[Pathogenetic therapy of cognitive impairment: results of a multicenter placebo-controlled clinical trial of the efficacy and safety of Miladean]. / Patogeneticheskaya terapiya kognitivnykh narushenii: rezul'taty mnogotsentrovogo platsebo-kontroliruemogo klinicheskogo issledovaniya effektivnosti i bezopasnosti preparata Miladean.

OBJECTIVE: Evaluation of the efficacy and safety of the use of the drug Miladean in the treatment of patients with cognitive disorders (CDs) of vascular genesis. MATERIAL AND METHODS: In during the double-blind multicenter prospective randomized placebo-controlled phase III clinical trial, 300 patients with CDs and chronic cerebral ischemia were randomized into 3 groups: group 1 (n=100) received Miladean (daily dose: memantine 10 mg + melatonin 6 mg), group 2 (n=101) - memantine (10 mg/day), group 3 - placebo (n=99) for 8 weeks. The dynamics of the overall score (the primary criterion of effectiveness) and the proportion of patients with improvement on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), the dynamics of visual-spatial orientation disorders (Benton test), sleep quality (Pittsburgh Sleep Quality Index scale) and the safety of therapy were evaluated. RESULTS: Miladean demonstrated efficacy in the treatment of CDs: a statistically and clinically significant decrease in the overall score on the ADAS-Sod scale was shown (by 6.1 versus 4.7 and 3.5 points in the 2nd (p=0.009) and 3rd (p<0.05) groups) and an increase in the proportion of patients (96.9%) with clinically and statistically a significant improvement compared to the 2nd and 3rd groups (p=0.019 and p<0.001 respectively). Miladean significantly improved the performance in the Benton test (1.20±1.66 vs. 0.64±1.69 points in group 3, p=0.026) and sleep quality (84.7% of patients with CDs), compared to placebo (63.9%) and memantine (64.3%) (p=0.002 in both cases). Miladean was well tolerated, there were no cases of interaction with basic therapy drugs. CONCLUSION: The combination of many different pathogenetic effects of Miladean suggests that it has the ability to slow down the rate of progression of CDs and stabilize the condition of patients. The unique combination of active substances in Miladean has been proven to be effective and safe in the treatment of patients with CDs.

Effects of cholinergic agonists and antagonists under conditions of spleen denervation in rats with endotoxic shock.

Model experiments on rats with endotoxic shock induced by intraperitoneal injection of LPS Salmonella Typhi strain ty-4441 (20 mg/kg) showed that crossing of the vagus nerve innervating the spleen increased HR, stimulated production of antibodies, and moderated serotonergic activity of splenocytes. Pharmacological correction of the shock with muscarinic receptor antagonist atropine and its combinations with anticholinesterase agent galantamine or muscarinic and nicotinic cholinoreceptor agonist choline alfoscerate 30 min before shock modeling moderated HR and normalized B cell functions and serotonin level in the spleen.

[Anti-inflammatory role of cholinergic and serotonergic systems in shock].

Development of anaphylactic shock initiated with the horse serum (anaphylactic index = 4.0 +/- 0.0 arbitrary units) leads to acute decrease in spleen concentration of serotonin (in shock--0.443 +/- 0.005; basal level--1.532 +/- 0.004 ng per mg of protein). Unlike of anaphylaxis, development of endotoxic shock in rats, caused by introduction of a sublethal dose (20 mg/kg) of lipopolysaccharide, results in acute increase in serotonin concentration (at a shock--56.588 +/- 0.006, basal level--5.465 +/- 0.005 ng per mg of protein) and marked tachycardia (+76 +/- 8, intact rats--+2 +/- 1 beats per min). Administration of atropine with galantamine leads to the most essential decrease of anaphylactic reaction (1.5 +/- 0.3 arbitrary units). Administration of choline alfoscerate (-16 +/- 3 beats per min) or galantamine (+9 +/- 2 beats per min) significantly reduces tachycardia. Data show, that inhibition of the central cholinergic mechanisms leads to increase and their excitation--to decrease in activity of the spleen serotonergic system. So, spleen concentration of serotonin is connected with a target of shock defeat (lungs or heart).

[Antianaphylactic effects of muscarinic antagonists].

The study was carried out on color guinea pigs, in which anaphylactic shock was induced by sensitizing and challenging doses of normal horse serum (HS). Administration of atropine, ipratropium, or ipratropium in combination with neostigmine led to reduction of sensitizing effect of HS: anaphylactic index was decreased up to (2.2 - 2.4) +/- 0.1 arbitrary units (a.u.). Methacine in combination with neostigmine (0.4 +/- 0.01 a.u.) or atropine in combination with galantamine (1.5 +/- 0.3 a.u.) effectively prevented the pathochemical stage of anaphylactic shock. Changes in plasma protein concentrations modified effects of methacine: application of methacine with IgG was protective (0.5 +/- 0.1 a.u.), while CRP abolish the antianaphylactic activity of methacine (3.8 +/- 0.1 a.u.). Guinea pigs which survived shock had a great number of AFC [(880 +/- 22) x 10(6) splenocytes in experimental group and (100 +/- 29) x 10(6) in control) and low concentration of 5-HT in the spleen (at a shock, 0.443 +/- 0.005; basal level, 1.532 +/- 0.004 ng/mg protein). Effective prevention of anaphylactic shock resulted in normalization of B cell activity and 5-HT level in the spleen. Thus, cholinergic drugs modulate the immunological and pathochemical stages of anaphylactic shock.

Blood plasma proteins modulate the broncholytic effects of a muscarinic receptor antagonist.

Blood plasma proteins modulated the effects of muscarinic receptor antagonist methacin. Administration of methacin in combination with albumin or C-reactive protein (but not with IgG) abolished the broncholytic effect of methacin. It was probably associated with allosteric antagonism to M2, cholinergic receptors on non-nervous cells, which increased antibody production and mediator response. The concentration of serotonin in mesenteric lymph nodes was high during shock.

[Non-neuronal effects of muscarinic antagonists in the prophylaxis of stress].

We have studied the stress-limiting role of the immune reaction initiated by cholinergic antagonists and the influence of these drugs on the dynamics of antibody formation in the spleen and the blood serum corticosterone level. The protective effect of immune reaction initiated by methacine (muscarinic receptor antagonist) or hexamethonium (nicotinic receptor antagonist) in prevention of stress gastric ulcer in rats (induced by water immersion stress, WIS) was estimated upon administration of the drugs for 5 days (local response) or 14 days (systemic response) prior to WIS. The pharmacological effects of drugs were estimated upon their administration 30 minutes prior to WIS. It is shown that, if cholinergic antagonists affect the systemic immune response the induction of WIS at this level of immune reaction leads to the effective prevention of stress gastric ulcer. The administration of methacine (but not hexamethonium) 14 days prior to WIS effectively reduces gastric lesions up to 1.0 +/- 0.1 arbitrary units in comparison to 3.6 + 0.2 arbitrary units in the control group. Under effective prophylaxis, the number of antibody-forming cells (AFC/10(6) of splenocytes) and corticosterone concentration are close to their basal level, while under stress conditions, these parameters significantly increase up to 870 +/- 21 and 350 +/- 4 vs. 100 +/- 17 and 107 +/- 6 in the control group, accordingly. It is established that both methacine and hexamethonium remain immunologically active for 28 days and more: the maximum amount of AFC upon administration of hexamethonium and methacine was on the 5th day and 14th day, respectively. Thus, determination of the drug influence on the systemic immune response allows one to predict the non-neuronal effects of cholinergic antagonists and, in this way, to affect the pathogenesis of stress gastric ulcer. Estimation of the AFC response and corticosterone level after WIS shows the efficacy ofprophylaxis of the gastric stress lesion.

[Modulation of the cholinergic system during inflammation].

This review describes the effects of realization of the central and peripheral "cholinergic antiinflammatory pathway" in a model of endotoxic and anaphylactic shock. Under endotoxic shock conditions, a pharmacological correction by means of the central m-cholinomimetic action (electrical stimulation of the distal ends of nervus vagus after bilateral cervical vagotomy, surgical implantation of the stimulant devise, activation of efferent vagal neurons by means of muscarinic agonist) is directed toward the elimination of LPS-induced hypotension. During the anaphylaxis, peripheral effects of the cholinergic system induced by blocking m-AChR on the target cells (neuronal and non-neuronal lung cells) and acetylcholinesterase inhibition are related to suppression of the bronchoconstrictor response. The role of immune system in the pathogenesis of endotoxic shock is associated with the production of proinflammatory cytokines by macrophages, increase in IgM concentration, and complement activation, while the role in the pathogenesis of anaphylactic shock is associated with IgE, IgG1 augmentation. Effects of B cell stimulation may be important in hypoxia and in the prophylaxis of stress ulcers and other diseases. Plasma proteins can influence the effects of the muscarinic antagonist methacine: IgG enhance its action while albumin and CRP abolish it.

[Effects of cholinergic drugs and blood plasma proteins on the development of Arthus reaction].

Delayed-type hypersensitivity (DTH) reaction was induced in (CBA x C57BL/6) F1 mice by subcutaneous injection of complete Freund adjuvant (0.02 ml) at the base of the tail. The effects of methacine (2 mg/kg), ipratropium bromide (0.01 mg/kg), their combinations with neostigmine (0.02 mg/kg), hexamethonium (10 mg/kg), acetylcholine (2 microg/kg), nicotine (0.5 mg/kg), gamma globulin and CRP (both 1 mg/kg), and albumin (500 mg/kg) on DTH reaction development, B cell functions and Arthus reaction were investigated. It was established that ipratropium bromide and CRP prevented Arthus reaction development. The administration of acetylcholine, nicotine, and combinations of muscarinic antagonists with neostigmine, as well as gamma globulin and albumin resulted in the later onset of Arthus reaction. The administration of hexamethonium increased DTH reaction and led to early appearance of the Arthus reaction and its maintenance during 21 days. These results demonstrate the role of cholinergic system and plasma proteins in the organism sensitization development.

Effects of cholinotropic and cytostatic drugs on the development of Arthus reaction.

Antimuscarinic effects of ipratropium bromide and atropine are associated with prevention of the development of Arthus reaction, while the cytostatic effects of cyclophosphamide and doxorubicin lead to involution of the thymus and spleen, suppression of antibody production, and aggravation of inflammation, which causes edema of the ankle joint (cyclophosphamide treatment). Apoptosis of tumor cell and inhibition of inflammation can be essential for chemotherapy of malignant and autoimmune diseases.