Biomedical subjects

M Chéron

Publications and source records attributed to M Chéron.

11 recordsLinked to original sources

PubMed2003

Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice.

OBJECTIVE: To study the toxicity and activity of two new amphotericin B formulations: poly(epsilon-caprolactone) nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM). MATERIALS AND METHODS: The toxicity of these formulations was evaluated in erythrocytes, J774.2 macrophages and LLCPK1 renal cells, as well as in mice. Activity was determined in clinical isolates and in neutropenic mice. Mice were made neutropenic with 5-fluorouracil, infected with Candida albicans and treated with the antifungal formulations for three consecutive days. AmB association in cells and accumulation in kidneys and liver of animals was quantified by HPLC. RESULTS: Both formulations decreased between 8- and 10-fold the MIC of the polyene against clinical isolates of C. albicans. However, their activity was lower than or equal to that of AmB-deoxycholate when it was assessed against C. albicans-infected macrophages. When given as a single intravenous dose in mice, AmB-MM and AmB-NP had an LD50 of 9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmB-deoxycholate. Comparison of residual infection burdens in the liver and kidneys showed that AmB-deoxycholate (0.5 mg/kg) was more effective and faster in eradicating yeast cells than polymeric formulations. This fact can be related to a lower AmB accumulation inside macrophages and in liver and kidneys (about 1.5 mg drug/g tissue) of mice, compared with those detected for AmB-deoxycholate (4 mg drug/g). Overall, the efficacy of these formulations at 2 mg/kg was equal to that of AmB-deoxycholate at 0.5 mg/kg. CONCLUSIONS: AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher concentrations were therefore necessary to obtain a similar therapeutic effect. However, these higher concentrations were achievable owing to the reduced toxicity of these formulations.

Amphotericin B↗

PubMed2001

[Primary Neisseria meningitidis arthritis of the knee without meningitis: contribution of synovial fluid culture in blood-culture vial].

INTRODUCTION: Primary meningococcal arthritis is a rare form of meningococcal disease. It occurs as an isolated acute purulent arthritis without meningitis, and presence of Neisseria meningitidis in articular fluid. We report a new case of typical primary meningococcal arthritis. EXEGESIS: A previously healthy 23-year-old female patient was admitted for purpuric lesions of the legs. At admission, conscience was normal and symptoms of meningitis were absent. During the 2nd day of hospitalisation, a warm and painful effusion in the right knee appeared. Aspiration from the right knee yielded a purulent fluid. N. meningitidis was isolated from a blood-culture vial inoculated with the synovial fluid, while blood cultures remained sterile. Anti-biotherapy was initiated as soon as microbiological diagnosis was established. The patient was symptom-free 1 month later. CONCLUSION: We emphasize the fact that agar cultures of the synovial fluid remained sterile, while N. meningitidis grew in a blood-culture vial. We suggest that diagnosis of primary meningococcal arthritis may be underestimated when inappropriate culture media are used.

Adult↗

PubMed2000

Lymph node infection by Trichomonas tenax: report of a case with co-infection by Mycobacterium tuberculosis.

In an 82-year-old woman, presenting with fever and asthenia, cervical adenopathy was noted. Clinical and radiological investigations were fruitless. Laboratory examinations detected a refractory anemia. The lymph node was excised and showed numerous trichomonads on touch preparations. Histologically, the node showed caseous necrosis and macrophagic reaction. Diagnosis of lymph node infection by Trichomonas tenax was made. Three weeks later, culture of the node showed Mycobacterium tuberculosis and let us conclude co-infection. T tenax is usually regarded as a harmless saprophyte of the oral cavity. This exceptional observation shows for the first time an invasive potential of T tenax. It raises questions about links with tuberculosis and refractory anemia.

Aged↗

PubMed1998

In-vivo therapeutic efficacy in experimental murine mycoses of a new formulation of deoxycholate-amphotericin B obtained by mild heating.

Heat-induced 'superaggregation' of deoxycholate-amphotericin B (AmB-DOC, Fungizone) was shown previously to reduce the in-vitro toxicity of this antifungal agent. We compared AmB-DOC with the formulation obtained by heating the commercial form (Fungizone, Bristol Myers Squibb, Paris, France) for 20 min at 70 degrees C, in the treatment of murine infections. An improvement of antifungal activity was obtained with heated AmB-DOC formulations due to a lower toxicity which allowed the administration of higher drug doses than those achievable with the commercial preparation. Single intravenous injections of heated AmB-DOC solutions were demonstrated to be two-fold less toxic than unheated ones to healthy mice. For mice infected with Candida albicans, the maximum tolerated dose was higher with heated than with unheated AmB-DOC solutions. In the model of murine candidiasis, following a single dose of heated AmB-DOC 0.5 mg/kg, 85% of mice survived for 3 weeks, whereas at this dose the immediate toxicity of the standard formulation in infected mice restricted the therapeutic efficacy to 25% survival. Both formulations were equally effective in increasing the survival time for murine cryptococcal pneumonia and meningoencephalitis. Injection of heated AmB-DOC solutions at a dose two-fold higher than the maximal tolerated dose observed with the unheated preparation (1.2 mg/kg) increased the survival time by a factor of 1.4 in cryptococcal meningoencephalitis. These results indicate that mild heat treatment of AmB-DOC solutions could provide a simple and economical method to improve the therapeutic index of this antifungal agent by reducing its toxicity on mammalian cells.

Amphotericin B↗

PubMed1997

Physico-chemical properties of the heat-induced 'superaggregates' of amphotericin B.

The aggregation state of amphotericin B (AmB) was previously reported to modulate its therapeutic efficiency. As a preliminary study to test the biological effects of 'superaggregates' generated by heat treatment, we present spectroscopic data related to their formation in aqueous solutions. Drastic changes in the AmB aggregation state in water were shown to occur on heating at 50-60 degrees C. The concentration of the aggregates formed at high (A(t)) or room (A) temperature, and the concentration of the monomeric form (M) of AmB were calculated by processing absorption data. The thermally induced conversion from A to A(t) depends on the AmB concentration. Rayleigh scattering measurements suggest that the A(t) aggregates are larger than the A aggregates. At room temperature, the condensation rate of A with M-leading to the 'superaggregated' form A(t)-was slower and depended on the concentration of M. The superaggregated species A(t) was shown to be the most chemically stable species. Physico-chemical properties of these superaggregates are discussed as a potential new solution to improve the therapeutic efficacy of AmB.

Journal Article↗

PubMed1997

Heat-induced superaggregation of amphotericin B reduces its in vitro toxicity: a new way to improve its therapeutic index.

Superaggregation of amphotericin B (AmB) was previously shown to occur upon heating of solutions at 70 degrees C. In the present study, we demonstrate that heat pretreatment of Fungizone (deoxycholate salt of AmB [AmB-DOC]) solutions induces a drastic decrease in the in vitro toxicity of this antibiotic. Heated AmB-DOC colloidal solutions, which mainly contained superaggregated and monomeric forms of the antibiotic, were strongly less hemolytic than unheated solutions (aggregates and monomers). Thermal pretreatment of AmB-DOC solutions also reduced the toxicity to the cell line HT29, as deduced from two simultaneous cell viability assays (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release). These heated colloidal solutions were only slightly less efficient than the unheated ones at inhibiting the growth of Candida albicans cells in vitro. Such results suggest that mild heat treatment of AmB-DOC solutions could provide a new and simple solution for improving the therapeutic index of this antifungal agent by reducing its toxicity to mammalian cells.

Amphotericin B↗

PubMed1997

Release of amphotericin B from delivery systems and its action against fungal and mammalian cells.

Spectroscopic studies of four amphotericin B (AmB) lipid preparations--small negatively charged unilamellar vesicles "AmBisome", positively charged oligolamellar liposomes "Ampholiposomes", AmB Lipid Complex "L-AmpB33"--and AmB association with gamma cyclodextrin demonstrated that the composition of drug delivery system directly influences AmB organization. The aggregation state and release in external medium of AmB was monitored by circular dichroism and UV-visible absorption. AmB short-term activity against Candida albicans (K+ leakage) was found to be correlated with the amount of free AmB released from lipid preparations. These data seem to indicate that lipid composition influences anti-Candida albicans activity, by modulation of AmB binding to lipids.

Amphotericin B↗

PubMed1994

In vitro renal toxicity and in vivo therapeutic efficacy in experimental murine cryptococcosis of amphotericin B (Fungizone) associated with Intralipid.

We compared the experimental toxicities and activities of deoxycholate amphotericin B (d-AmB) dissolved in glucose (Dd-AmB) or mixed with 20% Intralipid (ILd-AmB). In vitro, ILd-AmB against renal tubular cells in primary culture. In vivo, the toxicities and activities of Dd-AmB and ILd-AmB were studied in DBA2 mice with cryptococcosis. The maximum tolerated dose of intravenously administered d-AmB, i.e., the dose that induced less than 15% mortality because of toxicity, was 1.7 to 2.5 times higher when it was administered as ILd-AmB than when it was administered as Dd-AmB. Both treatments given intravenously at the same dose were equivalent for improving the survival of mice and reducing CFU counts in infected tissue, but at maximum tolerated doses, ILd-AmB (2 mg/kg of body weight) was more effective than Dd-AmB (0.8 to 1.2 mg/kg). AmB concentrations in spleen, liver, lung, and kidney were measured by high-pressure liquid chromatography 4 and 24 h after a single injection of 1.2 mg of Dd-AmB per kg, 1.2 mg of ILd-AmB per kg, or 2 mg of ILd-AmB per kg. In a given organ, AmB levels were similar after administration of 1.2 mg of Dd-AmB or ILd-AmB per kg but were significantly higher after administration of 2 mg of ILd-AmB per kg. The lower level of toxicity of ILd-AmB might be explained by circular dichroism experiments, showing that ILd-AmB contained 10-fold less soluble oligomeric AmB, which is believed to be the toxic form of the drug, than Dd-AmB. We conclude that ILd-AmB is as efficient as Dd-AmB and is better tolerated than Dd-AmB in mice with experimental cryptococcosis. By allowing higher doses of AmB to be infused, Intralipid enhances AmB concentrations in infected sites, and thus the therapeutic activity of the drug.

Amphotericin B↗

PubMed1988

Quantitative structure-activity relationships in amphotericin B derivatives.

The quantitative structure-activity relationships studies of amphotericin B and its 16 semisynthetic derivatives obtained by modification at carboxyl and amino groups have been done. The results of five biological tests were subjected to principal component analysis, a numerical method useful in the investigation of large sets of data. For some compounds, also, interaction with lipidic vesicles was investigated by spectroscopic methods. The results obtained indicate that: (i) The presence of positively charged nitrogen atom (protonable or bearing fixed charge) is indispensable for biological activity and antibiotic-sterol interaction; (ii) The lack of free carboxyl group in the molecule favours the differentiation between cholesterol and ergosterol containing cells.

Amphotericin B↗

PubMed1984

Inhibition by Cu2+ of amphotericin B induced lysis of erythrocytes.

Amphotericin B-induced lysis of erythrocytes is diminished in the presence of Cu2+, but the prelytic amphotericin B-induced K+ leakage is unaffected. These results and the weak binding of Cu2+ to amphotericin B, demonstrated by circular dichroism and EPR studies, are consistent with the view that Cu2+ protects erythrocytes by increasing their resistance to lysis.

Amphotericin B↗

PubMed1981

[Incorporation of (3R,3'R)zeaxanthin in vesicles of dipalmitoyl phosphatidylcholine. Circular dichroism analysis].

The organization of carotenoids in biological membranes has been investigated by monitoring by circular dichroism the incorporation of (3R, 3'R) zeaxanthin in small unilamellar vesicles of dipalmitoyl phosphatidylcholine (DPPC). For ratios zeaxanthin/phospholipid greater than 1/30, a drastic circular dichroism increase indicates the existence of a new type of interaction between zeaxanthin and DPPC.

Biophysical Phenomena↗