Biodistribution and Pharmacokinetics of O-Palmitoyl Tilisolol, a Lipophilic Prodrug of Tilisolol, after Intravenous Administration in Rats

The purpose of this study was to modify the biodistribution and pharmacokinetics of tilisolol, a β-blocker, using the palmitoyl prodrug approach. After intravenous administration of tilisolol and O-palmitoyl tilisolol in rats, drug concentrations were determined in blood, bile, urine, and several tissues. The concentration-time profiles of tilisolol and O-palmitoyl tilisolol were analyzed pharmacokinetically. The blood concentrations of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10-fold higher than those of tilisolol after intravenous administration of tilisolol. The biliary excretion rates of O-palmitoyl tilisolol and tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10- to 100-fold larger than those of tilisolol after intravenous administration of tilisolol. In addition, the hepatic uptake clearance of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol was 3.6-fold higher than that of tilisolol after the intravenous administration of tilisolol. In the in vitro experiments, it was demonstrated that the distribution ratios between blood cells and plasma (blood/plasma) of O-palmitoyl tilisolol and tilisolol was 95.7 and 55.5%, respectively. These findings suggest that O-palmitoyl tilisolol exists as a binding form with biological components, especially blood cells, in systemic circulation. In conclusion, the palmitoyl prodrug approach is useful as a drug delivery system to deliver the parent drug to the liver

Mechanisms explaining transitions between tonic and phasic firing in neuronal populations as predicted by a low dimensional firing rate model

Several firing patterns experimentally observed in neural populations have been successfully correlated to animal behavior. Population bursting, hereby regarded as a period of high firing rate followed by a period of quiescence, is typically observed in groups of neurons during behavior. Biophysical membrane-potential models of single cell bursting involve at least three equations. Extending such models to study the collective behavior of neural populations involves thousands of equations and can be very expensive computationally. For this reason, low dimensional population models that capture biophysical aspects of networks are needed. \noindent The present paper uses a firing-rate model to study mechanisms that trigger and stop transitions between tonic and phasic population firing. These mechanisms are captured through a two-dimensional system, which can potentially be extended to include interactions between different areas of the nervous system with a small number of equations. The typical behavior of midbrain dopaminergic neurons in the rodent is used as an example to illustrate and interpret our results. \noindent The model presented here can be used as a building block to study interactions between networks of neurons. This theoretical approach may help contextualize and understand the factors involved in regulating burst firing in populations and how it may modulate distinct aspects of behavior.Comment: 25 pages (including references and appendices); 12 figures uploaded as separate file

Alternating rhythmic activity induced by dorsal root stimulation in the neonatal rat spinal cord in vitro

Electrical stimuli applied to a single dorsal root (DR) of the neonatal rat spinal cord in vitro were used to test the possibility that the central pattern generator responsible for locomotion could be activated by synaptic inputs.Brief pulse trains evoked oscillatory patterns recorded from pairs of lumbar ventral roots. These patterns alternated rhythmically between the left and right sides and between predominantly flexor and extensor motoneuronal pools on the same side, thus displaying properties similar to the fictive locomotor pattern elicited by bath-applied excitatory transmitter agonists like NMDA and serotonin.Usually pulse trains rather than single pulses were necessary to induce these patterns, the period of which was independent of stimulation frequency (1-10 Hz) and only moderately dependent on stimulus intensity.Patterns reached a steady rhythm during the stimulus train, lasted for 50 ± 20 s with gradual period lengthening and finally ceased.Since DR stimuli activated the central pattern generator for locomotion in the rat isolated spinal cord, it is suggested that sensory inputs from the periphery can reach the spinal locomotor network and trigger its operation

Corrélations entre la dysfonction sexuelle et le profil clinicobiologique de l’insuffisant rénal en hémodialyse

Objectif: Etudier les corrélations entre la dysfonction sexuelle et le profil clinicobiologique de l’insuffisant rénal chronique en hémodialyse (HD) au CHU Hassan II de Fès, Maroc Matériel et méthodes: Nous avons réalisé une étude transversale descriptive et analytique à propos de 73 patients incluant les malades des deux sexes âgés de plus de 18 ans et suivis pour insuffisance rénale chronique (IRC) en stade d’HD. Une recherche de dysfonction sexuelle ainsi que l’étude de paramètres cliniques: âge, comorbidités, durée d’HD, néphropathie initiale et biologiques: taux d’hémoglobine, ferritine, LH, FSH, prolactine, œstradiol et testostérone ont été réalisés. Résultats: L’âge moyen de nos malades était de 45,5+/-1,5 ans avec une médiane de 45 ans. Environ 56% des malades étaient de sexe masculin. La néphropathie diabétique (11 cas, 15%) et la néphroangiosclérose (14 cas, 19,2%) étaient les néphropathies initiales les plus fréquentes. La durée moyenne de dialyse était 101,9+/-6,17mois. La fréquence de la dysfonction sexuelle était de 78% tous grades confondus. Les patients présentant une dysfonction sexuelle avaient un âge plus avancé, un début de dialyse plus ancien et des troubles hormonaux significativement plus marqués que les patients sans dysfonction sexuelle. La téstostéronémie était basse chez 32 patients et a été significativement plus bas chez les hommes présentant des troubles sexuels (p = 0,020). Les concentrations de l’estradiol n’étaient pas liées à la dysfonction sexuelle chez les femmes (p = 0,345). Conclusion: Certains facteurs cliniques et perturbations biologiques peuvent aider à la compréhension de l’étiopathogénie de ces troubles. Une approche globale peut être proposée basée sur une optimisation des facteurs intervenants. Notre étude souligne l’intérêt d’une surveillance clinique, biologique et hormonale de ces patients