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PubMed2006

Influence of the Plasmodium falciparum P-glycoprotein homologue 1 (pfmdr1 gene product) on the antimalarial action of cyclosporin.

BACKGROUND AND OBJECTIVES: The immunosuppressant cyclosporin A and a number of other cyclosporins have potent and selective antimalarial activity. Their exact mechanism of antimalarial action is unknown but the structure-activity relationships for malarial parasite inhibition and immunosuppression differ markedly. The 3'-keto derivative of cyclosporin D (valspodar) is particularly potent against the human malarial parasite Plasmodium falciparum in culture but causes negligible immunosuppression. Multidrug resistance in mammalian cancer cells, the result of overproduction of the P-glycoprotein, can be reversed by certain cyclosporins, particularly valspodar. We therefore investigated the possibility that the antimalarial target of cyclosporin might be a P-glycoprotein homologue. P. falciparum P-glycoprotein homologue 1 (Pgh1; the pfmdr1 gene product) is located in the digestive vacuole (DV) membrane of the parasite. Its function is unknown but it modulates the susceptibility of parasites to quinolines and related antimalarial drugs, including quinine, mefloquine, halofantrine and chloroquine, and to artemisinin. METHODS AND RESULTS: Here we demonstrate that (i) sequence polymorphisms in pfmdr1 altered the susceptibility of parasites to cyclosporin A and (ii) pfmdr1-overexpressing strains were slightly less susceptible to the drug. Furthermore, we found synergistic antimalarial interactions between cyclosporin A and quinine, mefloquine or halofantrine and antagonism between cyclosporin A and chloroquine. However, we were unable to detect a direct interaction between cyclosporin and Pgh1. CONCLUSIONS: The amino acid sequence and copy number of Pgh1 may influence cyclosporin susceptibility as a result of a direct interaction between the drug and the protein, or via indirect effects on the physiology of the DV.

Animals↗
PubMed2006

Utility of alkylaminoquinolinyl methanols as new antimalarial drugs.

Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.

3T3 Cells↗
PubMed1998

Effect of disposition of mannich antimalarial agents on their pharmacology and toxicology.

The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5' position of amodiaquine reduced or eliminated bioactivation, as determined by glutathione conjugate formation in vivo. This can be seen in two series of C-5'-substituted compounds: the bis-Mannich antimalarial agents, including cycloquine and pyronaridine, and mono-Mannich antimalarial agents containing a 5'-chlorophenyl group (tebuquine and 5'-ClPAQ). Chemical substitution at the C-5' position also resulted in compounds which underwent slower elimination (<5% of the dose excreted into bile and urine, compared with 50% for amodiaquine) and increased levels of accumulation in tissue (10% of the dose in the liver at 48 h compared with 1% with amodiaquine). This may be due to an increase in either the lipophilicity or the basicity of the analogs and may reflect the lack of metabolic clearance for these compounds. The alteration in the disposition following the introduction of the C-5' substituent resulted in an increased duration of antimalarial activity in the mouse compared with that for amodiaquine. While this is desirable in the treatment of malaria, repeated administration for prophylaxis may induce toxicity through accumulation. Therefore, by simple chemical modification it is possible to block the bioactivation of amodiaquine while maintaining and in some cases extending the duration of antimalarial activity.

Adult↗
PubMed2000

Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria.

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < or = 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.

Administration, Oral↗
PubMed2006

Potential new antimalarial chemotherapeutics based on sphingolipid metabolism.

The discovery of new antimalarial drugs is mandatory to improve the effectiveness of antimalarial prophylaxis and treatment. In this review, we focused on sphingolipids as potential new targets for antimalarial drugs. Inhibition of sphingomyelin and/or glucosylceramide synthases leads to increased intracellular concentrations of ceramide and results in growth inhibition of Plasmodium falciparum. In mammalian cells, ceramide mediates death by chemotherapeutic drugs. We demonstrated that ceramide mediates the antimalarial effect of artemisinin and mefloquine by depletion of glutathione levels. Furthermore, ceramide and artemisinin activated p38 mitogen-activated protein kinase in P. falciparum, thus inhibiting its growth, apparently by a non-apoptotic mechanism. In summary, we propose novel options of antimalarials based on ceramide cytotoxic activity.

Animals↗
PubMed2006

Pharmacovigilance of antimalarial treatment in Africa: is it possible?

Pharmacovigilance, defined as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug related problem", is increasingly being recognized in Africa. Many African countries have simultaneously adopted artemisinin derivative based combination therapy (ACT) as first-line treatment for uncomplicated malaria, offering an opportunity to assess the safety of these drugs when used widely. While ACTs appear to be safe and well-tolerated, there is little experience with these medicines in Africa, outside clinical trials. Pharmacovigilance for ACTs and other combination treatments in Africa is essential. Malaria transmission intensity is high and antimalarial medicines are used frequently. Presumptive treatment of fever with antimalarials is common, often in the absence of a confirmed diagnosis, using drugs obtained without a prescription. Informal use of antimalarial drugs may increase the risk of incorrect dosing, inappropriate treatment, and drug interactions, which may impact negatively on drug safety. Furthermore, the administration of antimalarial treatments in patients with a concomitant illness, including HIV/AIDs, tuberculosis and malnutrition, is a concern. African countries are being encouraged to establish pharmacovigilance systems as ACTs are rolled out. However, pharmacovigilance is difficult, even in countries with a well-developed health care system. The rationale for pharmacovigilance of antimalarial drugs is discussed here, outlining the practical challenges and proposing approaches that could be adopted in Africa.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Monitoring antimalarial drug resistance: making the most of the tools at hand.

Most countries in resource-poor, malaria-endemic areas lack current and comprehensive information on antimalarial drug efficacy, resulting in sub-optimal antimalarial treatment policies. Many African countries continue to use chloroquine despite very high rates of resistance, and others have changed policies based on limited data, with mixed success. Methods for measuring antimalarial drug efficacy and resistance include in vivo studies of clinical efficacy and parasitological resistance, in vitro susceptibility assays and molecular markers for resistance to some drugs. These methods have the potential to be used in an integrated fashion to provide timely information that is useful to policy makers, and the combined use of in vivo and molecular surveys could greatly extend the coverage of resistance monitoring. Malawi, the first African country to change from chloroquine to sulfadoxine/pyrimethamine at the national level, serves as a case study for resistance monitoring and evidence-based antimalarial policies. Molecular, in vitro and in vivo studies demonstrate that chloroquine-sensitive parasites reemerged and now predominate in Malawi after it switched from chloroquine to sulfadoxine/pyrimethamine. This raises the intriguing possibility of rotating antimalarial drugs.

Animals↗
PubMed1994

Specific inhibition of cyclic AMP-dependent protein kinase by the antimalarial halofantrine and by related phenanthrenes.

The phenanthrenemethanol antimalarial halofantrine is a potent inhibitor of bovine heart and rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) (IC50 values 2.1 microM and 0.6 microM, respectively). The inhibition of rat liver cAK by halofantrine is non-competitive with respect to both ATP and to the synthetic peptide substrate employed (LRRASLG). Halofantrine is a poor inhibitor of calmodulin-dependent myosin light chain kinase (MLCK) and wheat embryo Ca(2+)-dependent protein kinase (CDPK) and does not inhibit rat brain Ca(2+)- and phospholipid-dependent protein kinase C (PKC). In contrast, the acridine-based antimalarial quinacrine and a variety of quinoline-based antimalarials are very poor inhibitors of cAK, the best inhibitor being chloroquine (IC50 for bovine heart cAK, 80 microM). Quinacrine and the quinoline-based antimalarials variously inhibit CDPK, PKC and MLCK albeit at relatively high concentrations (about 1 to 4 x 10(-4) M), the best inhibitors found being primaquine, pentaquine and mefloquine (IC50 values for MLCK 49, 103 and 33 microM, respectively). A number of phenanthrene derivatives having a 9-hydroxy or 9-keto substituent, namely phenanthrenequinone, 6(5H)-phenanthridinone and 9-phenanthrol are potent inhibitors of bovine heart cAK (IC50 values 8, 10 and 10 microM, respectively) and of MLCK (IC50 values 6, 53 and 10 microM, respectively). The selective, high affinity interaction of halofantrine with cAK may contribute to biological effects in vivo of this clinically-employed antimalarial compound.

Amino Acid Sequence↗
PubMed2001

Pharmacokinetic interactions of antimalarial agents.

Combination of antimalarial agents has been introduced as a response to widespread drug resistance. The higher number of mutations required to express complete resistance against combinations may retard the further development of resistance. Combination of drugs, especially with the artemisinin drugs, may also offer complete and rapid eradication of the parasite load in symptomatic patients and thus reduce the chance of survival of resistant strains. The advantages of combination therapy should be balanced against the increased chance of drug interactions. During the last decade, much of the pharmacokinetics and metabolic pathways of antimalarial drugs have been elucidated, including the role of the cytochrome P450 (CYP) enzyme complex. Change in protein binding is not a significant cause of interactions between antimalarial agents. CYP3A4 and CYP2C19 are frequently involved in the metabolism of antimalarial agents. Quinidine is a potent inhibitor of CYP2D6, but it appears that this enzyme does not mediate the metabolism of any other antimalarial agent. The new combinations proguanil-atovaquone and chlorproguanil-dapsone do not show significant interactions. CYP2B6 and CYP3A4 are involved in the metabolism of artemisinin and derivatives, but further studies may reveal involvement of more enzymes. Artemisinin may induce CYP2C19. Several artemisinin drugs suffer from auto-induction of the first-pass effect, resulting in a decline of bioavailability after repeated doses. The mechanism of this effect is not yet clear, but induction by other agents cannot be excluded. The combination of artemisinin drugs with mefloquine and the fixed combination artemether-lumefantrine have been studied widely, and no significant drug interactions have been found. The artemisinin drugs will be used at an increasing rate, particularly in combination with other agents. Although clinical studies have so far not shown any significant interactions, drug interactions should be given appropriate attention when other combinations are used.

Animals↗
PubMed2006

The role of antimalarials in the exacerbation of psoriasis: a systematic review.

OBJECTIVE: To critically review the body of literature that refutes or supports the role of antimalarials in the exacerbation of psoriasis. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were reviewed to identify English-language publications from 1966-2005 examining the role of antimalarials in the exacerbation of psoriasis. A total of 374 articles were identified, of which 32 studies met the inclusion criteria. All available clinical trials or reported cases of the use of antimalarials for patients with psoriasis were included. Data from clinical studies were summarized according to the level of evidence and the outcome of the study. Data were entered into a standardized data extraction form by two independent reviewers. RESULTS AND CONCLUSION: No randomized trial evidence was found. Only one cohort study was available for review. A total of 31 case series and case reports were obtained. There is no strong evidence to refute or support the role of antimalarials in the exacerbation of psoriasis. Controlled trials of antimalarial therapy and its effect on psoriasis are warranted.

Antimalarials↗
PubMed2005

Dual molecules as new antimalarials.

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC(50) in the nanomolar range. To remedy their low per os absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities. Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors: prodrugs, which in vivo can lead to thiazolium drugs after enzymatic transformation. The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in vivo against P. vinckei-infected mice, with ED(50) lower than 0.2 mg/kg. They are able to cure highly infected mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P. cynomolgi in primate models with no recrudescence and at lower doses. Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity. Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect. It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps from commercial products. These crystalline molecules present a remarkable biological activity and low toxicity which is promising for the development of a new antimalarial drug.

Animals↗
PubMed1997

In vitro response of Plasmodium falciparum to atovaquone and correlation with other antimalarials: comparison between African and Asian strains.

Atovaquone (dihydroxynaphthoquinone 566C80) is a broad-spectrum antiprotozoal compound demonstrating potent antimalarial activity against multidrug-resistant malaria. We present the results of in vitro drug sensitivity tests of 142 Plasmodium falciparum isolates, 108 from 14 countries of West and Central Africa, 32 from the Philippines, and one each from Laos and Myanmar. These were tested in vitro against nine drugs: the classic antimalarials chloroquine, quinine, mefloquine and halofantrine, the four qinghaosu derivatives, artemisinin, artemether, artesunate, and arteether, and the new compound atovaquone. Results showed the Asian strains have a higher median 50% inhibitory concentration (IC50) to almost all drugs compared with those from Africa. This was significantly different for chloroquine, halofantrine, and artemisinin. We used three different approaches to estimate the threshold for resistance of atovaquone to be approximately 5-7 nmol/L. The global median of 96 pooled strains is 1.4 nmol/L and the 90th percentile is 5.5 nmol/L for atovaquone. There were no correlations of atovaquone with the eight other antimalarials among African strains, but significant correlations, except for halofantrine, were observed among Asian strains. The absence of a correlation between atovaquone and the other available drugs indicates the potential of atovaquone as an alternative antimalarial in Africa. The correlation observed among Asian strains, however, suggests that atovaquone has to be used cautiously in Asia. Nevertheless, the association with proguanil in recently concluded clinical trials in Europe, South America, Asia, and Africa has demonstrated its antimalarial efficacy.

Africa↗
PubMed2002

Molecular markers in epidemiological monitoring of the spread of resistance to antimalarials: a review.

OBJECTIVE: To review the prevalence and distribution of resistance to chloroquine and pyrimethamine-sulphadoxine combination and the use of molecular markers for monitoring the spread of the resistance. DATA SOURCES: Literature search on compact disk-read only memory (CD-ROM), Medline and Internet, using the key words: Malaria and epidemiology, malaria and resistance, sulphadoxine-pyrimethamine resistance and chloroquine resistance. Some articles were manually reviewed. STUDY SELECTION: Relevant studies or articles on resistance to chloroquine, sulphadoxine pyrimethamine combination and other antimalarials and molecular resistance markers from various sources are included in the review. DATA EXTRACTION: From individual study or articles. DATA SYNTHESIS: Information on antimalarial resistance is harmonised under the headings; Introduction, Prevalence and distribution of resistance to antimalarials, Use of molecular markers for epidemiological monitoring of antimalarial resistance. CONCLUSION: The spread and status of resistance to sulphadoxine-pyrimethamine (SP) and chloroquine should be monitored constantly in major health facilities. This will not only detect the emergence of resistance to these drugs but also generate information on the extent of resistance to these antimalarials. Mutations in the dhfr and dhps genes can be used as markers in SP resistance surveilance while the presence of pfcrt mutations thought to confer resistance should also be analysed to ascertain whether they truly correlate to the resistance patterns that have been observed in various malarious regions. Little is known on the interaction and exact role(s) of PfCRT protein in conferring the resistance trait.

Animals↗
PubMed2005

Parasite lactate dehydrogenase assay for the determination of antimalarial drug susceptibility of Kenyan field isolates.

BACKGROUND: Researchers have reported that parasite lactate dehydrogenase p(LDH) could be used to determine chemo-sensitivity of plasmodia to compounds with known or presumed antimalarial activities. OBJECTIVE: To determine the drug sensitivity profiles of field adopted malaria isolates from Kisumu using p(LDH) instead of hapoxanthine assay. DESIGN: Prospective field and laboratory study. SETTING: Walter Reed, KEMRI malaria laboratory (Nairobi) and Kisumu District Hospital. SUBJECTS: Twelve field laboratory adopted isolates from Kisumu, five laboratory adopted isolates from other regions in Africa and three reference strains from Walter Reed army Institute of Research, Washington, DC. RESULTS: The p(LDH) enzyme assay was successfully used to measure the IC50 of six antimalarial drugs, chloroquine, quinine, mefloquine, dehydroartemisinin, atovaquone and halofantrine but was not successful with the four other antimalarial drugs, doxycycline, azithromycin, pyrimethamine and sulphadoxine. The Kisumu isolates tested were resistant to chloroquine and mefloquine but sensitive to quinine and the new antimalarial drugs, atovaquone, halofantrine and dehydroartemisinin. CONCLUSION: The non-radioactive p(LDH) can be used for the determination of drug sensitivity to Kenyan field isolates. It is more suited for use in a resource limited environment and may lead to more judicious prescription of new and more expensive antimalarial drugs and mitigate against the rapid spread of multi-drug resistant parasites in the East African region.

Animals↗
PubMed1999

Heme-dependent radical generation: possible involvement in antimalarial action of non-peroxide microbial metabolites, nanaomycin A and radicicol.

Antimalarial screening was performed for microbial metabolites that simulate artemisinin in their mode of action, a potent antimalarial component of an herbal remedy with a characteristic peroxide structure. Nanaomycin A was identified in this screen as an antimalarial compound, together with radicicol and several other compounds already reported (J. Antibiotics 51: 153 approximately 160, 1998). Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM. It was as potent as radicicol and about 1/10 as potent as artemisinin. Studies on the mode of action suggested that the antimalarial action of the two non-peroxides, nanaomycin A and radicicol, involved heme-dependent radical generation, as is for the peroxide artemisinin. Namely, the inhibition of in vitro growth of malaria parasite by nanaomycin A or radicicol was reversed by tocopherol, a radical scavenger added to the assay mixture. Secondly, in a reaction system established for radical detection, in which a test radical donor and beta-alanylhistidine as a radical recipient were incubated with and without hemin, the two compounds caused heme-dependent decreases of beta-alanylhistidine, as did artemisinin. Among the 14 microbial metabolites identified during this screening, a correlation was observed between antimalarial activity and heme-dependent radical generating activity.

Animals↗
PubMed1975

The efficacy of antimalarials in systemic lupus erythematosus.

Of 209 patients who fulfilled the A.R.A. criteria for the diagnosis of systemic lupus erythematosus, 43 were selected for study because each had been treated for at least two years with antimalarials, but had not received antimalarials for at least one subsequent year. In each instance, the antimalarial was discontinued solely because of the development of retinopathy. Each year on antimalarials was matched with a subsequent year off antimalarials for each patient. The year immediately following diagnosis and years of pregnancy were excluded. Paired-t test analysis of matched years revealed that general symptoms (fever, fatigue, weight loss) were less common during years on 500 mg chloroquine daily than during years off the drug (p less than 0.05). Skin manifestations were also less frequent during the years on 500 mg chloroquine daily than during the years off (p less than 0.05). No significant steroid sparing effect was found. However, a greater incidence of flare-ups during the matched years off the drug was statistically significant.

Adolescent↗
PubMed2003

[Adverse drug reactions (ADRs) to antimalarial drugs. Analysis of spontaneous report from the French pharmacovigilance database (1996-2000)].

OBJECTIVE: Although the benefit/risk ratio of older antimalarial drugs (quinine, chloroquine) is well established less is known concerning the data about newer drugs. This article assesses and analyses the antimalarial-induced ADRs reported to the French pharmacovigilance system. METHODS: All cases of ADR(s) reported to the French pharmacovigilance database over a period of 5 years, from January 1, 1996 to December 31, 2000. Our study included the antimalarials (excluding doxycycline) used in France for the cure and prophylaxis of malaria. For each notification we noted the data relative to the patient (gender, age), the antimalarial drug (prevention or cure), the associated drugs and the adverse events (imputability, delay before onset, severity and evolution). RESULTS: Between 1996 and 2000, a total of 508 reports were collected, representing 0.6% of the notifications reported to the French pharmacovigilance database over the same period. For chemoprophylaxis, the chloroquine-proguanil combination predominated (n=230, i.e. 54%), followed by mefloquine (n=163, i.e. 38%) and chloroquine (n=36, i.e. 8%). Women predominated (53%). The mean age of the patients was of 40.6+/-16.1 years (range: 0-77 years). The majority of cases (67%) were aged 26 to 60 years (n=337). For curative treatment, halofantrine was the first line drug (n=30, i.e. 38%), followed by mefloquine (n=20, i.e. 26%), quinine (n=18, i.e. 24%) and chloroquine (n=9, i.e. 12%). Whatever the indication, the chloroquine-proguanil combination (n=230) and mefloquine (n=183) represented 81% of the reports (45 and 36% respectively). We noted 1 040 adverse events corresponding to 508 observations. The adverse events were classified as severe in 41.4% of cases. However, the percentage was highest for the curative (64%) than for the prophylactic treatments (37.5%) (p<0.01). For halofantrine and quinine, the adverse events were classified as severe in respectively 76 and 67% of cases. We studied the profile of adverse events of each antimalarial drug. CONCLUSION: Our study underlined several elements: the considerable number of psychiatric problems related to the use of chloroquine-proguanil and the hepatic disorders due to halofantrine, the profile of the adverse events of each drug and the unexpected adverse events which should not be neglected in some cases.

Adolescent↗
PubMed2003

Antimalarial effect of agmatine on Plasmodium berghei K173 strain.

AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173 strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm on P berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm (12.5-200 mg/kg, ig, daily) decreased the parasitemia for both P berghei K173 S strain (IC(50)=139 mg/kg) and R strain (IC(50)=126 mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40 mg/kg, tid) showed relatively stronger antimalarial effect than intragastric gavage (IC(50)=30 mg/kg ) in P berghei K173 S strain. Spermidine antagonized the antimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistance of P berghei K173 S strain. dl-alpha-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P Berghei K173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect and the mechanism is related to its inhibition of polyamine synthesis.

Agmatine↗