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PubMed2001

Mode of action and mechanisms of resistance for antimalarial drugs.

Understanding the mode of action of and mechanism of resistance to drugs is central to optimising their use, and discovering new therapeutics with novel targets. We have limited understanding of how antimalarial drugs work and how resistance emerges. With few exceptions, antimalarial drugs in current use belong to a limited collection of chemical structures that act on a small number of partially characterised biochemical targets. Resistance has emerged to many of these compounds. The use of closely related compounds has promoted the spread of multidrug resistant parasites. This review intends to collate contemporary knowledge, and also to highlight conflicting views on unresolved issues.

Animals↗
PubMedDate not supplied

Artemisinin and its derivatives: an important new class of antimalarial agents.

Artemisinin and its derivatives are a potent new class of antimalarials, originated from Artemisia annua, L. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitaemia. Their efficacy is high in such areas as well where multidrug-resistance is rampant, but in these areas, their combination with other (effective) antimalarials (e.g., mefloquine) is highly recommended. In this short review, the chemical structures, pharmacological properties, and clinical uses of artemisinin drugs are discussed.

Animals↗
PubMedDate not supplied

Antimalarial activity of synthetic analogues of distamycin.

Malaria, one of the most serious diseases transmitted by arthropods, is largely present in tropical and even temperate zones in endemic or epidemic form. More than 40% of the world's population lives in areas at risk for exposure, and the World Health Organization reports that approximately 300 million people are affected by the infection (mostly caused by the species Plasmodium falciparum), with 1-2 million deaths per year. These data, and the fact that malaria is becoming increasingly refractory to treatment through resistance of the parasite to antimalarial agents currently in use, e.g., chloroquine, emphasize the need to develop new drugs. The well-known antiparasitic activity of oligopyrrolamidine natural products, such as distamycin and netropsin, suggested the antimalarial evaluation of related compounds obtained by new chemical modifications. Besides possessing antiviral and antitumoural properties, distamycin exhibits interesting in vitro activity against P. falciparum. Unfortunately, the high toxicity associated with this product precludes its development as a drug. However, some synthetic analogues of distamycin proved to be highly active against chloroquine-sensitive and -resistant strains of P. falciparum, besides showing low toxicity in vitro.

Animals↗
PubMed2004

[Up-dated ophthalmological screening and follow-up management for long-term antimalarial treatment].

The early detection of macular toxicity linked to long-term antimalarial treatment requires regular ophthalmological screening based on patients'classification based on their results compared to successive controls. Patients are classified as "low risk" with screening every 18 months if all of the following criteria are met: age under 65 years, no associated renal, hepatic or retinal disease, treatment for less than 5 years, dose less than or equal to 6,5mg/kg/d for hydroxychloroquine and 3mg/kg/d for chloroquine (for a lean patient's weight); "at risk, without fundus findings" with screening every 12 months if one of the following criteria is met: age over 65 years (at the start of or during treatment), antimalarial treatment for more than 5 years, daily dose higher than recommended, presence of renal and/or hepatic disease; "at risk, with fundus findings" with screening every 6 months if a retinal dysfunction has been detected and even if treatment is established or followed. Screening consists of an in-depth clinical examination and at least two complementary tests of macular function: color vision (desaturated-Panel-D15 test) and/or static macular perimetry (central 10 degrees) and/or macular electroretinography (pattern ERG/multifocal ERG). If any changes or anomalies are found between two successive check-ups, the state of the retina can be assessed by angiography and global retinal function by full-field-ERG and electro-oculogram (EOG). The progression from one check-up to the next decides whether a course of treatment will be followed.

Antimalarials↗
PubMedDate not supplied

The future outlook of antimalarial drugs and recent work on the treatment of malaria.

With the emergence of multidrug-resistant falciparum malaria, new drugs and drugs in combination are urgently needed. New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand in recent years for treatment of uncomplicated and severe falciparum malaria are as follows: atovaquone, and artemisinin derivatives (artesunate, artemether, arteether, and dihydroartemisinin) combined with other antimalarials.Malarone, artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline have been evaluated with improvement of the cure rate in uncomplicated malaria. Artemisinin derivatives intravenously or intrarectally combined with mefloquine may be alternatives to intravenous quinine for treatment of severe malaria. In Thailand, drug treatment for uncomplicated malaria consists of the combinations or artesunate plus mefloquine or artemether plus lumefantrine or quinine plus tetracycline. In treatment of severe malaria, antimalarial drugs of choice are intravenous quinine or artemisinin derivatives.

Animals↗
PubMed1999

Antimalarial drugs modulate the expression of monocyte receptors.

The cytoadherence of four Plasmodium falciparum malaria isolates (FCR-3, RSA-14, 15 and 17) to monocytes was used as a measure of the expression of monocyte receptors after the monocytes had been exposed to seven antimalarial drugs. Quinine, chloroquine, primaquine, pyrimethamine, artemesinin, mefloquine and proguanil all down-regulated the expression of monocyte receptors by 40% or greater at the therapeutic concentrations of each drug. Each malaria isolate had a unique adherence profile for drug induced changes in monocytes. Each drug appeared to alter the expression of more than one monocyte receptor. The most effective drugs were quinine, pyrimethamine and palludrin and the least effective were artemether and mefloquine. The results suggest a previously undetected immunomodulatory action of antimalarial drugs.

Animals↗
PubMed2001

Synthesis of quinolinyl chalcones and evaluation of their antimalarial activity.

Quinolinyl chalcones were synthesized and evaluated for their inhibition of the Plasmodium falciparum cystein protease falcipain and their activity against cultured P. falciparum parasites. They were also tested for in vivo efficacy in a rodent P. berghei model. Their activity against falcipain and as antimalarials was moderate, but antimalarial activity was probably not due to the inhibition of falcipain and may follow a different mechanism. 1-(2,4-Dichlorophenyl)-3-[3-(2-chloro-6,7-dimethoxiquinolinyl)]-2-propen-1-one 3j was the most promising compound among those here reported (IC50 19.0 microM).

Animals↗
PubMed1998

Antimalarial drugs inhibit phospholipase A2 activation and induction of interleukin 1beta and tumor necrosis factor alpha in macrophages: implications for their mode of action in rheumatoid arthritis.

1. The effects of antimalarial drugs on the intracellular signaling leading to activation of the phospholipase C and phospholipase A2 pathways and the induction of proinflammatory cytokines have been studied in mouse macrophages. 2. Both chloroquine and quinacrine, and to a lesser extent hydroxychloroquine, inhibited arachidonate release and eicosanoid formation induced by phorbol diester. This inhibition was due to that of the activation of the arachidonate-mobilizing phospholipase A2. 3. All three antimalarials potently inhibited arachidonate release induced by zymosan. They also inhibited the zymosan-induced formation of inositol phosphates, which hints that an inhibitory effect at the phospholipase C level might explain the inhibition of the response to zymosan. 4. Quinacrine, and to a lesser extent chloroquine, has an inhibitory effect on the lipopolysaccharide- or zymosan-induced expression of interleukin 1beta and tumor necrosis factor alpha, both at the mRNA and protein levels. This, in particular, has important implications for the mode of action of these compounds in rheumatoid arthritis.

Animals↗
PubMed1988

Rapid and sensitive quantitative analysis of the new antimalarial N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8- quinolinyl]-1,4-pentanediamine in plasma by liquid chromatography and electrochemical detection.

A rapid, sensitive and simple method was developed for the quantitation of the plasma concentration of N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8- quinolinyl]-1,4-pentanediamine, a new antimalarial active against Plasmodium vivax. N4-(5-Hexoxy-6-methoxy-4-methyl-8-quinolinyl)-1,4- pentanediamine diphosphate, a similar 8-aminoquinoline, was used as an internal standard. The method involves sample clean-up by a prepacked cyano solid-phase column followed by reversed-phase liquid chromatography and oxidative electrochemical detection at +0.95 V. The assay has been validated to 5 ng/ml of plasma and is sensitive to 1 ng/ml of plasma. The results of a pilot study assessing the relative oral bioavailability of two different salt forms of the new antimalarial in dogs show the usefulness of the method for animal and human pharmacokinetic studies.

Aminoquinolines↗
PubMed2003

Antimalarial activity of Cinchona-like plants used to treat fever and malaria in Brazil.

For centuries, malaria was treated with the bark of Cinchona calisaya and Cinchona succirubra plants named "quinas" in Brazil, from which the quinine molecule was isolated. Other plant species known also as "quinas" are used to treat fever and malaria, like Deianira erubescens (roots and leaves), Strychnos pseudoquina (bark), and Remijia ferruginea (bark). Based on this popular knowledge, we evaluated the in vivo antimalarial activity of the ethanol crude extracts of these plant species in mice infected with Plasmodium berghei. Only Remijia ferruginea showed antimalarial activity, reducing parasitaemia and mortality at the highest dose tested. Its phytochemical analysis showed the presence of alkaloids but not quinine. The other two plant species were inactive.

Animals↗
PubMed1999

Antimalarial activity of extracts of Malaysian medicinal plants.

In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species.

Animals↗
PubMed2000

A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part III. Evaluation Of the antimalarial activity of plants used by Alteños Indians.

A total of 40 plant extracts traditionally used by the Alteños Indians, a native community living between the Andean block and the tropical valleys of Bolivia, were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant (Indo) strain, and in vivo on rodent malaria Plasmodium vinckei petteri. Eleven extracts displayed good or moderate activity in vivo, and ten extracts good or very good antimalarial activity in vitro. Results of the screening are discussed here, in relation with the traditional use of plants.

Antimalarials↗
PubMed2000

Effect of three structurally related antimalarial drugs on liver microsomal components and lipid peroxidation in rats.

Changes in microsomal drug oxidizing enzymes, microsomal lipids, hepatic glutathione (GSH), glutathione S-trans-ferase (GST) and malondialdehyde (MDA) formation following administration of rats with therapeutic doses of three structurally related antimalarial drugs, amodiaquine (AQ), mefloquine (MQ) and halofantrine (HF) were investigated. There was a significant decrease in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase in AQ, MQ and HF treated rats. AQ elicited the greatest effect with 50, 37 and 67% reductions in the activities of aniline hydroxylase, p-nitroanisole O-demethylase and pentoxyresorufin O-dealkylase, respectively. All the drugs prolonged hexobarbital-sleeping time to varying extents. The three drugs increased significantly the cholesterol per phospholipid ratio. AQ, MQ and HF decreased significantly the GSH level, GST activity and increased the formation of MDA. The results indicate that the alterations in hepatic microsomal components and lipid peroxidation caused by the antimalarials are related to the structural differences in the compounds.

Amodiaquine↗
PubMed2001

Antimalarial t-butylperoxyamines.

Twelve t-butylperoxyamines (6-17) were synthesized as targeted antimalarials and evaluated for antimalarial activity in vivo against Plasmodium berghei in mice and in vitro against both chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum. Compound 8 was found to have highest potency with activity at 80 and 160mg/kg dose in vivo and compound 11 exhibited highest efficacy in vitro.

Animals↗
PubMed2002

In vivo active antimalarial isonitriles.

Building on the lead from antimalarial isonitriles 1-4 of marine origin, several easily accessible synthetic isonitriles were assessed for their antimalarial activity against Plasmodium falciparum (in vitro) and multidrug resistant Plasmodium yoelii in Swiss mice model (in vivo). Isonitrile 11 has shown promising activity in both these assays.

Animals↗
PubMed2003

Design, synthesis and antimalarial activity of novel, quinoline-based, zinc metallo-aminopeptidase inhibitors.

PfA-M1, a neutral zinc aminopeptidase of Plasmodium falciparum, is a new potential target for the discovery of antimalarials. The design and synthesis of a library of 45 quinoline-based inhibitors of PfA-M1 is reported. The best inhibitor displays an IC(50) of 854 nM. The antimalarial activity on a CQ-resistant strain and the specificity towards mammalian aminopeptidase N are also discussed.

Aminopeptidases↗
PubMed2000

Antimalarial sulfide, sulfone, and sulfonamide trioxanes.

A series of trioxanes featuring sulfide, sulfone, and sulfonamide substituents in diverse positions has been prepared. Structure-activity relationship (SAR) generalizations highlight two major factors controlling the antimalarial potency of these new chemical entities: (1) the proximity of the sulfur-containing substituent to the crucial peroxide bond and (2) the oxidation state of the sulfur-containing substituent. Generally, sulfones are more antimalarially potent than the corresponding sulfides.

Antimalarials↗
PubMed2001

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents.

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Alkaloids↗