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Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal genetic disease characterized by a restrictive muscle weakness: pharyngeal muscles (including cricopharyngeal muscle (CPM)) as well as eyelid muscles are primarly affected leading to swallowing difficulties (dysphagia) and eyelid drooping (ptosis) respectively. This disease stems from a short polyalanine expansion in the Poly(A) Binding Protein Nuclear 1 (PABPN1) leading to the formation of nuclear aggregates in the muscle of OPMD patients. The objectives of this study are : 1/ to characterize PABPN1 nuclear aggregates on human muscle biopsies to evaluate if age and genotype influence their features and 2/ to assess the efficacy of the anti-aggregates molecule guanabenz (GA) on mammalian models of OPMD. The results show that aging and genotype of OPMD patients influence the size, the percentage or the composition of nuclear aggregates. Treatment of cellular and mouse model of OPMD with guanabenz allows a diminution in the percentage and the size of nuclear aggregates as well as an improvement of the mice muscle phenotype. GA acts through the unfolded protein response to endoplasmic reticulum stress (ER) showing for the first time that ER stress is activated in OPMD. This study suggestes that the use of pharmacological molecules modulating notably ER stress is a promising strategy to treat OPMD., La dystrophie musculaire oculopharyngée (OPMD) est une maladie autosomique dominante à apparition tardive (50-60 ans) et à progression lente caractérisée par des faiblesses musculaires restreintes dans un premier temps à deux types de muscles : les muscles du pharynx, dont le cricopharyngien fait partie (CPM) et le muscle releveur de la paupière aboutissant à des difficultés de déglutition (dysphagie) et à une chute des paupières (ptosis) respectivement. Cette maladie est due à une petite expansion d’alanine dans la protéine PABPN1 (polyA Binding Protein Nuclear 1) ce qui aboutit à la formation d’agrégats nucléaires dans les muscles des patients OPMD. Les objectifs de cette étude sont : 1/ caractériser les agrégats de PABPN1 à partir de biopsies de patients OPMD pour voir si l’âge et le génotype des patients influencent leurs caractéristiques et 2/ d’évaluer l’efficacité de la molécule anti-agrégats guanabenz (GA) dans des modèles mammifères de la maladie. Les résultats montrent que l’âge et le génotype des patients OPMD influencent la taille, la composition ou le pourcentage de noyaux avec agrégats. L’utilisation de GA dans nos modèles murins de l’OPMD permet de diminuer le nombre et la taille de noyaux avec agrégats et d’améliorer les phénotypes musculaires chez la souris. Nous montrons dans cette étude que le GA module la réponse au stress du réticulum endoplasmique (ER) qui est pour la première fois mis en évidence dans l’OPMD. Cette étude nous permet de proposer que l’utilisation de molécules pharmacologiques atténuant entre autre le stress de l’ER est une bonne stratégie thérapeutique pour l’OPMD.

Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal genetic disease characterized by a restrictive muscle weakness: pharyngeal muscles (including cricopharyngeal muscle (CPM)) as well as eyelid muscles are primarly affected leading to swallowing difficulties (dysphagia) and eyelid drooping (ptosis) respectively. This disease stems from a short polyalanine expansion in the Poly(A) Binding Protein Nuclear 1 (PABPN1) leading to the formation of nuclear aggregates in the muscle of OPMD patients. The objectives of this study are : 1/ to characterize PABPN1 nuclear aggregates on human muscle biopsies to evaluate if age and genotype influence their features and 2/ to assess the efficacy of the anti-aggregates molecule guanabenz (GA) on mammalian models of OPMD. The results show that aging and genotype of OPMD patients influence the size, the percentage or the composition of nuclear aggregates. Treatment of cellular and mouse model of OPMD with guanabenz allows a diminution in the percentage and the size of nuclear aggregates as well as an improvement of the mice muscle phenotype. GA acts through the unfolded protein response to endoplasmic reticulum stress (ER) showing for the first time that ER stress is activated in OPMD. This study suggestes that the use of pharmacological molecules modulating notably ER stress is a promising strategy to treat OPMD.; La dystrophie musculaire oculopharyngée (OPMD) est une maladie autosomique dominante à apparition tardive (50-60 ans) et à progression lente caractérisée par des faiblesses musculaires restreintes dans un premier temps à deux types de muscles : les muscles du pharynx, dont le cricopharyngien fait partie (CPM) et le muscle releveur de la paupière aboutissant à des difficultés de déglutition (dysphagie) et à une chute des paupières (ptosis) respectivement. Cette maladie est due à une petite expansion d’alanine dans la protéine PABPN1 (polyA Binding Protein Nuclear 1) ce qui aboutit à la formation d’agrégats nucléaires dans les muscles des patients OPMD. Les objectifs de cette étude sont : 1/ caractériser les agrégats de PABPN1 à partir de biopsies de patients OPMD pour voir si l’âge et le génotype des patients influencent leurs caractéristiques et 2/ d’évaluer l’efficacité de la molécule anti-agrégats guanabenz (GA) dans des modèles mammifères de la maladie. Les résultats montrent que l’âge et le génotype des patients OPMD influencent la taille, la composition ou le pourcentage de noyaux avec agrégats. L’utilisation de GA dans nos modèles murins de l’OPMD permet de diminuer le nombre et la taille de noyaux avec agrégats et d’améliorer les phénotypes musculaires chez la souris. Nous montrons dans cette étude que le GA module la réponse au stress du réticulum endoplasmique (ER) qui est pour la première fois mis en évidence dans l’OPMD. Cette étude nous permet de proposer que l’utilisation de molécules pharmacologiques atténuant entre autre le stress de l’ER est une bonne stratégie thérapeutique pour l’OPMD.

alpha 2-adrenoceptors are involved in various renal functions regulating blood pressure. They were classified in subtypes whom genes were identified in both humans and rats. In rat renal cortex it was evidenced that the alpha 2B isoform is predominant. This result was confirmed in Sabra rats. However, the renal cortex alpha 2B density is higher in salt-sensitive (SBH) than in salt-resistant (SBN) Sabra rats. alpha 2B-adrenoceptors were recently subclassified in two pharmacologically distinct subtypes exhibiting high and low affinity for guanoxabenz and respectively called alpha 2B1 and alpha 2B2. We studied sodium loading effect on alpha 2B1 and alpha 2B2 distribution in Sabra rat renal cortex using competition experiments between [3H]-yohimbine and guanoxabenz. The rats were submitted to normal (0.2%) or high sodium diet (8%) for six weeks. Under normal diet, proportion alpha 2B1 and alpha 2B2 was similar in SBH and SBN. Nevertheless, their respective densities were significantly higher in SBH as compared to SBN (alpha 2B1: 90.6 +/- 4.1 vs 57.4 +/- 2.5 fmoles/mg prot, p0.0001; n = 5; alpha 2B2: 102.7 +/- 4.0 vs 66.4 +/- 4.6 fmoles/mg prot; p0.0001; n = 5). Under high sodium diet the distribution of these two isoforms was altered. The densities of alpha 2B1 were decreased by 27.0 +/- 5.9% in SBH (68.0 +/- 4.0 fmoles/mg prot; p0.0001, n = 5) and by 47.3 +/- 7.4% for SBN (29.2 +/- 3.1 fmoles/mg prot; p0.0001; n = 5). Conversely, the densities of alpha 2B2 were increased by 28.3 +/- 5.4% in SBH (131.1 +/- 9.5 fmoles/mg prot; p0.001; n = 5) and by 75.0 +/- 17% in SBN (123.2 +/- 9.1 fmoles/mg prot; p0.0001; n = 5). In conclusion, alpha 2B1- and alpha 2B2-adrenoceptor subtypes are found in renal cortex of both SBH and SBN. Our data demonstrated an equal distribution of these two isoforms between SBH and SBN under normal salt diet. This distribution is largely altered, especially in SBN, by the high sodium diet. From these modifications might result differential renal responses to activation of alpha 2B-adrenoceptors between SBH and SBN, and consequently responsible for normal or high blood pressure after high sodium diet.

The hemodynamic effects of a single dose of fentanyl (4 micrograms/kg) and of thiopental (5 mg/kg) were studied on cranial trauma patients who have hypertension and who are ventilated at constant volume and frequency. At first the results were collected without an hypertensive treatment, in the second time the same results were collected after the injection of an anti-hypertensive drug (guanoxabenz 70 micrograms/kg). The results showed that in two series the modification in the measured parameters was not statistically significant; the used drugs produced little change in the hemodynamic profile: a) Even with insignificant, we noted that the injection of fentanyl after an anti-hypertensive drug caused a smaller change in the blood pressure and cardiac index then was seen in untreated subjects. b) With thiopental treated subjects, the arterial pressure is not decreased because of the increased systemic resistances, at the same time changes in cardiac index are essentially identical whether or not the subject was treated with guanoxabenz. The results therefore tend to show that the anti-hypertensive treatment can be continued without any interruption by a surgical operation.

The inhibitory effect of the predominantly alpha-2 adrenoceptor agonist, guanabenz, on the peristaltic reflex and on the pendular movements of the rabbit isolated ileum was investigated. Guanabenz depressed or abolished the peristaltic reflex as well as the pendular movements. These effects were concentration-dependent. Guanabenz is much more potent inhibiting the peristaltic reflex (IC50 1 X 10(-7) M) than the pendular movements (IC50 1 X 10(-5) M). The choline ester, acetylcholine restored the peristaltic reflex and the anticholinesterase, eserine, restored the pendular movements previously abolished by guanabenz. During the blockade of the peristaltic reflex produced by guanabenz, the pendular movements were virtually not changed. It is therefore reasonable to suppose that the inhibitory effect of guanabenz reflects the different properties of alpha-2 adrenoceptors associated with cholinergic nerve terminals within the myenteric plexus and the longitudinal smooth muscle subserving the peristaltic reflex and the pendular movements.

We report the results of two studies carried out in the Drug Addiction Unit of Fernand-Widal hospital, on the use of presynaptic alpha-mimetic drugs in the treatment of heroin addicts. The authors briefly recall the mode of action of these drugs, and then describe the methodology of these two studies of Guanoxabenz and Guanfacine; characteristics of this group, outcome of therapy, mode of prescription, side effects. The results are analysed and compared with the usual methods of treatment using synthetic opiates.

Guanabenz was found to produce a concentration-dependent depression of the isometric contractility of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of guanabenz on the heart rate was weaker than its effect on the isometric contraction. A time-dependent depression of both the isometric contraction and of the atrial rate after the addition of a single dose of guanabenz was also found up to 10th min. Guanabenz did not change the maximal driving (following) frequency of the atria. Aminophylline partially, isoprenaline almost completely and calcium completely antagonized the negative inotropic action of guanabenz. They, however, did not antagonize the negative chronotropic action of guanabenz. It seems, regardless of what the precise mechanism(s) of action of guanabenz may be (probably nonspecific on the isolated guinea-pig atria), that all these substances (aminophylline, isoprenaline and calcium) restore the contractility of the isolated atria by compensating the calcium balance which has been previously changed by guanabenz.

A molecule sensitive to light, to variations in temperature and pH, guanoxabenz hydrochloride cannot be estimated in biological fluids according to classical technics. The authors propose an analytical method based, during the extraction phase, on the formation of a copper complex extractable in organic medium and in the true phase of measurement, on the transformation, by hydrochloric acid hydrolysis in dichloro-2-6-benzaldehyde, estimated by gas phase chromatography with detection by capture of electrons. The sensitivity and the specificity of the technic authorise its use in pharmacokinetic studies in man.