Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials.

Background: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person).

Adenosine improves cardiomyocyte respiratory efficiency.

The role of adenosine on the regulation of mitochondrial function has been studied. In order to evaluate this the following experiments were done in isolated rat cardiomyocites and mitochondria using polarographic techniques. Cardiomyocyte oxygen consumption (MVO2) and mitochondrial respiratory function (State 3 and State 4, respiratory control index, and ADP/O ratio) were evaluated after exposure to adenosine.

[The effect of the parenteral administration of alpha-ketoglutarate on the resistance of rats to ionizing radiation and on their cholinergic systems].

We have investigate the effect of sodium ketoglutarate intraperitoneal injection (20 mg/100 g body weight) made 0.5 hour before and 1, 2 and 3 hours after total X-ray treatment (259 mKl/kg) on the survival of rats. Simultaneously we have define changes in cholinesterase-acetylcholine system and content of adrenaline and noradrenaline in liver and pancreas tissues, small intestines mucous and in blood.

[Role of calcium ions in the mechanism of action of acetylcholine on energy metabolism in rat liver mitochondria].

It is shown that administration of acetylcholine to animals (50 micrograms per 100 g of body weight) leads to the activation of respiration and oxidative phosphorylation in the rat liver mitochondria under oxidation of alpha-ketoglutarate; this effect depends on the concentration of calcium ions in the incubation medium of mitochondria. The rate of ADP-stimulated respiration of mitochondria of experimental animals reaches its maximum level under lower concentrations of Ca2+ than in the control animals. The results of investigation of dependence of acetyl choline effect on respiration of mitochondria on the concentration of alpha-ketoglutarate in calcium and calcium-free incubation medium have shown that the half-maximum effect of acetylcholine is observed in calcium medium at lower concentration of the substrate than in calcium-free medium.

[The effect of hypoxic hypoxia on energy metabolism in the liver mitochondria and the acetylcholine content of different tissues].

It has been found, the 1 or 2 days exposure of animals to hypoxic hypoxia (during 4 hours every day; 32 mm Hg) leads to the decrease of acetylcholine level in rat heart, liver and pancreas tissues and to activation of succinate oxidation in rat liver mitochondria. Beginning from the 7th day of hypoxia treatment the level of acetylcholine in the tissues was increasing and it was connected with the activation of NAD-dependent substrate alpha-ketoglutarate oxidation in the rat liver mitochondria and with the increase of the efficiency of oxidative phosphorylation. The effect increases to the 12-16-th day of animal adaptation.

[Adrenergic and cholinergic regulation of respiratory efficiency of secretory cells].

The influence of sympathetic and parasympathetic systems on the secretory cell respiration is mediated at the subcellular level by adreno- and cholinoreceptors of plasmatic membranes and is related to selective oxidation of two different substrates of the Krebs cycle: succinate and alpha-ketoglutarate, both being involved into two reciprocal mediator-hormonal-substrate-nucleotide systems: catecholamines-succinate-cAMP-ATP and acetylcholint-alpha-ketoglutarate-cGMP-GTP. The reciprocation of these systems is necessary for regulation of cell oxygen demand and effective oxygen utilization for ATP-synthesis and synthesis of other macroergical compounds depending on the functional state of a cell.

[Mechanism of reciprocal effects of acetylcholine on oxidation of alpha-ketoglutarate and succinate in heart and liver mitochondria. Factors influencing detection of the acetylcholine effect].

Effect of acetylcholine administration (50 mg/100 g) on phosphorylating oxidation in the liver and heart mitochondria of rats and guinea pigs has been studied. The reciprocal effect of acetylcholine on alpha-ketoglutarate and succinate oxidation (acceleration and inhibition, respectively) was observed. In both cases, the ADP/O coefficient increased.

[Acetylcholine and effectiveness of oxidative phosphorylation in isolated rat hepatocytes].

It is shown that ADP and DNP does not intensify the respiration rate in hepatocytes of rats obtained by means of trypsin or EDTA. The same cells obtained using collagenase, phosphorylate added ADP and increase the respiration rate after DNP addition. Acetylcholine added to the cell suspension in a dose of 5 x 4 x 10(-8) M) increases the efficiency of oxidative phosphorylation.

[EFFect of alpha-ketoglutarate and acetylcholine synergism on energy metabolism in mitochondria].

The influence of Na alpha-ketoglutarate intraperioneally injected in dose of 20 mg per 100 g of body weight on substrate oxidation in the rat liver and heart mitochondria, cholinesterase activity in the blood, liver and pancreas and acetylcholine level in the rat liver and pancreas has been studied. Alpha-ketoglutarate is found to have a pronounced reciprocal effect on intramitochondrial alpha-ketoglutarate and succinate oxidation (acceleration and inhibition, respectively). The effect of Na alpha-ketoglutarate is specific for the two substrates as it is absent when another substrate of the tricarboxylic acid cycle is oxidized.