Ethics committee recommendations for laboratory animals in private research in France.

Complementary to existing legislation, non-public research companies in France have been working together voluntarily within an organization known as Grice (Interprofessional Working Group on Ethics Committees for Laboratory Animals/Groupe de Réflexion Interprofessionnel sur les Comites d'Ethique appliquée à l'animal de laboratoire) with the objective of creating institutional ethics committees in an effort to promote animal welfare and good scientific procedures. Each company's commitment to the creation of these committees has been expressed by signing the Charter. Each ethics committee is composed of at least three members, including one who is not a scientist; a veterinarian is highly desirable. The committee examines all procedures and protocols involving animals and hands down a favourable or unfavourable opinion, or requests improvements, especially concerning animal well-being. Consensual approval of the protocol is an essential requirement before the purchase or allocation of animals. The committee examines every aspect of laboratory animal housing and care, and inspects all temporary or permanent animal housing facilities. Grice will continue its efforts in relation with public research organizations as well as with groups and in other countries whose objectives are in line with its own.

Synthesis of various analog derivatives of ORG13514 as 5-HT1A ligands.

In connection with the development of new potential 5-HT1A ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-dihydro-1,4-dioxinol[2,3-b]pyridin e derivatives as ORG13514 analogs are described. Their biological activity as 5-HT1A type ligands is reported and compared with ORG13514 affinity and selectivity for 5-HT1A receptors.

[(Arylpiperazino-4-butyryl)-6 benzoxazolinones and reduction products: chemistry and pharmacodynamic study]. / (Arylpipérazino-4 butyrl)-6 benzoxazolinones et preduits de réduction: étude chimique et pharmacodynamique.

The synthesis of various 6-(4-arylpiperazino-butyryl)-3-methyl-benzoxazolinones and their reduction products, 6-(4-arylpiperazino-1-hydroxy-butyl)-3-methyl-benzoxazolinones and 6-(4-arylpiperazino-butyl)-3 methyl-benzoxzolinones, is described. These compounds were tested for psychotropic and analgesic activities.

[Synthesis and pharmacologic study of 6-(amino-2 ethyl) benzoxazolinones]. / Synthèse et étude pharmacologique d'(amino-2 éthyl)-6 benzoxazolinones.

Reaction of various amines on 6-(2-bromoethyl)benzoxazolinone or its N-methylated derivative provided eleven new 6-substituted aminoalkyl analogues. In a pharmacological evaluation, several compounds bearing an arylpiperazinic moiety were found to possess significant effects on arterial blood pressure and on the central nervous system; two of them showed interesting analgesic activity.

Sudden death and experimental acute myocardial infarction.

Acute myocardial ischemia was produced by ligature of the anterior descending coronary artery on 658 dogs in 3 separate laboratories. Overall, 12% of the dogs died within the first hour (instantaneous death) and 25% within the first 24 hours (sudden death). The sudden death rate was significantly related to the logarithm of the weight of the dogs in the range studied. It varied widely if values from small series, comprising the same number of dogs, were considered. Values became less dispersed as the size of the series increased. In series of 10 dogs, sudden death rates ranged from 0 to 70%, whereas in series of 100 dogs the range was 14 to 36%. Stable values were obtained for 50 to 60 dogs per series. Accordingly, reliable assessment of preventive measures can be made only with experimental series of at least this size.

Comparative antidysrhythmic profiles of bepridil, amiodarone and disopyramide in the guinea-pig and dog.

The antiarrhythmic effects of a novel antianginal agent, bepridil, were compared with four reference products. Bepridil increased the effective refractory period in isolated guinea-pig atria slightly more than hydroquinidine, and much more than disopyramide and lidocaine. Amiodarone was without effect. The doses of bepridil necessary for correcting atrial fibrillation induced by local application of aconitine, were similar for hydroquinidine, higher than for lidocaine and disopyramide but lower than for amiodarone. Bepridil depressed the tachycardia and ventricular fibrillation induced by perfusing aconitine in anesthetized guinea-pigs at doses of the same order of magnitude as for disopyramide and hydroquinidine. Lidocaine only exerted weak activity in this system, while amiodarone was without effect. Bepridil was less active than the four reference products, particularly disopyramide, on rhythm disorders induced by coronary artery ligation.

[Derivatives of 2,3,4,5,-tetrahydro-1H-pyrido-(3,2-b)azepine and 2,3,4,5-tetrahydro-1H-pyrido(2,3-b)azepine and their corresponding lactams. II. Synthesis and pharmacologic study of their psychotropic activity]. / Derivés de la tétrahydro-2,3,4,5 1H-pyrido[3,2-b]azépine, de la tétrahydro-2,3,4,5 1H-pyrido[2,3-b]azépine et de leurs lactames correspondants. II. Synthèse et étude pharmacologique de leur activité psychotrope.

Preparation of the N-(2-diethylaminoethyl) derivatives of lactam (II) and of the N-(3-dimethylaminopropyl) derivative of lactam (XI) is described. Synthesis of the N-[4-(2-hydroxyethyl)piperazinylacetyl]- and 1-carbothiamide derivatives of azepine (I) and of the n-(chloroformyl)- and N-(carbamoyl) derivatives of azepine (XII) are also described. Some pharmacological results indicate a partial tranquilizing activity.

[Prolongation of the effective refractory period on isolated guinea pig atria by some anti-arrhythmia agents: relevance in a comparison of their potentialities]. / Prolongation de la période réfractaire effective de l'oreillette isolée de cobaye par quelques antidysrythmiques: intérêt d'une comparaison de leurs potentialités.

The effects of bepridil, nifedipine, verapamil, lignocaïne and amiodarone on the atrial effective refractory period were investigated in the guinea-pig. The observed results permitted elucidation of a remarkable activity by both nifedipine and verapamil, and by bepridil and lignocaïne. In contrast, in the experimental conditions, no activity was detected with amiodarone up to concentrations of 10(-4) M. The efficacity rating of the test compounds is not reflected by their anti-arrhythmic efficacity as demonstrated in vivo in the animal, nor by their therapeutic anti-arrhythmic efficacity as reported in the clinical literature. However, this efficacity rating may be related to the interaction of the compounds with the transmembrane sodium or calcium movements.

[Chronic vascular catheterization in the rat. Adaptation to injections and semi-continous blood sampling for hormonal studies]. / Cathétérismes vasculaires chroniques chez le rat. Adaptation aux injections et prélèvements sanguins semi-continus pour études hormonales.

A method for frequent sampling of blood and injections of fluids in undisturbed rats is described. The right external jugular vein and the left carotid artery are cannulated without completely blood stream interruption in the vessel. Injection or perfusion can be performed during several weeks. Blood was collected for at least 15 post-operative days. The technique appears suitable for pituitary kinetics studies which can be carried out several times in rats bearing indwelling catheters.

[Morphine self-administration added to food conditioning: methodological variant in rats]. / Auto-injections morphiniques substituées au conditionnement alimentaire: étude chez le rat d'une variante méthodologique.

Rats with permanent intra-jugular cannula are submitted to an alimentary operant reinforcement schedule with fixed ratio type FR 1, FR5, then FR 20. As a result, the animals are self administering (together with the alimentary inducer) a slow (about 5 sec) intravenous infusion of morphine (0.05 mg/kg). 20 per cent only of the experimental population exhibit a psychogenic dependance afterward. On the other hand, the animals for which morphine self-administration has been substituted to the alimentary reinforcement without respecting a transitory period combining both types of reinforcement have never shown any tendancy toward morphine self-administration. The lack of positive results could be related to the marked duration of the self-injection.