.8%) and 1 resistance out of 25 successful tests to mefloquine (4%) were recorded. No resistance to quinine nor to amodiaquine were noticed. Alternative antimalarial drugs such as quinine, amodiaquine or mefloquine can be used in patients for whom the treatment with chloroquine is not possible. Nevertheless, the level of therapeutic failures to chloroquine detected in this study highlights the need and importance of drug sensitivity test for the development of a rational national antimalarial drug policy.     

Metallocenes and malaria: a new therapeutic approach

Rapid development of significant resistance to antimalarial drugs has been a major force driving research to identify and develop new compounds. The use of synthetic organometallic complexes seems to be promising for treatment of malaria infections. Recent progress in identification and development of new drugs promises to lead to a much greater range of antimalarial agents. Organometallic complexes and metalloporphyrins have shown in vitro activity against Plasmodium falciparum. Ferroquine (ferrocenyl chloroquine) is more active than chloroquine against strains and isolates of P. falciparum and shows efficacy against murine parasites.     

Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential.

Halofantrine is an orally administered blood schizontocide which is active against both chloroquine-sensitive and chloroquine-resistant plasmodia. Dose-finding and noncomparative clinical trials have confirmed the efficacy of halofantrine in the treatment of falciparum malaria in areas of chloroquine- and sulfonamide/pyrimethamine-resistant malaria and vivax malaria. However, poor results obtained in patients who failed mefloquine prophylaxis suggest that the efficacy of halofantrine may not extend to mefloquine-resistant P. falciparum, although more studies are needed to confirm this. Data concerning halofantrine in the treatment of P. ovale and P. malariae infections are still limited. One comparative study indicates that halofantrine has an efficacy equivalent to that of mefloquine and may be better tolerated. Halofantrine is generally well tolerated in both adults and children, the most common drug-associated effects being abdominal pain, pruritus, vomiting, diarrhoea, headache and rash, although it is difficult to distinguish between disease- and treatment-related events. The development of parasite resistance to halofantrine, like other blood schizontocides, is inevitable. Poor absorption resulting in variable peak plasma halofantrine concentrations, and possible cross-resistance with mefloquine, may accelerate the emergence of resistance to halofantrine. Thus, it is of primary importance that halofantrine is used only in areas where chloroquine- and sulfonamide/pyrimethamine-resistance are established in order to preserve and sustain its efficacy. If used with care, halofantrine will provide an important treatment option for falciparum malaria, a widespread parasitic disease associated with considerable morbidity against which the number of effective drugs available is being increasingly compromised by the spread of resistance.     

Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

Malagashanine (MG) is the parent compound of a new type of indole alkaloids, the N(b)C(21)-secocuran, isolated so far from the Malagasy Strychnos species traditionally used as chloroquine adjuvants in the treatment of chronic malaria. Previously, it was shown to have weak in vitro intrinsic antiplasmodial activity (IC(50) = 146.5 +/- 0.2 microM), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant strain of Plasmodium falciparum. The purpose of the present study was to further investigate its reversal activity. Thus, the previous in vitro results were tested in vivo. The interaction of MG with several antimalarials against various strains of P. falciparum was also assessed. As expected, MG enhanced the effect of chloroquine against the resistant strain W2, but had no action on the susceptible strain 3D7 and two sensitive isolates. Interestingly, MG was found to exhibit significant chloroquine-potentiating action against the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant result that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoacridines (quinacrine and pyronaridine), and a structurally unrelated drug (halofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chloroquine on the old trophozoite stage of the P. falciparum cycle. Similarities and differences between verapamil and MG reversal activity are briefly presented.