Extended Driving Impairs Nocturnal Driving Performances

Though fatigue and sleepiness at the wheel are well-known risk factors for traffic accidents, many drivers combine extended driving and sleep deprivation. Fatigue-related accidents occur mainly at night but there is no experimental data available to determine if the duration of prior driving affects driving performance at night. Participants drove in 3 nocturnal driving sessions (3–5am, 1–5am and 9pm–5am) on open highway. Fourteen young healthy men (mean age [±SD] = 23.4 [±1.7] years) participated Inappropriate line crossings (ILC) in the last hour of driving of each session, sleep variables, self-perceived fatigue and sleepiness were measured. Compared to the short (3–5am) driving session, the incidence rate ratio of inappropriate line crossings increased by 2.6 (95% CI, 1.1 to 6.0; P<.05) for the intermediate (1–5am) driving session and by 4.0 (CI, 1.7 to 9.4; P<.001) for the long (9pm–5am) driving session. Compared to the reference session (9–10pm), the incidence rate ratio of inappropriate line crossings were 6.0 (95% CI, 2.3 to 15.5; P<.001), 15.4 (CI, 4.6 to 51.5; P<.001) and 24.3 (CI, 7.4 to 79.5; P<.001), respectively, for the three different durations of driving. Self-rated fatigue and sleepiness scores were both positively correlated to driving impairment in the intermediate and long duration sessions (P<.05) and increased significantly during the nocturnal driving sessions compared to the reference session (P<.01). At night, extended driving impairs driving performances and therefore should be limited

Impact of the Nature of the Substituent at the 3-Position of 4H-1,2,4-Benzothiadiazine 1,1-Dioxides on Their Opening Activity toward ATP-Sensitive Potassium Channels.

The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe

New trends in the design of drugs against Alzheimer's disease

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors. based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD

Recent developments in the chemistry of potassium channel activators: the cromakalim analogs.

Potassium channels play a crucial role in controlling the cell membrane potential. Among the different varieties of K(+) channels, the ATP-sensitive potassium channels (K(ATP) channels) have been characterized in numerous cell types, such as skeletal and smooth muscle cells, endocrine cells, cardiac cells and central neurons. Several molecules are known to activate K(ATP) channels and have been named "potassium channel openers" (PCOs). Such compounds may have a wide therapeutic potential and a few drugs are currently used as antihypertensive agents. Different chemical series of PCOs have been explored. This heterogeneous group of organic compounds comprises the benzopyran series including potent vasorelaxant drugs, such as cromakalim. The latter compound, a typical example of potassium channel opener, exerts its biological effect by activating K(ATP) channels. This review presents recent developments in the chemistry of cromakalim analoges and reports chemical aspects governing their potency and tissue selectivity.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

4,6-Disubstituted 2,2-dimethylchromans structurally related to the K(ATP) channel opener cromakalim: design, synthesis, and effect on insulin release and vascular tone.

Five series (ureas, thioureas, carbamates, sulfonylureas, and amides) of 4,6-disubstituted-2,2-dimethylchromans structurally related to cromakalim were prepared and evaluated, as putative ATP-sensitive potassium channel activators, on rat pancreatic islets and rat aorta rings. The biological data indicate that most compounds were, like the reference molecule cromakalim, more active on the vascular smooth muscle tissue (myorelaxant effect on 30 mM KCl induced contractions of rat aorta rings) than on the pancreatic tissue (inhibition of 16.7 mM glucose induced insulin release from rat pancreatic islets). However, some drugs (8h, 8i, 9f, 9g, 9h, and 9i) markedly inhibited insulin release and exhibited an activity equivalent or greater than that of diazoxide. Compounds 9h and 9i were also found to be more active on pancreatic beta-cells than on vascular smooth muscle cells. Last, the amide 6b was selected in order to examine its mechanism of action on vascular smooth muscle cells. Pharmacological results suggest that the compound acted as a K(ATP) channel opener. In conclusion, the present data indicate that appropriate structural modifications can generate dimethylchromans with pharmacological profiles different from that of cromakalim.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Effect on K(ATP) channel activation properties and tissue selectivity of the nature of the substituent in the 7- and the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides.

The present work explored 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides diversely substituted in the 7-position. Those compounds, structurally related to previously described potassium channel openers such as the benzothiadiazine dioxide BPDZ 73, were tested as putative K(ATP) channel activators on the pancreatic endocrine tissue and on the vascular smooth muscle tissue. The nature of the substituent introduced in the 7-position as well as the nature of the alkylamino side chain in the 3-position strongly affected both potency and tissue selectivity of 4H-1,2,4-benzothiadiazine 1,1-dioxides. Thus, compounds bearing in the 7-position a methyl or a methoxy group or devoid of a substituent in this position, and bearing an ethyl, an isopropyl, or a cyclobutylamino group in the 3-position were found to be potent and selective inhibitors of insulin release from rat pancreatic B-cells (i.e. 10a, 10b, 12b, 12d, 22c). In contrast, 3-alkylamino-7-trifluoromethyl- (20a-c) and 3-alkylamino-7-pentyl-4H-1,2,4-benzothiadiazine 1,1-dioxides (11a,b) expressed a marked myorelaxant activity on rat aorta ring. Among the latter compounds, the 3-alkylamino-7-pentyl derivative (11a) showed a clear selectivity for the vascular smooth muscle tissue. The present work gives new insights into the role of the substituent in both the 7- and the 3-position for the design of 4H-1,2,4-benzothiadiazine 1,1-dioxide potassium channel openers exhibiting different tissue selectivity profiles.In VitroJournal Articleinfo:eu-repo/semantics/publishe

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel openers: effect of 6,7-disubstitution on potency and tissue selectivity.

A series of 6,7-disubstituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing a short alkylamino side chain in the 3-position were synthesized. These compounds were tested on rat pancreatic islets and on rat aorta rings. In vitro data indicated that in most cases substitution in the 6 and the 7 positions increased their activity as inhibitors of insulin secretion, while the myorelaxant potency of the drugs was maintained or enhanced according to the nature of the substituent in the 7-position. The presence of either chlorine or bromine atoms in the 6 and 7 positions did not improve the apparent selectivity of the drugs for the pancreatic tissue. By contrast, the introduction of one or two fluorine atoms, as well as the presence of a methoxy group in the 7-position, generated potent and selective inhibitors of insulin release. Radioisotopic and fluorimetric experiments performed with the most potent compound inhibiting insulin release (34, BPDZ 259, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) confirmed that the drug activated K(ATP) channels. 34 was found to be one of the most potent and selective pancreatic potassium channel openers yet described.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Effect on insulin release of compounds structurally related to the potassium-channel opener 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73): introduction of heteroatoms on the 3-alkylamino side chain of the benzothiadiazine 1,1-dioxide ring.

7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe