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Biomedical subjects

G Meyniel

Publications and source records attributed to G Meyniel.

At least 19 recordsLinked to original sources

[Effects of radiation on man].

Living on Earth, man is subjected to a shower of radiation, of cosmic, telluric and internal origin. Variations in the level of radiation over time have left biological imprints; Man first learned about artificial radiation, then learned how to produce it, revolutionizing medical diagnosis and treatment, and producing huge quantities of energy, particularly electric energy. In les than a century, knowledge or radiobiology brought man to a good mastery of the use or radiation within precise norms. With the application of these norms, a corollary appeared: the halt in increasing incidences of cancer and leukemia, as had been the case for the pioneers in radiobiology at the beginning of the century. However, the notion persists that ionising radiation, even at insignificant doses, is dangerous for man. Recent advances concerning DNA repair, hormesis and cancerogenesis are reassuring with regard to the present standards The French Académie des Sciences has pronounced that the present rules "are prudent and ensure an appreciable margin of security".

Humans

[Involvement of PAF (Platelet-Activating Factor) in chloroquine-induced retinopathy].

Chloroquine retinopathy is a severe toxic retinal impairment which may result in loss of vision by alterations of the pigmentary epithelium and photoreceptors. Currently, there is no specific treatment for this retinopathy. In order to test the possible involvement of Platelet-Activating Factor (PAF) in chloroquine-induced retinopathy and the use of PAF antagonists for prevention of this condition, we have examined the effect of these substances on the electroretinogram (ERG) of isolated rat retina. When retinas from normal rats were perfused with chloroquine (10(-6) M), a marked and rapid decrease in ERG b-wave amplitude was observed. In contrast, chloroquine had no effect on the ERG of retina isolated from animals pretreated with the PAF antagonist, BN 50730 (30 mg/kg/day i.p., 5 days). The results obtained indicate that (i) chloroquine is a toxic drug for retinal function, (ii) PAF plays a key role in chloroquine retinopathy and (iii) PAF antagonists may constitute valuable agents for the treatment of this retinal impairment.

Animals

Excision of imidazole ring-opened N7-hydroxyethylguanine from chloroethylnitrosourea-treated DNA by Escherichia coli formamidopyrimidine-DNA glycosylase.

Alkylkation of the N7 of guanine residues in DNA favours the opening of the imidazole ring, yielding a formamidopyrimidine (Fapy). This Fapy residue blocks DNA replication and is actively excised by a DNA glycosylase. We have cloned and sequenced the Escherichia coli gene responsible for synthesis of the enzyme, which has also been purified to homogeneity. It was found to have associated apurinic/apyrimidinic (AP) lyase activity, nicking DNA at AP sites. Chloroethylnitrosoureas are used in cancer chemotherapy. The lesions induced in DNA by these compounds, including N7-chloro- and hydroxyethylguanine, are excised by E. coli 3-methyladenine DNA glycosylase II, and we report that the corresponding imidazole ring-opened forms are repaired by Fapy-DNA glycosylase. Human cells have the counterpart to these enzymes, which could contribute to the repair of these lesions during chemotherapy.

Antineoplastic Agents

[Perspectives of scintigraphic diagnosis of malignant lymphoma using a new radiopharmaceutical].

In the sequence of our studies on radiopharmaceuticals for malignant melanoma detection the results were most promising for the possible use of 125I or 123I-N-(2-diethyl amino ethyl)4-iodobenzamide. The biodistribution in mice bearing melanoma either human or animal from 4 to 24 hrs. post i.v. injection showed high uptake in tumor tissue together with relatively low uptake in muscle, brain, lung and liver. Scintigraphic images of the tumor obtained at the same times confirmed that melanoma detection was very promising.

Animals

Presence of specific platelet-activating factor binding sites in the rat retina.

The specificity of the effects of platelet-activating factor (PAF) on the electrophysiology of the retina suggests the existence of specific sites for PAF in this tissue. In this study, we report the presence of tritiated PAF ([3H]PAF) specific binding sites in membrane preparations of the retina of albino rats. The binding of [3H]PAF was saturable, specific, time-dependent and reversible. Scatchard analysis of the data revealed that the high-affinity retinal binding site possessed a Kd of 2.9 +/- 0.4 nM and Bmax of 0.85 +/- 0.16 pmol/mg protein. These values are comparable with those found for the membranous PAF receptor sites in platelets, neutrophils, lung tissue and brain. We have recently reported that PAF dose dependently modulates the b-wave of the electroretinogram (ERG) obtained from the isolated rat retina. The results of the present study suggest that such PAF-induced disturbances of the ERG may be mediated via specific receptors located in the retina.

Animals

Metabolism of a new radioprotector; S-acetyl-N-glycyl cysteamine. II. Main tissue metabolites in mice bearing EMT6 tumours.

1. The major tissue metabolites of the radioprotector S-acetyl-N-glycl cysteamine (I) labelled with 14C on the cysteamine group, were quantified and identified in normal tissues and EMT6 tumours implanted in mice, by chromatographic comparison with authentic reference compounds. 2. In all tissues the radioprotector undergoes rapid deacetylation and hydrolysis leading to the formation of cysteamine, which is the main metabolite involved in radioprotection. A major part of this metabolite is reversibly inactivated by binding to endogenous SH. 3. The differential radioprotection of healthy tissues versus EMT6 tumour is explained both by a lower uptake of radioprotector, and a weaker deacetylation and hydrolysis rate, in the tumour cells.

Animals

[Inhibition of transducin by lithium: electrophysiological demonstration using the isolated retina].

Recently Avissar et al. have established that Li+ can inhibit G proteins implicated in brain function. In order to investigate the effect of Li+ on transducin, the evolution of the electroretinogram (ERG) recorded on isolated rat retina has been studied in presence of lithium. Results indicate that 10(-5) M Li+ had no effect on ERG while 10(-3) M Li+, which corresponds to therapeutic blood levels, significantly decreases ERG amplitude. This effect being nearly totally inhibited by cholera toxin (75 micrograms/l), it is concluded that Li+ acts on transducin and so inhibits the visual transduction process.

Animals

Effects of platelet-activating factor on electrophysiology of isolated retinas and their inhibition by BN 52021, a specific PAF-acether receptor antagonist.

The effects of (R)PAF-acether have been tested on the isolated rat retina model. Results indicate that (R)PAF-acether inhibits the electrophysiological response (electroretinogram) elicited on isolated retina by a brief light flash. Immediately after the administration of (R)PAF-acether, an irreversible decrease of the electroretinogram b-wave amplitude is observed. This effect is dose-dependent (2 X 10(-11) M, 2 X 10(-9) M, 2 X 10(-7) M) and partially inhibited by simultaneous administration of Ginkgolide B (BN 52021; 2 X 10(-5) M). These results suggest the existence of (R)PAF-acether-specific receptors inside the retina.

Animals

Disposition of new sulphur-containing 2-(chloroethyl)nitrosoureas in rats.

N'-(2-Chloroethyl)-N-[2-(methylsulphinyl) ethyl] and N'-(2-chloroethyl)-N-[2-(methylsulphonyl) ethyl]-N and N'-nitrosoureas (CMSOEN1, CMSO2EN1, CMSOEN2 and CMSO2EN2) are new nitrosoureas derived from cysteamine. Two of them (CMSOEN2 and CMSO2EN2) have shown excellent efficacy against several murine tumours. The inactive agents (CMSOEN1 and CMSO2EN1) display low alkylating activity but high carbamoylating activity. In contrast, the active agents (CMSOEN2 and CMSO2EN2) are strong alkylating agents but relatively weak carbamoylators. The disposition of CMSOEN2 and CMSO2EN2 was studied in rat, using two differently labelled species of each compound, administered i.v. (60 mumol/kg). Plasma disappearance, tissue distribution (with the exception of the brain) and elimination of radioactivity are similar for the two compounds similarly labelled. In contrast, these parameters are strongly influenced by the label position used. Plasma disappearance of unchanged CMSOEN2 and CMSO2EN2 follows a first-order kinetic process with the same half-life for both compounds (30-31 min). More unchanged CMSO2EN2 is found in brain compared to its congener (55 nmol/g and 37 nmol/g respectively at five minutes). This is most likely the consequence of the higher lipophilic character of the former compound. The breakdown product 2-chloroethanol was identified in plasma.

Alkylation

Effects of PAF-acether on electrophysiological response of isolated retina.

Results of experiments performed on rat isolated retina indicate that platelet-activating factor (PAF) is able to inhibit the functional response of the retina electroretinogram (ERG) recorded in response to a brief light flash. In the presence of PAF, the ERG b-wave amplitude decreases according to a dose-dependent (2.10(-11) M; 2.10(-9) M; 2.10(-7) M) process. This effect is partially inhibited by the simultaneous administration of a Ginkgo biloba extract (GBE, 10 mg/l) or Ginkgolide B (BN 52021, 2.10(-5)M). The authors interpret these results with reference to the main mechanism of the membrane signal triggered by PAF, namely the activation of phosphatidylinositol cycle with the formation of inositol-triphosphate, the inhibition of the light-induced response of the retina by administration of inositol-triphosphate, and the antagonistic effect of GBE and BN 52021 on specific PAF-receptors demonstrated on other models. Thus specific PAF-receptors may exist at the level of the retina, which suggests that they are also present in the brain.

Animals

Cytostatic action of two nitrosoureas derived from cysteamine.

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26. 6 Haematological toxicity of both active metabolites is lower than that of CNCC, particularly on platelets which is the main toxicity location due to nitrosoureas.

Animals

IgG purification to measure the level of an iodinated thyroglobulin peptide, the 3,5,3',5' tetraiodo-l-tyrosyl-l-tyrosine in human serum.

Antibodies reacting with 3,5,3',5' tetraiodo-l-tyrosyl-l-tyrosine (I2Tyr-I2Tyr) were elicited in rabbits by immunization with an oxidized yeast conjugate coupled with I2Tyr-I2Tyr. Ion-exchange chromatography was used to purify immunoglobulins, in order to improve the specificity in measurement of I2Tyr-I2Tyr level in patient serum. IgG binding capacity versus I2Tyr-I2Tyr was considerably increased after immunoglobulin purification.

Animals

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice. Among these compounds, two of them exhibited a greater antitumor activity compared to that of the parent mixture.

Animals

Disposition in rats and mice of 7-methoxy-2-nitronaphtho[2,1-b]furan.

The disposition of 7-methoxy-2-nitronaphtho[2,1-b]furan (MNNF), labelled with 14C in the furan ring (label 1) and in the methoxy group (label 2) has been studied in rats and mice. After i.p. administration to rat (5 mg/kg), both labelled species were absorbed by the lymphatics; and after oral administration, through the intestinal lumen. Excretion of the furan ring (label 1) is mainly urinary (44% dose in 24 h); label 2 was mostly expired as 14CO2 (48% dose in 24 h), indicating considerable demethylation. No target organ was found for MNNF, except liver and kidney. For both labelled species given orally, radioactivity was bound to the intestinal wall. Preliminary metabolic studies, using t.l.c. and h.p.l.c., have shown the presence of an urinary metabolite, namely, the glucuronide of 7-hydroxy-2-nitronaphtho[2,1-b]furan (15-20% of the urinary radioactivity). The remaining radioactivity comprises basic compounds, that bind to a cationic resin, which might be formed by enzymic reduction of the nitro group.

Administration, Oral

Effects of leukotrienes on the electroretinographic profile of the isolated rat retina.

The isolated retina represents an excellent membrane model since it provides a specific electrophysiological response that is easy to quantify. Therefore the authors have tested the effects of B4, C4 and D4 leukotrienes on this model. In the presence of leukotrienes, electrical response generally decreases and survival duration of the isolated retina is generally shortened. No significant difference between the effects of the three tested products has been found. These results are discussed in relation to, on the one hand, the mechanism of intraretinal generation of its electrophysiological signal and, on the other hand, the leukotrienes' role in inflammatory diseases of the retina.

Animals

Effects of lipid peroxidation on the isolated rat retina.

The effects of membrane lipid peroxidation are determined in isolated albino rat retina. Lipoperoxidation induced by addition of Fe2+ + ascorbate to the perfusion liquid leads to an irreversible decrease of amplitude in the electroretinogram. The experimental model proposed here provides the possibility to monitor the survival of the retina and demonstrates that ocular lipid peroxidation very notably shortens the survival time. The specific role of the rod membranes for the excitation mechanism in the retina as revealed by these experiments is discussed.

Animals