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Objectives CYP2C9 gene polymorphic variants can decrease the effects of losartan, reducing active metabolite (E-3174) formation. Study aims to determine the influence of *2 (+430C>T; rs799853) and *3 (+1075A>C; rs1057910) CYP2C9 gene polymorphic variants on the hypotensive and uricosuric effect of losartan on patients with arterial hypertension. Methods Eighty one patients with stage 1–2 arterial hypertension newly diagnosed with ABMP were enrolled in the study. Physicians started losartan treatment and then we measured urine concentration of E-3174/losartan to estimate CYP2C9 activity. After 3-month losartan treatment we compared effectiveness of the therapy with ABPM and plasma uric acid level between carriers of CYP2C9 *1/*1 and CYP2C9 gene polymorphic variants (*2 and *3). Results Carriage of CYP2C9*2 and CYP2C9*3 alleles reduced the hypotensive effect of losartan (p Conclusions Carriage of low function polymorphic variants of the CYP2C9 gene (*2 and *3) reduced the hypotensive effect of losartan according to ABPM and don’t affect uric acid level in plasma and E-3174/losartan in urine.

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.

Objectives Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). Methods 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). Results The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, pCYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p Conclusions CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Aim. To study the effect of class III antiarrhythmic drugs (amiodarone and sotalol), and the β-blocker bisoprolol on the spectral parameters of heart rate variability in patients with different forms of atrial fibrillation (AF).Material and methods. Spectral analysis of heart rate variability of 5-minute electrocardiography intervals was used. The study included patients with newly diagnosed AF and having a duration of the disease from 6 months to 8 years. Arterial hypertension, coronary artery disease, myocardial infarction (in history), conduction disorders and type 2 diabetes mellitus were diagnosed as comorbidities. The following parameters were calculated: the total power (TP) of the spectrum, the power of very low frequencies (VLF), low frequencies (LF) and high frequencies (HF).Results. In the group of patients with newly diagnosed AF without concomitant diseases after administration of amiodarone, VLF prevails in the spectrum structure, which indicates a significant role of humoral factors in the regulation of heart rate. The power of LF, reflecting the activity of the sympathetic nervous system, prevails over HF power after administration of amiodarone. In patients with newly diagnosed AF, having concomitant diseases, sympathetic influences prevail over parasympathetic ones by 3.6 times after administration of amiodarone. In the group of patients who have reduced the number of comorbidities, the LF/HF decreases and is only 1.66 after administration of amiodarone. The decrease in the number of negative factors is also accompanied by an increase in the influence of the vagus nerve on the activity of the heart. In the study of the effects of sotalol, the LF/HF in this group was twice lower in the group of patients with long-term AF. In patients receiving bisoprolol as antiarrhythmic therapy, the proportion of LF in the group of patients with newly diagnosed AF is 2 times lower, and the proportion of HF is twice higher than in the group of patients with long-term AF.Conclusion. The effect of antiarrhythmic drugs on the spectral parameters of heart rate variability depends on the duration AF. The presence of concomitant diseases of the cardiovascular system can significantly change the effect of antiarrhythmic drugs on the spectral parameters of heart rate variability and is accompanied by an increase in sympathetic activity. In patients with newly diagnosed AF, amiodarone and sotalol cause a similar effect – the predominance of sympathetic influence; when using bisoprolol, the predominant influence belongs to the vagus nerve. In patients with long-term AF, the opposite effect of drugs is observed: the use of amiodarone is accompanied by a more pronounced influence of the vagus nerve, and bisoprolol – the predominance of sympathetic influence. When using sotalol, sympathetic influences also prevail, more pronounced in patients with newly diagnosed AF.

Background: The ability of the human body to produce metabolic energy from light modifies fundamental concepts of biochemistry. Objective: This review discusses the relationships between the long-accepted concept is that glucose has a unique dual role as an energy source and as the main source of carbon chains that are precursors of all organic matter. The capability of melanin to produce energy challenges this premise. Methods: The prevalent biochemical concept, therefore, needs to be adjusted to incorporate a newly discovered state of Nature based on melanin’s ability to dissociate water to produce energy and to reform water from molecular hydrogen and oxygen. Results and Discussion: Our findings regarding the potential implication of QIAPI-1 as a melanin precursor that has bioenergetics capabilities. Conclusion: Specifically, we reported its promising application as a means for treating retinopathy of prematurity (ROP). The instant report focuses on the long-term treatment medical effects of melanin in treating ROP.

Background:In this review we survey medical treatments and research strategies, and we discuss why they have failed to cure degenerative disc diseases or even slow down the degenerative process.Objective:We seek to stimulate discussion with respect to changing the medical paradigm associated with treatments and research applied to degenerative disc diseases.Method Proposal:We summarize a Biological Transformation therapy for curing chronic inflammations and degenerative disc diseases, as was previously described in the book Biological Transformations controlled by the Mind Volume 1.Preliminary Studies:A single-patient case study is presented that documents complete recovery from an advanced lumbar bilateral discopathy and long-term hypertrophic chronic rhinitis by application of the method proposed.Conclusion:Biological transformations controlled by the mind can be applied by men and women in order to improve their quality of life and cure degenerative disc diseases and chronic inflammations illnesses.

Spectral analysis of heart rate variability gives an idea of the role of the autonomic nervous system in the regulation of chronotropic heart function. This method can be used to evaluate the effectiveness of drug therapy. Drug therapy should be carried out taking into account the individual clinical form of atrial fibrillation. Information about the vegetative status of the patient will undoubtedly increase the effectiveness of treatment. In this study, spectral parameters were studied in patients with atrial fibrillation. The effect of sotalol on the spectral parameters of heart rate variability was studied.

Background: The concept of metabolic syndrome (MetS) as a cluster of risk factors of type 2 diabetes and cardiovascular diseases has undergone some evolutionary transformations over the past years. Integrating the autonomic dysfunction into the pathogenesis of MetS creates the possibility of including a range of nosologies affecting treatment and clinical manifestations of pathologies belonging to MetS into the MetS cluster. The purpose of this work is to determine the involvement of autonomic dysfunction in the pathogenesis of associated pathological conditions in patients and MetS. Methods: A cross-sectional study was conducted. The sample consisted of 158 patients with metabolic syndrome. The patients underwent a physical examination, including BMI; a blood chemistry test with the determination of the hormonal status (insulin, testosterone, dihydrotestosterone); a 24-hour monitoring of blood pressure (BP); an assessment of heart rate variability; studies showing the presence of gastric reflux (рН-measurement) or its damaging impact (endoscopy); men were tested with the IPSSQOL questionnaire and underwent transrectal ultrasound of the prostate and ultrasound of the bladder. Results: It is revealed that because of MetS, the occurrence of cardiac autonomic neuropathy reaches 37.5%. Some features of gastroesophageal reflux disease in patients with MetS are shown. Regurgitation prevails in the structure of complaints. In case of fibrogastroduodenoscopy, an endoscopynegative form of the disease occurs in 38%. According to the data of daily pH-measurement, when DeMeester score is high, in the supine position, 25% of the time accounts for alkaline reflux (рН > 7). It is found out that young men experience the enlargement of prostate volume and size; according to the IPSS questionnaire, the scores correspond to the initial manifestations of hyperplastic diseases of the prostate gland due to insulin resistance and normal level of androgens. Conclusions: The paper demonstrates that the autonomic dysfunction of the nervous system (on a par with insulin resistance) is the main link in the development of MetS. This provides the basis for including the mentioned states – cardiac autonomic neuropathy, lower urinary tract symptoms, and gastroesophageal reflux disease – into the MetS cluster..

Cardiovascular diseases, and among them certainly myocardial infarction, remain leading cause of death worldwide. Diabetes increases risk of occurrence as well as adverse outcome of myocardial infarction. Conditioning maneuvers are the most attractive method for alleviating both the consequences of ischemia and reperfusion. Minocycline is a tetracycline derivative which exerts antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this study was to assess the protective ability of preconditioning and postconditioning of isolated hearts from healthy and rats with experimentally induced type 2 diabetes with minocycline on functional recovery and redox status after ischemia and reperfusion. The hearts from healthy and diabetic rats were excised and retrogradely perfused according to the Langendorff technique. Using sensor in the left ventricle, the cardiodynamic parameters were recorded and in the samples of the coronary venous effluent oxidative stress biomarkers were analyzed. Minocycline was injected directly into the coronary vessels, in preconditioning 5 min before global ischemia, and in postconditioning during the first 5 min of reperfusion. Results of this study clearly show beneficial effects of minocycline applied both before ischemia and in the first minutes of reperfusion fashion in both healthy and diabetic rat hearts. The most prominent protective effect regarding oxidative stress is related to the decreased production of superoxide anion radical due postconditioning with minocycline in diabetic hearts. Cardiodynamic parameters were significantly improved in minocycline conditioned groups. Superoxide anion radical stands out as the most susceptible to changes induced by minocycline.

We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC50 values in the range 1.73–10.5 μM and exhibited low potencies against CaE (9.8–26% inhibition at 20 μM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases.

Background. Atrial Fibrillation is one of the most common arrhythmias. Despite the different attitude to the pharmacotherapy of Atrial Fibrillation, the problem of selection of adequate antiarrhythmic therapy for the prevention and treatment of persistent Atrial Fibrillation remains relevant and is of great interest to researchers. For the effective selection of drugs in the treatment of arrhythmia can be successfully used the method of spectral analysis of heart rhythm variability. Aims: to study the effect of antiarrhythmic drug Sotalol and β-adrenoblocker Bisoprolol on the spectral parameters of heart rhythm variability in patients with Atrial Fibrillation. Methods. 167 patients with Atrial Fibrillation of both sexes aged 46 to 94 years were examined. The study included patients with the first diagnosed Atrial Fibrillation, and with persistent Atrial Fibrillation during of 6 months to 8 years. Arterial hypertension has diagnosed in all patients. Also, patients were diagnosed with coronary heart disease with a history of myocardial infarction and without myocardial infarction. Spectral analysis of heart rhythm variability was conducted in patients with Atrial Fibrillation. Therapy in patients was performed with the antiarrhythmic drug Sotalol (80−160 mg, orally) and Bisoprolol (2.5−5 mg, orally). Results. Spectral analysis of heart rhythm variability in patients Atrial Fibrillation using Sotalol showed that the proportion of VLF in patients with the first diagnosed Atrial Fibrillation is more than half of the spectrum, whereas in patients with persistent Atrial Fibrillation this parameter is 18%, the proportion of LF is higher in patients with persistent Atrial Fibrillation. The coefficient LF/HF in patients with persistent Arial Fibrillation is two times lower than in patients with the first diagnosed Atrial Fibrillation. Spectral analysis of heart rhythm variability in patients Atrial Fibrillation using Bisoprolol, it was shown that the proportion of LF in patients with the first diagnosed Atrial Fibrillation was 2 times lower, and the proportion of HF was twice higher than in patients with persistent Atrial Fibrillation. Conclusions. In this study, a spectral analysis of heart rate variability in patients with Atrial Fibrillation, who receive antiarrhythmic drug therapy with sotalol and bisoprolol, was carried out. It was found that humoral factors play a significant role in patients with the first diagnosed Atrial Fibrillation during sotalol therapy, the role of the vagus in this group of patients is minimal, while in patients with bisoprolol therapy the vagus has a dominant effect on the activity of the heart.

The use of the spectral analysis of the heart rate variability to assess the effectiveness of therapy is of great attention of researchers and doctors. This method allows you to get knowledge of the influence of the autonomic nervous system on the heart activity, which is an important factor for the manifestation of the effects of antiarrhythmic drugs. In this study, we studied the effect of antiarrhythmic drugs of class III amiodarone and sotalol on spectral indices of the heart rate variability in patients with atrial fibrillation. The power of slow frequencies prevailed in the structure of the spectrum with the introduction of amiodarone and sotalol. This suggests that the sympathetic nervous system have a predominant influence on the heart.

Objective. Specific activity of an antiplatelet drug of indolinone series (codenamed DI) was studied in vitro in a model of ADP-induced platelet aggregation in vitro and in vivo in a model of streptozotocininduced diabetes mellitus in rats. Material and Methods. Acetylsalicylic acid and dipyridamole were used as reference drugs. In vitro tests have demonstrated that DI exhibits antiplatelet activity in a wide range of concentrations (0,75×10-6 – 1.5×10-5 М, р

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Background: Statins are currently used for secondary prevention of Coronary Heart Disease (CHD), as the lipid-lowering therapy with them is proven safe and effective. Objective: The purpose of this research is to investigate the dose-dependent effect of statins used for secondary prevention of coronary heart disease, as well as mechanisms of quantitative and qualitative changes in lipoproteins, fatty acids and cholesterol in the blood and tissues of people of both sexes. Methods: In a clinical trial (n=125, of which 89 patients belong to group 1 and 36 to group 2) and an experiment on laboratory animals (n = 100), simvastatin reduced the total level of fatty acids in blood plasma, when given in the amount that was within the therapeutic dose range. Results: This effect was achieved through a drug-induced improvement in the capacity of hepatic cells to absorb Low-density (LDL) and Very-low-density (VLDL) lipoproteins. Conclusions: Considering the formation of saturated fatty acids, statin performed better in males. With Omega-3 polyunsaturated fatty acids involved, changes in lipoproteins, cholesterol and fatty acids (liver and myocardium) were similar to those caused by small doses of a statin drug. Effects of the combination of bisoprolol and acetylsalicylic acid were completely different from those caused by the use of statin.

The pathophysiology of the intervertebral discs plays a significant role in the people’s life quality. There is not adequate research done in the pathogenesis and treatment of intervertebral disc degeneration. Alternately, self-educated physiology offers a novel and noninvasive method to reverse the degenerated discs. In this single case study, report attempts have been made to highlight the effect of the self-educative physiology, on magnetic resonance imaging investigations, of progressive healing, on the degenerated intervertebral discs. Based on this novel method, an effort has been made to review literature on the degeneration of intervertebral discs and available mode of treatments and then to propose a hypothesis for the biochemical mechanisms of healing. The idea is that transforming growth factor-β1 from seminal plasma secretions may contribute to releasing the osteogenic protein- 1 which induces nucleus pulposus and annulus fibrosus cells in intervertebral discs for repairs. In addition, the patient’s medical history is presented with background information.

Background: It was previously shown that inactivation of gamma-synuclein which is a small soluble neuronal protein affects psycho-emotional status and cognitive abilities in knock-out mice. Objective: Determine the role of gamma-synuclein inactivation on memory performance in aging animals. Method: We used the passive avoidance test and acute amphetamine administration in aging gammasynuclein knock-out mice. Results: As a result, we found moderate aging-unlinked deficit of dopaminergic neurotransmitter system of gamma-synuclein knock-out mice. At the same time, the evidence of progressive synaptic vesicle trafficking machinery impairment was obtained. Conclusion: Therefore most likely these dysfunctions are associated with a reduction in the highefficient learning performance in tests that require intact working memory.

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

Background: Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. Methods: In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. Results: We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation. Conclusion: Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.