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PubMedDate not supplied

[The influence of the Soviet antimalarial preparation dabequin on the hemostatic system and on the anticoagulant effect of heparin].

In experiments on rabbits and experiments in vitro dabechin was shown to decrease the blood coagulation status and to change the anticoagulant effect of heparin. The latter depends on the route and duration of administration of the antimalarial drug. Injections of heparin in the period of the maximal blood content of dabechin decrease the specific action of the anticoagulant. A prolonged oral administration of dabechin enhances the anticoagulant effect of heparin. During in vitro experiments the ability of dabechin to neutralize heparin with a simultaneous decrease of its specific action was shown.

Aminoquinolines↗
PubMedDate not supplied

Studies of the disposition and metabolism of mefloquine HCl (WR 142,490), a quinolinemethanol antimalarial, in the rat. Limited studies with an analog, WR 30,090.

The overall fate of the quinolinemethanol antimalarial, mefloquine-HCl [WR 142,490, erythro-DL-alpha-(2-piperidyl)-2,9-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride] was investigated in the rat with 14C-labeled drug. Despite its extensive binding to plasma proteins, high tissue/plasma concentration ratios were found. Fecal excretion accounted for most of the drug and metabolites. This fate was rationalized on the basis of physical properties of mefloquine (and its metabolites) and extensive biliary and gastric secretion, followed by reabsorption. Evidence was obtained for the formation of several metabolites. Limited studies were carried out in rats, dogs, and one human subject with another quinolinemethanol, WR 30,090-14C [DL-6,8-dichloro-2-(3',4'-dichlorophenyl)-alpha-(di-n-butylaminomethyl)-4-quinolinemethanol hydrochloride]. Its general fate and physical properties were similar to mefloquine. The disposition of the two quinoline compounds studied was compared to that of quinine and quinidine reported in the literature. This revealed that modification of the quinine molecule resulted in new drugs which were more highly bound and exhibited longer half-lives than quinine.

Acetylation↗
PubMed1989

[Electron microscopic observation of the sporogonic stage of Plasmodium gallinaceum after five antimalarials].

Ultrastructural changes in Plasmodium gallinaceum oocysts and sporozoites were studies after 5 antimalarials (pyrimethamine, primaquine, artemisinine, 5-p-fluorobenzoxyl-primaquine citrate and nitroquine) were administered to Aedes albopictus. Obvious disfigurement, such as abnormal vacuoles of various sizes in the cytoplasma, thickened oocyst capsules and damaged sporozoite pellical membranes were found in many oocysts and sporozoites in the mosquitoes. When the grade of infection of sporozoites in the salivary glands of the 5 different groups of mosquitoes were compared with the control, the rank test (Hc = 271) showed a very significant variance (P less than 0.01).

Aedes↗
PubMedDate not supplied

[A new antimalarial on the market: halofantrine. Various observations].

To face the geographical extension of chloroquine resistant strains of Plasmodium falciparum and the extant of multiple drug resistant strains (with sometimes a loss of quinine sensitivity), a new antimalarial drug which comes on to the market is wellcome. Halofantrine, a phenanthren methanol, licensed as Halfan has been authorized for sell in France in 1988 and is also available in four countries of Tropical Africa: Ivory Coast, Togo, Congo and Zaïre. The current prescription of Halfan is the treatment of acute attacks of P. falciparum in areas where chloroquine resistant strains occur. Halfan is only available under oral form (tablets and drinkable solution). Its clinical and biological tolerability is good.

Administration, Oral↗
PubMed1989

Antimalarial drug susceptibility of Plasmodium falciparum isolates from forest fringe dwelling aborigines (Orang Asli) of Peninsular Malaysia.

The drug susceptibility of 70 isolates of Plasmodium falciparum to standard and experimental antimalarials was evaluated using a radioisotope microdilution method. All isolates were from forest fringe dwelling Orang Asli, the aborigines of Peninsular Malaysia. The geometric mean IC50 values were: chloroquine, 10 ng/ml; amodiaquine, 4.7 ng/ml; mefloquine, 2.8 ng/ml; quinine, 40.5 ng/ml; halofantrine, 1.5 ng/ml; enpiroline, 3 ng/ml; and pyrimethamine, 21 ng/ml. Four isolates exhibited decreased susceptibility to chloroquine (IC50 greater than 60 ng/ml), and one exhibited decreased susceptibility to quinine (IC50 = 161 ng/ml). Three isolates showed decreased susceptibility to mefloquine (IC50 = 10-11 ng/ml). The lack of drug pressure may account for the high prevalence of P. falciparum isolates susceptible to chloroquine.

Animals↗
PubMed1989

Studies on 2,3,N,N'-substituted 4,4'-diaminodiphenylsulfones as potential antimalarial agents.

A series of new 4,4'-diaminodiphenylsulfones substituted at 2 and 3 position and also at primary amino group of the phenyl rings have been synthesized and evaluated for their antimalarial activity against Plasmodium berghei infection in mice. Some of these compounds were active and showed complete inhibition of parasitaemia which included 7a1-7a4, 7b3, 7b4 and 16a at 1 mg/kg i.p. for 4 days and 16a, at 0.3 mg/kg for 4 days. Some compounds tested for their synthetase inhibitory action in cell-free system isolated from P. berghei (7b1, 7b2 and 8b2) were found to be more active than diaminodiphenylsulphone. The difference in order of activity between these in vivo and in vitro tests may be due to differences in their pharmacokinetic properties.

Animals↗
PubMed1989

Antimalarial and toxic effect of triple combination of pyronaridine, sulfadoxine and pyrimethamine.

The triple combination of pyronaridine, sulfadoxine and pyrimethamine which has been proven to be efficient in delaying emergence of drug resistance of rodent malarial parasites was further studied for potential application to malaria control. The antimalarial effect of the triple combination on Plasmodium berghei ANKA-infected mice and the toxic effects in mice and rats were additive. A single dose of pyronaridine 500 mg in combination with sulfadoxine, 1000 or 1500 mg, and pyrimethamine, 50 or 75 mg, given to 72 acute falciparum malaria patients resulted in a 100% cure rate with nil or mild side effects, and no recrudescence of asexual parasite over 4-week follow-up. Preliminary experiments on the drug effect on sporogony showed that the drug combination at the dose used could not completely interrupt the sporozoite formation although many retarded oocysts were found.

Animals↗
PubMed1989

Antagonism of serum of mice infected with chloroquine-resistant 'NS' line to the antimalarial action of chloroquine.

Chloroquine (CQ) solution was separately mixed with the serum of mice infected with chloroquine-resistant 'NS' line (SMNS), the serum of mice infected with chloroquine-sensitive Plasmodium berghei ANKA strain (SMCS), and the serum of normal mice (SM). These mixtures were then used in treating mice inoculated with P. berghei ANKA strain. The results obtained on d 5 after drug-serum administration showed that the erythrocyte infection rates in the SMNS + CQ, SMCS + CQ, and SM + CQ groups were 32, 16, and 14% respectively. There were significant differences with respect to parasitemia between the SMNS + CQ group and the SMCS + CQ or SM + CQ group (P less than 0.05), suggesting that SMNS may be antagonistic to the antimalarial action of chloroquine. Further study showed that when the 'NS' line lost resistance to chloroquine, the antagonism of SMNS to chloroquine disappeared. The antagonism rates of SMNS to chloroquine, piperaquine, hydroxypiperaquine and pyronaridine were 75, 56, -5, and -17% respectively, a trend similar to that of the results from cross-resistance tests on chloroquine-resistant P. berghei ANKA strain. The results indicate that drug-resistant malaria parasites may produce and release a certain 'specific anti-drug substance'.

Animals↗
PubMed1989

[Synthesis and antimalarial and antineoplastic activities of some derivatives of 2,4-diamino-5-methyl-6-substituted benzylaminoquinazolines].

This paper reports the synthesis and the antimalarial and anticancer activities of some derivatives of 2,4-diamino-5-methyl-6-substituted benzylaminoquinazolines. These compounds were synthesized by condensation of 5-methyl-2,4,6-triaminoquinazoline with substituted benzyaldehyde to produce Schiff base, followed by reduction, formylation or nitrosation. The suppressive therapeutic effects against Plasmodium berghei in mice showed that the suppressive rate of three compounds (IV 2,5,6)was 100 per cent at the dosage 5 mg/kg. The anticancer activity in vitro showed that II7 and IV3 had the strongest inhibition and their IC50 against L1210 Leukemia cell were 3.910 X 10(-3) micrograms/ml and 6.172 X 10(-3) micrograms/ml.

Aminoquinolines↗
PubMed1987

[The OCCGE (Organisation de Coordination et de Coopération pour la Lutte contre les Grandes Endémies) and the surveillance of the drug sensitivity of Plasmodium falciparum to antimalarials].

Spreading of chemoresistance from East Africa to Central Africa is a very worrying problem for Western Africa. In fact, chemotherapy of febrile attacks is at present admitted as malaria control strategy in the framework of Primary Health Care. This new strategy is based on the fact that commonly used antimalarial drugs as chloroquine are surely efficacious. Thus, the surveillance of chemosensitivity of Plasmodium falciparum local strains becomes a priority. From studies carried out in Burkina Faso during many years, Centre Muraz of O.C.C.G.E. has organized a surveillance system with several levels: a Reference Center, a National Center for each country and sentinel centers located in the different epidemiological features of the countries. This surveillance concerning many states can allow to detect more quickly some possible problems in relation with chemoresistance and to take measures to limit its impact.

Africa, Western↗
PubMed1986

Antimalarial activity of neplanocin A with perturbations in the metabolism of purines, polyamines and S-adenosylmethionine.

Neplanocin A, a novel carbocyclic analog of adenosine, was found to be a mixed type inhibitor of S-adenosylhomocysteine hydrolase of human red blood cells with a Ki of 2 nM and an inactivating constant, Ki, of 3 nM. When tested against Plasmodium falciparum cultured in human red blood cells, neoplanocin A inhibited malarial growth with an ED50 of 3 microM. Above 2.5 microM, some red blood cells showed morphological aberrations and became echinocytes (spiculated red blood cells). In infected red blood cells, neplanocin A caused an elevation of the concentrations of S-adenosylmethionine and S-adenosylhomocysteine in a dose-dependent manner. Concurrently, a new analog of S-adenosylmethionine, S-neplanocinylmethionine, was formed. Analysis of polyamines showed that only putrescine was decreased significantly; the others were not changed. Purine analyses showed two putative neplanocinyl nucleotides, possibly the di-and the triphosphates. Neplanocin A most likely exerted its in vitro antimalarial effect via the inhibition of S-adenosylhomocysteine hydrolase and the attendant perturbation of methylation reactions.

Adenosine↗
PubMedDate not supplied

[Pharmacokinetics of antimalarials: quinine and mefloquine, halofantrine, qinghaosu, amino-4-quinolines].

The development of new sensitive and specific assays (HPLC) have enabled the pharmacokinetics of antimalarial drugs to be studied. Parameters such as half-life distribution volume, clearance and bioavailability, are defined. In healthy subjects, quinine is rapidly eliminated (t1/2 beta: 6-12 h). Hepatic biotransformation accounts for approximately 80% of its total clearance. In malaria, the pharmacokinetic properties of quinine (decrease in the apparent volume of distribution, prolongation of the t1/2 beta, reduction in systemic clearance), are altered in proportion to the severity of infection. Red cell concentrations and plasma binding are increased. Parenteral quinine should be given by slow intravenous infusion and a loading dose is recommended in severe infections. Chloroquine (t1/2 beta: 6-50 days) and mefloquine (t1/2 beta: 6-33 days) have extensive tissue distribution and prolonged activity after a single dose. Both drugs are concentrated in erythrocytes and are bound considerably to plasma proteins. Amodiaquine is not found in the blood after oral administration. Hepatic biotransformation accounts for almost all orally administered drug. Its antiplasmodial activity is thus almost entirely due to monodesethylamodiaquine, the main metabolite. In healthy subjects, the t1/2 beta of this metabolite is 9 to 18 days in plasma. Amodiaquine is concentrated in erythrocytes. The protein binding of this drug has not been studied to date. For prophylaxis, it has been suggested that the dosage of 10 mg/kg/wk should be spread over the week (3.5 mg/kg every other day, or 1.5 every day). Halofantrine has an elimination half-life of between 1.3 and 6.6 days. This drug has been suggested as a single-dose treatment. No pharmacokinetic studies of qinghaosu have been reported in humans. In rabbits, the elimination half-life in plasma was found to be 40 min. Although rapidly eliminated, this drug appears to be highly effective. More information is required on the pharmacokinetics of these drugs in malaria, during pregnancy, in children and in renal and hepatic failure.

Adult↗
PubMed1987

The effect of artemisinin combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.

The activity of artemisinin (qinghaosu) in combination with some commonly-used antimalarial drugs was tested in vitro against a chloroquine-sensitive (NF54) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. Both mefloquine and tetracycline showed marked potentiative synergism with artemisinin against both strains, whilst primaquine showed potentiation against K1. Combinations of artemisinin with pyrimethamine and with chloroquine were antagonistic. The results confirm observations on rodent malaria in vivo and indicate that the drug interactions seen were direct, through actions on the parasite, and not merely effects on drug distribution and metabolism in the mouse host.

Animals↗
PubMed1978

Pharmacokinetics of antimalarials and proposals for dosage regimens.

Blood level data for the antimalarials amodiaquine, chloroguanide, chloroquine, pyrimethamine, quinine and sulphadoxine have been retrieved from the literature and pharmacokinetically analyzed. Minimum, average and maximum blood level concentrations at steady state in suppressive treatment and peak concentrations in therapeutic treatment were predicted and blood level-time curves simulated. Based on the computer-predicted data, changes in dosage regimens are proposed to reduce the fluctuations between maximum and minimum levels in suppressive treatment, and for obtaining maximum peak levels in therapeutic treatment already with the loading dose.

Antimalarials↗
PubMed1985

Effect of antimalarial treatment on circulating immune complexes in rheumatoid arthritis.

The relationship between the effect of chloroquine treatment on circulating immune complexes in patients with rheumatoid arthritis (RA) was determined by the 125I Clq binding assay. Three groups were studied: (a) 20 patients treated daily for 6 months with chloroquine sulphate 250 mg plus prednisone 7.5 mg and nonsteroidal antiinflammatory drugs (NSAID); (b) 20 patients not taking antimalarials but treated with prednisone and NSAID; (c) 41 controls. Results suggest that chloroquine sulphate therapy induced a marked decrease of immune complexes in patients with RA, an effect not observed with treatment by prednisone and NSAID only.

Adult↗
PubMed1974

Assessment of causal prophylactic activity in Plasmodium berghei yoelii and its value for the development of new antimalarial drugs.

The causal prophylactic activity of several reference and experimental antimalarial compounds was assessed in sporozoite-induced infections of NMRI mice with Plasmodium berghei yoelii (strain 17X). The animals were inoculated with 10 000 sporozoites per mouse and treated once 2-4 hours later. The test system has proved to be very suitable in experiments involving more than 3 000 mice. The infection rate in 448 untreated controls was 97.3%. Lowering the sporozoite content of the inoculum to 1 000 or 100 sporozoites markedly reduced the rate (65.1% and 32.7%). In experiments with primaquine the causal prophylactic activity was also influenced by the time of drug administration before or after sporozoite inoculation. No causal prophylactic effect was demonstrable with quinine, chloroquine, amodiaquine, amopyroquine, RC-12, or B 505. Primaquine was active, but pamaquine and pentaquine were only sporadically active. The pre-erythrocytic stages of P. b. yoelii were only slightly sensitive to dapsone, sulfadiazine, and sulformethoxine; they were 10-100 times more susceptible to proguanil, cycloguanil, and pyrimethamine. The experimental 6-aminoquinolines NI 147/36, NI 187/82, and BA 138/111 and the 7-chlorolincomycin derivative U 24729 were also studied. Experiments in which curative activity against blood-induced infections of P. b. yoelii was evaluated showed that the causal prophylactics act more specifically against the pre-erythrocytic than against the erythrocytic forms. This specificity was most pronounced among the DHFR-inhibitors, whose outstanding activity may be explained by the fact that the rate of multiplication of the pre-erythrocytic forms of P. b. yoelii is greater than that of other plasmodia used hitherto; it is also greater than the rate shown by the malaria parasites of man and that of the erythrocytic forms of P. b. yoelii itself. We believe that this feature will render P. b. yoelii very useful for determination of the causal prophylactic activity of new compounds, but it may also overrate the potency of drugs that interfere with nucleic acid biosynthesis.

Animals↗
PubMed1978

[Antimalarial 6-aminoquinolines. VII. 2- and 4-Alkoxy derivatives of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxyquinoline (author's transl)].

19 derivatives, 10 a--t, of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxyquinoline (1a) with alkoxy-, hydroxy-, and methylmercapto substituents in 4- and/or 2-position were synthesized with the aim of studying the influence of these substituents on antimalarial activity and toxicity of 1a. The alkoxy derivatives of 1a are highly active against P. vinckei (mouse). The 2- and 4-hydroxy derivatives, 10 l and 10 m, are inactive.

Aminoquinolines↗