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PubMed2000

In vitro antimalarial activity of trovafloxacin, a fourth-generation fluoroquinolone.

Trovafloxacin, a recently-developed fourth-generation fluoroquinolone, is more potent than other quinolone drugs against a wide range of organisms including Toxoplasma gondii. We assessed the in vitro antimalarial activity of trovafloxacin against three laboratory-adapted Plasmodium falciparum isolates and compared the results with those of ciprofloxacin and norfloxacin. Synchronous and asynchronous cultures were exposed to a range of drug concentrations, and growth inhibition was assessed using 3H-hypoxanthine incorporation. All isolates, both synchronous and asynchronous, exhibited comparable sensitivities with trovafloxacin (EC50 range, 1.8 x 10(-5) to 3.7 x 10(-5) mol/l) and ciprofloxacin (2.0 x 10(-5) to 3.9 x 10(-5) mol/l), but were less sensitive to norfloxacin (5.4 x 10(-5) to 6.6 x 10(-4) mol/l). These results confirm that ciprofloxacin is twice as potent as norfloxacin against P. falciparum in vitro, but also show that trovafloxacin and ciprofloxacin have similar antimalarial potency. The EC50 concentrations of all three drugs were generally higher than those achieved after conventional doses in humans, suggesting that their clinical application may be limited to combination therapy. Recent reports of hepatotoxicity with trovafloxacin may also prevent the use of this drug in humans. However, newer fourth-generation quinolones may prove safer and have similar antimalarial potency.

Animals↗
PubMed1987

Neutropenia associated with dual antimalarial chemoprophylaxis--use of bone-marrow culture as an aid in further drug management.

Bone-marrow culture in soft agar was used to determine the cause of neutropenia in a visitor to Tanzania who had been taking both amodiaquine and proguanil for antimalarial prophylaxis. Desethyl-amodiaquine, a major metabolite of amodiaquine (but not amodiaquine itself, proguanil, cycloguanil or chloroquine) was implicated. Supplementary studies using amodiaquine binding techniques supported the notion that the parent compound, amodiaquine, was not the cause of the neutropenia. The bone-marrow culture technique proved useful in deciding further anti-malarial prophylaxis and in formulating the choice of curative antimalarial therapy, should this have proved necessary. The procedure may help in the managing other such patients with presumed drug-induced blood dyscrasias when the choice of appropriate and effective antimalarial drugs is limited.

Adult↗
PubMed1998

Preventing antimalarial drug resistance through combinations.

Throughout the tropical world antimalarial drug resistance is increasing, particularly in the potentially lethal malaria parasite Plasmodium falciparum. In some parts of Southeast Asia, parasites which are resistant to chloroquine, pyrimethamine-sulfadoxine, and mefloquine are prevalent. The characteristics of a drug that make it vulnerable to the development of resistance are a long terminal elimination half-life, a shallow concentration-effect relationship, and that one or two base-pair mutations confer a marked reduction in susceptibility. The development of resistance can be delayed or prevented by drug combinations. The artemisinin derivatives are the most potent of all antimalarial drugs. They reduce the infecting parasite biomass by approximately 10 000-fold per asexual life cycle. There are good arguments for combining, de novo, an artemisinin derivative with all newly introduced antimalarial drugs.

Journal Article↗
PubMed2001

A potent antimalarial activity of Hydrangea macrophylla var. Otaksa leaf extract against Plasmodium yoelii 17XL in mice.

The antimalarial activity of the hot-water extract of Hydrangea macrophylla var. Otaksa leaves was evaluated against Plasmodium yoelii 17XL in mice. Non-treated control mice died from 6 to 7 days after infection, but mice treated with the leaf extract survived during the experiment. Mice given the extract orally showed low parasitemia levels during administration. Following a transient recrudescence of malaria parasites in the bloodstream of treated mice, no parasites could be detected by a microscopic examination. Furthermore, the 30% MeOH aq. eluate and 50% MeOH aq. eluate from dried leaves of H. macrophylla var. Otaksa showed an antimalarial activity in vivo. Sulfamonomethoxine was orally given to infected mice to compare with the antimalarial activity of the hot-water extract of leaves. Sulfamonomethoxine given orally reduced parasitemia, but no complete cure of mice was observed.

Animals↗
PubMed2002

Antimalarial drugs inhibit the acetylcholine-receptor-operated potassium current in atrial myocytes.

BACKGROUND: It has been reported that halofantrine, an antimalarial drug, was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias. Inhibition of the delayed rectifier potassium channel, a voltage-gated potassium channel, by halofantrine was the likely underlying cellular mechanism for this cardiotoxicity. However, influences of anti-malarial drugs on the ligand-gated potassium channels have not been well-documented. The influences of three different antimalarial drugs, chloroquine, primaquine and pyrimethamine, on the acetylcholine-receptor-operated potassium current (I(K.ACh)), a ligand-gated potassium current, were compared with the effect of quinidine in isolated guinea pig atrial myocytes using patch-clamp techniques. METHODS: The whole-cell patch-clamp method was used in the present studies he I(K.ACh) was induced by extracellular application of carbachol (1 micromol/L) or intracellular loading of guanosine 5'-O-(3-thiotriphosphate) GTPgammaS (100 micromol/L) in acutely isolated guinea pig atrial myocytes. RESULTS: The I(K.ACh) induced by carbachol was inhibited by chloroquine, primaquine, pyrimethamine and quinidine in a concentration-dependent manner, and the concentrations required to produce 50% of the maximal inhibitory effect (IC(50) values) were 0.7, 2.5, 12 and 1.8 micromol/L, respectively. These drugs also inhibited the intracellular GTPgammaS-activated I(K.ACh), and the IC(50) values were 0.8,13,19 and 21 micromol/L, respectively. CONCLUSIONS: Chloroquine and pyrimethamine may inhibit I(K.ACh) by interacting with the muscarinic potassium channel itself and/or associated guanosine 5'-triphosphate-binding proteins, whereas primaquine and quinidine may mainly inhibit the current by the blockade of the muscarinic receptors. These results indicate that antimalarial drugs exert anticholinergic effects via different molecular mechanisms.

Journal Article↗
PubMed1996

Antimalarial activity in crude extracts of Malawian medicinal plants.

Aqueous and organic fractions from Cassia abbreviata, Senna petersiana (both Caesalpiniaceae) and Azanza garckeana (Malvaceae) were tested for in-vitro antimalarial activity against the multi-drug-resistant, Vietnam-Smith strain of Plasmodium falciparum; VI/S. Both roots and leaves from these Malawian medicinal plants were investigated. High activity, with a median inhibitory concentration < 3 micrograms/ml, was seen in the organic fractions of C. abbreviata and S. petersiana, the two species most commonly cited by traditional healers in an ethnobotanical investigation of Malawian antimalarials. Extracts of A. garckeana showed weaker activity. Biologically active compounds have thus been detected within species of the family Caesalpiniaceae. Ethnobotanical investigation appears to be useful in identifying plants with antimalarial activity.

Animals↗
PubMed1981

Hypergammaglobulinemia and erythrocyte autoantibody complicate enzyme immunoassay of antimalarial antibody.

Enzyme immunoassay of specific antimalarial antibody in sera from Plasmodium yoelii-infected mice was complicated by hypergammaglobulinemia and erythrocyte (RBC) autoantibody. Malarious serum had higher immunoglobulin levels which resulted in a substantial nonspecific adsorption of antibody to antigen uncoated microliter wells even in the presence of a surfactant. Since it was possible that some of the antibody binding to solid phase-bound malarial antigen was also due to nonspecific adsorption, the antibody binding of nonimmune serum was compared to that of malarial immune serum diluted to an equivalent immunoglobulin concentration. This allowed differentiation of specific antimalarial antibody binding from nonspecific adsorption of immunoglobulin. Although malarial antigen was partially purified from intraerythrocytic parasites, it bound a significant amount of rabbit anti-mouse RBC antibody, indicating the presence of residual RBC antigens. Serum from immune mice, but not nonimmune mouse serum, also showed substantial binding to RBC stroma antigen, suggesting that a component of the observed antibody binding to malarial antigen was anti-RBC antibody. Hypergammaglobulinemia and the induction of RBC autoantibody may both be related to the polyclonal activating property of the malaria infected mice necessitates a more conservative interpretation of specific antimalarial antibody levels until a more purified malarial antigen is available.

Animals↗
PubMed1988

Inbred mice infected with Plasmodium yoelii differ in their antimalarial immunoglobulin isotype response.

Antibodies are known to be important in mediating malarial immunity, but the influence of the various immunoglobulin isotypes on parasite elimination is unclear. The purpose of this study was to provide basic information on the induction of isotype expression in genetically different mice during primary malaria. Parasitaemias and the serum antimalarial IgM, IgG1, IgG2, IgG3 and IgA antibody titres measured in a radioimmunoassay were followed in outbred and 11 inbred strains of mice infected with 17XNL Plasmodium yoelii. Severity of infection, as judged by length of infection, peak parasitaemias and death, was found to differ between the strains. All strains developed rapid IgM responses, but only 3/11 inbred strains produced significant antimalarial IgG1 levels during primary infection. All strains produced an IgG2 response, which developed slightly more quickly in strains with the least severe courses of malaria. A large variation in the IgG3 response was noted between strains. In general, IgG3 antibodies were the first IgG-isotype to appear in serum. They were detected as early as day 8 in strains that developed mild infections but were not present until around day 20 in strains with the most severe cases of malaria. Only one strain produced detectable antimalarial IgA antibodies. These results show that different patterns of isotype expression are induced in inbred strains of mice during primary P. yoelii infection.

Animals↗
PubMed1986

Antioxidant action of antimalarials.

The effects of antimalarials, chloroquine and quinacrine, on the generation of reactive oxygen species were examined both in polymorphonuclear leucocytes and in the xanthine-xanthine oxidase system. Antimalarials showed inhibitory effects on the production of reactive oxygen species probably by affecting cell functions, such as membrane phospholipid methylation. It is suggested that antimalarial agents can work as antioxidants at the site of inflammation protecting against auto-oxidative tissue damage with resultant anti-inflammatory effects.

Cells, Cultured↗
PubMed1994

The association of the two antimalarials chloroquine and quinacrine for treatment-resistant chronic and subacute cutaneous lupus erythematosus.

Antimalarials are the first line in the treatment of chronic and subacute cutaneous lupus erythematosus (LE). However, some patients show either no or only minor improvement on antimalarial monotherapy. We treated 14 patients (9 with chronic LE and 5 with subacute cutaneous LE) who had poorly responded to chloroquine or hydroxychloroquine with an association of chloroquine and quinacrine. The initial dose was: chloroquine 100 mg 3x/day and quinacrine 65 mg 3x/day. The skin lesions improved significantly or cleared totally in 5 of the 9 patients with chronic LE and in all the 5 patients with subacute cutaneous LE. These findings suggest that a chloroquine-quinacrine combination may sometimes be superior to the usual antimalarial monotherapy, especially for subacute LE. If chloroquine or hydroxychloroquine fails to control chronic or subacute cutaneous LE, chloroquine-quinacrine is worthy to be tried.

Adult↗
PubMed1983

Oxygen enhances the antimalarial activity of the imidazoles.

We have previously reported the antimalarial activity of imidazoles and amphotericin B against chloroquine-resistant Plasmodium falciparum. We now report the enhancement of imidazole activity in an atmosphere with 17-18% oxygen (the candle jar) vs. 3% or 0.3% oxygen. Based on both morphologic and radiometric testing, smaller amounts of the imidazoles were required to inhibit parasite growth by 50% in the candle jar vs. 3% or 0.3% oxygen. The use of older (more oxidant-sensitive) red cells also enhanced the antimalarial activity of ketoconazole. Neither increased concentrations of oxygen nor the use of older red cells affected the activity of amphotericin B. These results suggest that the imidazoles may exert their antimalarial effect by increasing the oxidant stress on the red cell-parasite complex.

Amphotericin B↗
PubMed1989

Home treatment of febrile children with antimalarial drugs in Togo.

In Togo, the principal strategy for preventing death from malaria in children is prompt treatment of fever with antimalarial drugs. A household survey was conducted in a rural area of south-central Togo in which information was collected from mothers on the treatment received by 507 children under 5 years of age who, according to their mothers, had recently had fever. Altogether, 20% of the children (95% confidence interval (Cl): 15-25%) were seen at a health centre during their illness, while 83% (95% Cl: 76-90%) were treated at home with an antimalarial drug. Of the children in the latter group, 97% received the drug on the first day of fever. In contrast, only 17% of children who attended a health centre were seen on the first day of their fever. Chloroquine, usually obtained from a street or market vendor, was used for 94% of the treatments given at home. Based on children's weights and treatment histories provided by their mothers, the median total dosage of chloroquine given at home was 12.8 mg per kg body weight--more than that recommended and known to be fully effective in Togo at the time of the survey (10 mg per kg) and less than the total dosage recommended at present (25 mg per kg). The dosage administered was considered to be inadequate for 70% of home treatments, because less than 10 mg per kg was given during the first 24 hours of treatment. In the study area, parents were the main providers of antimalarial drug treatment to children with fever and need guidance on the correct dosage of chloroquine.

Child↗
PubMed1984

Antimalarial red cells.

It is difficult to overestimate the evolutionary pressures exerted over the past few thousand years by endemic malaria. For most of hominid evolution, these parasites probably caused little morbidity and mortality. However, as Livingstone (1964, 1967, 1971) has pointed out, the advent of slash and burn horticulture and associated sedentary living patterns dramatically changed this situation. For many human populations, endemic malaria became an evolutionary emergency. In such pressing circumstances, genetic traits which ordinarily would carry with them an intolerable genetic load actually increase in frequency. Thus, although a few antimalarial red cell characteristics such as Duffy negativity are evidently innocuous, the majority of malaria-selected traits are not. Ovalocytosis, the abnormal hemoglobins and G-6-PD deficiencies are all quite deleterious in the homo- or hemizygote. This, more than anything else, bespeaks the extraordinary evolutionary pressures exerted by malaria. Needless to say, the mechanisms by which these various red cell traits protect are incompletely known. Although our discussion of such mechanisms has revolved about parasite/host cell relationships, the actual antimalarial effect may involve more distal interactions, especially of infected erythrocytes with the immune and reticuloendothelial systems. Protection exerted by modifications of such interactions would not be revealed by in vitro culture experiments upon which we rely for much of our information. For example, as normal red cells age and senesce, they express novel surface antigens which are recognized by specific immunoglobulins (Kay, 1983). Cells which have bound such antibodies are likely recognized and destroyed rapidly by the reticuloendothelial system. The expression of such senescence antigens may be hastened in already abnormal cells subject to the additional burden of an internal parasite. Therefore, it is quite possible that congenital defects of the red cell membrane, hemoglobin and metabolism may afford protection against malaria via immunologic mechanisms rather than by blocking penetration or predisposing the cell to spontaneous intravascular lysis. To be successful in the mammalian host, erythrocytic phase of malaria must recognize and attach to the host red cell, successfully penetrate, and replicate within. Remarkably, there are antimalarial red cells which impair each one of these individual steps. In this case, the ingenuity of natural selection has been almost--but not quite--a match for that of the malaria parasite.

Adenosine Triphosphate↗
PubMed1998

Antimalarial activity of 77 phospholipid polar head analogs: close correlation between inhibition of phospholipid metabolism and in vitro Plasmodium falciparum growth.

Seventy-seven potential analogs of phospholipid polar heads, choline and ethanolamine, were evaluated in vitro as inhibitors of Plasmodium falciparum growth. Their IC50 ranged from 10(-3) to 10(-7) mol/L. Ten compounds showed similar antimalarial activity when tested against three different parasite strains (2 chloroquine-sensitive strains and 1 chloroquine-resistant strain). Compounds showing marked antimalarial activity were assayed for their effects on phospholipid metabolism. The most active compounds (IC50 of 1 to 0.03 micromol/L) were inhibitors of de novo phosphatidylcholine (PC) biosynthesis from choline. For a series of 50 compounds, there was a close correlation between impairment of phospholipid biosynthesis and inhibition of in vitro malaria parasite growth. High choline concentrations caused a marked specific shift in the curves for PC biosynthesis inhibition. Concentrations inhibiting 50% PC metabolism from choline were in close agreement with the Ki of these compounds for the choline transporter in Plasmodium knowlesi-infected erythrocytes. By contrast, measurement of the effects of 12 of these compounds on rapidly dividing lymphoblastoid cells showed a total absence of correlation between parasite growth inhibition and human lymphoblastoid cell growth inhibition. Specific antimalarial effects of choline or ethanolamine analogs are thus likely mediated by their alteration of phospholipid metabolism. This indicates that de novo PC biosynthesis from choline is a very realistic target for new malaria chemotherapy, even against pharmacoresistant strains.

Animals↗
PubMed2005

Evidence basis for antimalarial policy change in Sierra Leone: five in vivo efficacy studies of chloroquine, sulphadoxine-pyrimethamine and amodiaquine.

OBJECTIVES: To provide nationally relevant information on the antimalarial efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) in Sierra Leone, with a view to updating antimalarial policy in the country. METHODS: Between October 2002 and May 2003, standard WHO methodology for in vivo efficacy assessment was used in five sites to study the therapeutic response of 6-59 months old uncomplicated Plasmodium falciparum malaria cases treated with CQ (n = 247), SP (n = 353) or AQ (n = 434). Follow-up was of 28 days, with polymerase chain reaction genotyping to distinguish late recrudescences from re-infections. RESULTS: Overall 85.3% of patients reached an analysable endpoint. CQ failure proportions were very high, ranging from 39.5% (95% CI: 25.0-55.6) in Kabala to 78.8% (65.3-88.9) in Kailahun. Early failures under CQ were frequent. SP efficacy was also disappointing, with failure from 23.2% (13.9-34.9) in Kabala to 46.1% (35.4-57.0) in Kailahun. AQ resistance was more moderate, ranging from 5.4% (1.8-12.1) in Makeni to 29.8% (20.3-40.8) in Kailahun, with almost no early failures. AQ also provided more rapid fever and parasite clearance. CONCLUSION: In a consensus meeting organized by the Ministry of Health and Sanitation, and based on these findings, artesunate (AS) + AQ and artemether-lumefantrine (Coartemtrade mark) were identified as the only options to rapidly replace CQ. The choice fell on AS + AQ because of expected high efficacy, lower cost in a blister presentation, and the absence of safety data on artemether-lumefantrine in pregnancy. Donor support is required to support this policy change. Throughout Africa, as SP resistance increases, these two regimens are probably the only options available while newer combinations are developed. Efficacy studies should focus on testing AQ and AS + AQ.

Amodiaquine↗
PubMed1998

Synthesis of some novel 2-oxo-pyrano(2,3-b)- and 2-oxo-pyrido(2,3-b)quinoline derivatives as potential antimalarial, diuretic, clastogenic and antimicrobial agents.

The 2-chloro-3-formyl quinoline derivatives (1a-e) on treatment with acetic anhydride and sodium acetate, afforded the corresponding novel 2-oxopyrano(2,3-b) quinoline derivatives (2a-e), and these were subjected to ammonia treatment to yield the corresponding naphthyridine derivatives (3a-e). The prepared compounds (2a-e) were tested for their antimalarial, diuretic, clastogenic and antimicrobial properties. Not all the compounds showed a diuretic effect and the significant increase in the frequency of micronuclei shows that they are non-clastogens, whereas the 7-chloro derivative (2e) was a very effective antimalarial agent against the mosquito species. All the compounds were found to have optimum antimicrobial activity against Staphylococcus aureus, Escherichia coli and Salmonella typhi. Compounds 2d and 2e were found to be most active against the bacteria tested.

Animals↗
PubMed2002

Synthesis of ferroquine enantiomers: first investigation of effects of metallocenic chirality upon antimalarial activity and cytotoxicity.

Ferroquine (FQ) is a new antimalarial agent with a high blood schizotoncidal activity. Previous studies on this compound were done with racemate mixtures. As FQ possesses planar chirality, pure enantiomers were obtained by enzymatic resolution in order to compare their antimalarial activities and cytotoxicities. (+)-FQ and (-)-FQ were equally active in vitro, at nanomolar concentrations. Both enantiomers were slightly less active than the racemate in vivo; cytotoxicities were similar. Actually, the racemate represents the optimal formulation. To the best of our knowledge, this is the first investigation of biological activities of compounds with metallocenic chirality.

Animals↗
PubMedDate not supplied

Antimalarial activity of 1,4-epidioxy-bisabola-2,12-diene derivatives.

1,4-Epidioxy-bisabola-2,12-diene (3) and aromatic hydroperoxides (4, 5) were prepared by photoxidation of gamma-curcumene (1). Reduction and esterification of 6 and 7 afforded compounds 9 to 10. All compounds were tested in vitro for antimalarial activity. The activity could not be increased significantly, compared with 3. The most active compounds, 3 and 9, did not show in vivo antimalarial activity in mice.

Animals↗