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M Calas

Publications and source records attributed to M Calas.

11 recordsLinked to original sources
PubMed2000

Antimalarial activity of compounds interfering with Plasmodium falciparum phospholipid metabolism: comparison between mono- and bisquaternary ammonium salts.

On the basis of a previous structure-activity relationship study, we identified some essential parameters, e.g. electronegativity and lipophilicity, required for polar head analogues to inhibit Plasmodium falciparum phospholipid metabolism, leading to parasite death. To improve the in vitro antimalarial activity, 36 cationic choline analogues consisting of mono-, bis-, and triquaternary ammonium salts with distinct substituents of increasing lipophilicity were synthesized. For monoquaternary ammonium salts, an increase in the lipophilicity around nitrogen was beneficial for antimalarial activity: IC(50) decreased by 1 order of magnitude from trimethyl to tripropyl substituents. Irrespective of the polar head substitution (methyl, ethyl, hydroxyethyl, pyrrolidinium), increasing the alkyl chain length from 6 to 12 methylene groups always led to increased activity. The highest activity was obtained for the N,N,N-tripropyl-N-dodecyl substitution of nitrogen (IC(50) 33 nM). Beyond 12 methylene groups, the antimalarial activities of the compounds decreased slightly. The structural requirements for bisquaternary ammonium salts in antimalarial activity were very similar to those of monoquaternary ammonium salts, i.e. polar head steric hindrance and lipophilicity around nitrogen (methyl, hydroxyethyl, ethyl, pyrrolidinium, etc.). In contrast, with bisquaternary ammonium salts, increasing the lipophilicity of the alkyl chain between the two nitrogen atoms (from 5 to 21 methylene groups) constantly and dramatically increased the activity. Most of these duplicated molecules had activity around 1 nM, and the most lipophilic compound synthesized exhibited an IC(50) as low as 3 pM (21 methylene groups). Globally, this oriented synthesis produced 28 compounds out of 36 with an IC(50) lower than 1 microM, and 9 of them had an IC(50) in the nanomolar range, with 1 compound in the picomolar range. This indicates that developing a pharmacological model for antimalarial compounds through choline analogues is a promising strategy.

Animals↗
PubMed2000

[Vocal cord dysfunction simulating severe corticoid-dependent asthma].

We report a case of severe asthma initially considered as cortico-resistant. Clinical analysis of dyspneic attacks demonstrated they were atypical, sometimes associated with dysphonia and syncopes. Severity of clinical presentation was discordant with lung function tests. The diagnosis of vocal cord dysfunction was confirmed by ENT specialized examination. It showed paradoxal inspiratory adduction of the vocal cords triggered by exercise. Treatment remained however difficult, based on speech therapy, relaxation and psychotherapy. This observation underlines the influence of searching a vocal cord dysfunction in cortico-dependent asthma, especially if clinical presentation is atypical. Treatment of this condition may allow to decrease steroid treatment in such patients.

Adrenal Cortex Hormones↗
PubMed1999

Transport of phospholipid synthesis precursors and lipid trafficking into malaria-infected erythrocytes.

Phospholipid biosynthesis in Plasmodium is of crucial importance considering the high degree of membrane biogenesis. In the de novo phosphatidylcholine pathway, the major plasmodial phospholipid, choline, first enters infected erythrocytes by a transport-mediated process, whose main kinetic characteristics are the same as in normal cells except for a considerable increase in Vm. The kinetic and functional characterizations of the choline carrier (affinity, specificity, stereoselectivity, asymmetric cyclic model, ionic dependence, limiting step in carrier translocation) have now been done, although there is no information concerning its nature and structure, despite the fact that it is likely an outstanding pharmacological target. Other unanswered questions concern the mechanisms for choline entry into the parasite. The intense lipid trafficking between the intracellular parasite and the host cell membrane also indicates that Plasmodium controls its own lipid composition as well as that of its host cell. Organelles that house the machinery for lipid synthesis, and mechanisms for trafficking and sorting, have not yet been described because of the lack of appropriate tools, but they could address fundamental questions in the contemporary cell biology of this parasite.

Animals↗
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↗
PubMed1997

Antimalarial activity of molecules interfering with Plasmodium falciparum phospholipid metabolism. Structure-activity relationship analysis.

A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.

Animals↗
PubMed1994

Present development concerning antimalarial activity of phospholipid metabolism inhibitors with special reference to in vivo activity.

The systematic screening of more than 250 molecules against Plasmodium falciparum in vitro has previously shown that interfering with phospholipid metabolism is lethal to the malaria parasite. These compounds act by impairing choline transport in infected erythrocytes, resulting in phosphatidylcholine de novo biosynthesis inhibition. A thorough study was carried out with the leader compound G25, whose in vitro IC50 is 0.6 nM. It was very specific to mature parasites (trophozoïtes) as determined in vitro with P. falciparum and in vivo with P. chabaudi -infected mice. This specificity corresponds to the most intense phase of phospholipid biosynthesis activity during the parasite cycle, thus corroborating the mechanism of action. The in vivo antimalarial activity (ED50) against P. chabaudi was 0.03 mg/kg, and a similar sensitivity was obtained with P. vinckei petteri, when the drug was intraperitoneally administered in a 4 day suppressive test. In contrast, P. berghei was revealed as less sensitive (3- to 20-fold, depending on the P. berghei-strain). This difference in activity could result either from the degree of synchronism of every strain, their invasion preference for mature or immature red blood cells or from an intrinsically lower sensitivity of the P. berghei strain to G25. Irrespective of the mode of administration, G25 had the same therapeutic index (lethal dose 50 (LD50)/ED50) but the dose to obtain antimalarial activity after oral treatment was 100-fold higher than after intraperitoneal (or subcutaneous) administration. This must be related to the low intestinal absorption of these kind of compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The design of original antimalarial drugs. An example of phospholipid metabolism.

The aim of our program was to find an original chemotherapeutical treatment (and eventually a preventive treatment) of malaria, an illness largely predominant in developing countries, by interfering on an essential metabolism developed by Plasmodium during its erythrocytic phase. Apart from what has been learnt about metabolism and the pharmacological target, a crucial step has been taken during this contract by passing from micromolar in vitro active concentrations (during 1986-1990) to nanomolar ones (during 1990). These compounds should naturally short-circuit resistance phenomena already established against drugs in current use, as has already been verified on polypharmacoresistant strains or isolates of P. falciparum. The administration of a therapeutic dose of our molecules would now appear to be possible in all cases.

Animals↗
PubMed1992

Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism.

The future of antimalarial chemotherapy is particularly alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaying resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate the phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug able to interfere with this Plasmodium membranes. Any drug able to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity threshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphoblastoid cell line, demonstrating a total absence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20- to 100-fold lower than their acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble.

Animals↗
PubMed1991

[Management of unilateral vocal cord paralysis].

The phoniatric analysis evaluates the importance of the vocal disorder and the appearance of the larynx what permets to find five clinical cases. For each one, there is a precise treatment: no treatment, rehabilitation with precises exercises in each case, collagen injection, early or secondary to rehabilitation. The rehabilitation will be intensive and done as soon as possible. It is based on a well known body proprioception. Intrinsic laryngeal muscles work, breathing exercises, exercises aimed at restoring the laryngeal sphincter will precede the pure vocal work. Author's experience shows that the results are good if rehabilitation is well indicated from the beginning and the patient with good motivations.

Humans↗
PubMed1989

[Vocal pathology of teachers].

Out of 100 teachers referred to a phoniatric department for dysphonia, we recorded 11 dysfunctional lesion-free dysphonias, 86 dysphonias with lesions, 3 post-surgical dysphonias, 76 patients referred for a dysphonia with a modification of the spoken voice, and only 3 for the singing voice. 96 suffered from vocal fatigue, and in the course of the clinical examination 85 patients presented a faulty vocal attitude. The most frequent lesions were nodules and para-nodular formations. Vocal re-education was prescribed in 90 cases, and laryngeal microsurgery in 25 cases. The other medical therapies are not be overlooked, such as physiotherapy, thermal cures, psychiatric treatment, treatments of the terrain, and endocrinic treatments. A vocal examination, better information and vocal training of future teachers will make it possible to obviate such disorders.

Adult↗