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PubMed1981

[Ocular electrophysiology and synthetic antimalarial agents (author's transl)].

Ocular electrophysiology investigations are essential for detecting retinal complications of prolonged treatment with synthetic antimalarial agents. The techniques employed and the principal lesions discovered by the examination are described. The analysis of lesions found in 29 out of 120 cases examined showed that only simple close surveillance was necessary in 17 cases, a reduction in daily dosage in 11 cases, and interruption of treatment in one case only. The modalities of ocular electrophysiology surveillance during prolonged treatment with antimalarial agents are outlined.

Antimalarials↗
PubMed1995

In vitro antimalarial activity of monoterpenic fragment analogues of aplasmomycin.

Synthetic analogues of a monoterpenic fragment of aplasmomycin were tested for their antimalarial activity in Plasmodium falciparum culture in vitro. The antimalarial activities of these agents were evaluated in chloroquine sensitive strains. Parasite growth was inhibited in a dose dependent manner in the presence of the synthetic compounds (3-9).

Animals↗
PubMed1994

In-vitro tests on Philippine isolates of Plasmodium falciparum against four standard antimalarials and four qinghaosu derivatives.

In-vitro drug sensitivity tests were performed on Philippine isolates of Plasmodium falciparum between 1991 and 1993, using the radioisotope microdilution method. The success of the tests varied significantly with the level of parasitaemia, the source of the strains, the period that elapsed before culturing, and the detectable concentrations of antimalarials in the blood. There was a significant positive correlation between the IC50 values for chloroquine and artesunate and the level of chloroquine in the blood before testing. In the Philippines the sensitivity profiles of the standard antimalarials (chloroquine, quinine, mefloquine, and halofantrine) were less severe than those in other south-east Asian countries. Fairly low IC50 values were obtained for the qinghaosu derivatives artemisinin, artemether, arteether and artesunate. There was a positive correlation between quinine, mefloquine, halofantrine and some of the qinghaosu derivatives, and between the qinghaosu compounds themselves, raising the possibility of either cross-resistance or possible drug associations.

Adolescent↗
PubMed1993

Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation.

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of alpha-Ii and beta-Ii chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, alpha-Ii and beta-Ii; (e) the displacement of Ii chains by peptides to form alpha-beta-peptide complexes in the endosome; and (f) the migration of alpha-beta-peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the alpha-beta-peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[The cornea and synthetic antimalarials].

The main targets of antimalarial ocular toxicity are the cornea, ciliary body and retina. In sixty patients treated with chloroquine (Nivaquine) 73% showed keratopathy. The clinical features and clinical course of this keratopathy and its relationship with retinopathy were described. In contrast with retinopathy, keratopathy is not contraindication to antimalarial treatment.

Adolescent↗
PubMed1993

[Synthesis of pyronaridine related compounds and comparison of antimalarial activities].

The paper reports the synthesis of pyronaridine (I) related compounds II-V for exploring whether the antimalarial activity of pyronaridine is by virtue of a nitrogen atom at position 1 in the ring and a pair of pyrrolidinyl Mannich base side chains in its structure. The condensation of 2-methoxy-6,9-dichloroacridine or 4,7-dichloro-1,5-naphthyridine with 4-hydroxy-3,5-bis-(pyrrolidinyl-1'-methyl) aniline yielded the related compound II, 1-deazapyronaridine, or V, 5-azabispyroquine, respectively. 2-Methoxy-7,10-dichlorobenzo (b) 1,5-naphthyridine or 4,7-dichloro-1,5-naphthyridine was condensed with 4-diethylamino-1-methylbutylamine to obtain the related compound III, azacrin, or IV, 5-azachloroquine, respectively. The results of in vivo tests against Plasmodium berghei chloroquine-resistant ANKA strain, drug-sensitive P. berghei N line and drug-resistant P. yoelii nigeriensis line showed that all the related compounds II-V were less effective than pyronaridine (I). It suggests that the nitrogen atom at position 1 and pyrrolidinyl Mannich base side chains on the structure of pyronaridine play an important and indispensable role for antimalarial activity of pyronaridine. The pyrrolidinyl Mannich bases impart increased activity to the corresponding compounds.

Animals↗
PubMed1994

Antimalarial quinones: redox potential dependence of methemoglobin formation and heme release in erythrocytes.

A number of quinones have been shown to be effective antimalarials. In addition some have been shown to have oxidant effects on glucose-6-phosphate dehydrogenase-deficient red cells. To clarify the mechanism of this oxidant effect and to determine whether it is a general property of antimalarial quinones, the effects of five compounds on red cells were studied. Two, 5-hydroxy-6-demethyl pentaquine (5H6DP) and menadione, caused marked methemoglobin production and the insertion of heme into the red-cell membrane. The other three, atovaquone, daphnetin, and menoctone, did not. The insertion of heme into membranes caused diminished deformability, and this might account for the hemolytic effects. Redox potentials of all five compounds were measured. The two quinones that caused heme release, menadione and 5H6DP, had redox potentials of -141 +/- 12 and -97 +/- 25 mV, respectively, which are similar to the reported redox potentials for hemoglobin. The other three quinones had redox potentials that were either significantly higher or lower. Thus only quinones of the appropriate redox potentials are likely to be toxic to red cells.

Antimalarials↗
PubMed1993

Toxicity of antimalarial drugs in rheumatoid arthritis.

Antimalarials have the lowest incidence of toxicity among the disease modifying antirheumatic drugs (DMARDs). Low daily dose and regular ophthalmologic examination has minimised potential retinopathy. Some toxicity may be related to the lysosomotropic action of antimalarials. DMARD toxicity may affect the variability in response to antirheumatic drugs.

Antimalarials↗
PubMed1996

Ophthalmologic considerations in using antimalarials in the United States.

Ophthalmologic considerations continue to be important in the use of antimalarials. In the United States, hydroxychloroquine is prescribed much more frequently than chloroquine. Despite the favorable safety record, potential retinal problems cause patients to often be afraid to take antimalarial medicine. Ophthalmologic visits are recommended every three months by the drug manufacturer, but most often are scheduled every six months by physicians. Ophthalmologic examination includes questioning about visual symptoms, visual acuity tests, careful fundoscopic evaluation and a visual field assessment. Amsler grid self evaluation is not yet wide-spread.

Antimalarials↗
PubMedDate not supplied

Influence of antimalarials chloroquine, quinine, primaquine and mepacrine on the evolution of Ehrlich ascites tumour.

Substances like imidazoles, benzimidazoles and also quinolines, whose chemical structure includes a heterocyclic nitrogen, are known to interfere with the microsomal oxidation and, in some cases, with the metabolism of drugs. Since chloroquine and primaquine exert this effect in vivo and in vitro, we studied the influence of other antimalarials (quinine and mepacrine) in mice with induced Ehrlich ascites tumour (EAT) to find out whether variations in oxygen consumption affected the course of the disease. In vitro data, obtained by a polarographic technique, indicate that primaquine and, in particular, mepacrine increase EAT-cell oxygen consumption, while in vivo data, obtained in mice injected with an inoculum of about 1 x 10(6) tumour cells per mouse, show that both drugs, but notably mepacrine, accelerate tumour growth, as monitored by Cox's statistical method for body weight, and lead to earlier death. In cases of existing neoplasia, therefore, the potentially toxic effects of certain antimalarials must be borne in mind.

Animals↗
PubMed1997

Direct comparison of antimalarial activity among PS-15 combination therapies by bioassay of serum samples from treated Saimiri sciureus.

Sixteen Saimiri sciureus monkeys were administered PS-15-atovaquone, PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. The in vitro antimalarial activity of serum against Plasmodium falciparum obtained from these monkeys at 3, 6, and 12 hr after the administration of drug(s) were measured by bioassay and analyzed by Duncan's and Newman-Keul's tests. PS-15-atovaquone was found to be the most effective antimalarial combination, followed by PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. These dual PS-15 combinations are effective combinations and, in-particular, PS-15-atovaquone is worthy of further evaluation.

Animals↗
PubMed1998

Unum facere et alterum non omittere: antimalarial strategies in Italy, 1880-1930.

At the end of the XIXth Century the attitude towards malaria changed dramatically from fatalism and resignation to an active policy that made the eradication of the disease a possible objective. This dramatic change in the scientific political and cultural attitudes towards malaria was the result of two main phenomena: i) the impact of the scientific medicine and Pasteurian revolution on medicine and health policies, and ii) the discovery of the theoretical simplicity of the cycle of malaria transmission and of the possibility to interrupt it, by avoiding the contacts between people and the Anopheles mosquitoes. However, scientifically based strategies against malaria were in place before the discovery of the real causative agents and of the transmission cycle at the end of the XIXth century, as the origin of the scientific medicine had already produced a 'rationale' for local and national campaigns against malaria. According to Tommasi-Crudeli, for example, the cause of malaria was not a 'chemical compound', a 'miasma', but a 'living ferment', specific and autonomous. As a consequence, the aim of antimalarial measures was to eliminate the conditions indispensable to the multiplication of the specific ferment contained in the soil. The theory of malaria aetiology changed after the discovery of the transmission cycle by Ross and Grassi, but the general strategy remained the same: to eliminate one of the factors indispensable to the multiplication and diffusion of the agent. The detailed knowledge of the malaria transmission cycle made it possible to define the exact conditions which were alone responsible for the propagation of the disease and its persistence in the endemic areas. The theoretical linearity and the specificity of the 'Grassi's law' was decisive and produced a fundamental paradigmatic shift in the antimalarial policies. The essential point for the epidemiology and prophylaxis of malaria became to clarify the conditions which contribute to facilitate or to prevent the infection of the Anopheles.

Animals↗
PubMed1998

Interventions to improve the use of antimalarials in south-east Asia: an overview.

There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved.

Antimalarials↗
PubMed1978

Cholinomimetic teratogens. VI. The interaction of cholinomimetic teratogens with the antimalarial drugs chloroquine and chlorguanide.

A typical syndrome of short and crooked neck together with muscular hytoplasia of the legs occurs with low incidence in chicken embryos following injection into the egg at 24 hours of incubation of the antimalarial drug chloroquine; but treatment at later stages does not have similar effects. When, however chloroquine was used in addition to carbachol or neostigmine at 96 hours of incubation the malformations caused by the two cholinomimetic compounds, i.e., carbachol and neostigmine, occurred with greatly increased frequency and tended also to be exaggerated in expression. Chlorguanide, another antimalarial drug, when used as additive, reduced the teratogenic effects of such compounds as decamethonium and neostigmine. It appears that the neuromuscular pathways to teratogenicity are for carbachol and neostigmine and for chloroquine clearly related, if at different levels of expressivity.

Abnormalities, Drug-Induced↗
PubMed2000

Establishment of an in vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type..

The establishment of an in vitro screening model for neurodegeneration inducing antimalarial drugs was conducted in stepwise fashion. Firstly, the in vivo selective neurotoxic potency of artemisinin was tested in neuronal cells in vitro in relation to the cytotoxic potency in other organ cell cultures such as liver and kidney or versus glial cells. Secondly, a comparison between different parts of the brain (cortex vs. brain stem) was performed and in the last step, a fast and sensitive screening endpoint was identified. In summary, non-neuronal cell lines such as hepatocytes (HEP-G2), liver epithelial cells (IAR), proximal tubular cells (LLC-PK(1)) and glial cells from the rat (C6) and human (GO-G-IJKT) displayed only moderate sensitivity to artemisinin and its derivatives. The same was found in undifferentiated neuronal cell lines from the mouse (N-18) and from human (Kelly), whereas during differentiation, these cells became much more sensitive. Primary astrocytes from the rat also were not specifically involved. In the comparison of primary neuronal cell cultures from the cortex and brain stem of the rat, the brain stem was found to be more sensitive than the cortex. The neurotoxic potential was determined by cytoskeleton elements (neurofilaments), which were degradated in vitro by diverse neurodegenerative compounds. In comparison of dog and rat primary brain stem cultures, the dog cells were found to be more sensitive to artemisinin than the rat cells. In addition to the primary brain stem cell cultures it was shown that the sprouting assay, which determines persistent delayed neurotoxic effects, is also useful for screening antimalarial drugs. To other compounds, artemether and artesunate, showed that use of the sprouting assay followed by primary brain stem cultures of the rat will be a good strategy to select candidate compounds.

Journal Article↗
PubMed1993

Further evidence for the interaction of the antimalarial drug amodiaquine with ferriprotoporphyrin IX.

Evidence for complex formation of the antimalarial drug amodiaquine (AD) with ferriprotoporphyrin IX (FP) in aqueous medium is presented, in addition to previous preliminary data. A mole ratio of one between the complex components is determined for the insoluble complex at pH 6.7-6.8. Mössbauer data obtained at pH 7-8 and at higher concentrations in the millimolar range confirm the interactions existing between the complex components. These data are considered to aid in removing previous objections to a mechanism of antimalarial action involving complexes of FP with AD and related drugs.

Amodiaquine↗
PubMed1993

Effect of the antimalarial agents primaquine and (N'-3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl)1,4-pent ane-diamine on oxidative stress and antioxidant defences in mice.

The effects of the newly developed antimalarial compound, CDRI 80/53 [(N'-3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl)1,4- pentane-diamine], and primaquine (PQ) on the antioxidant system of mice were determined at equi-effective antimalarial doses on enzyme systems responsible for protection against oxygen, i.e. hepatic superoxide dismutase and catalase. While PQ significantly inhibited these enzyme activities CDRI 80/53 did not. However, both compound 80/53 and PQ increased the level of superoxide anion and lipid peroxidation. It is concluded that compound 80/53 has less effect on antioxidant defence enzymes than PQ.

Animals↗
PubMed1984

Pharmacokinetics of oral contraceptive steroids following the administration of the antimalarial drugs primaquine and chloroquine.

The effects of a single dose of two antimalarial drugs chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (O.C.) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyloestradiol (EE2) and levonorgestrel were measured by radioimmunoassay following administration of a single dose of O.C. (30 micrograms EE2 + 150 micrograms levonorgestrel) in the absence and presence of the antimalarial drugs (PQ, 45 mg; CQ, 300 mg). Neither CQ or PQ given 1 h before the O.C. had any significant effect on plasma concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of O.C.'s. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

Adult↗