Analytical Algorithm Expressions in Simulation of the Temperature Field in Electric Resistance Spot Welding

The paper presents the method of obtaining mathematical equations named "Analytical algorithm expressions" which enable simple creation of computer programs for simulation of the temperature field in the weld zone in electric resistance spot welding. Knowledge of these equations and the manner of their formulation make creation of program packages easier but they do not change anything with respect to the structure and scope of necessary input data which determine concrete initial and boundary conditions. In addition to providing algorithm description of the temperature field, the considered approach is applied for mathematical description of the field of any other physical value relevant for the welding process (specific current, electric potential, density, etc.). In this paper they are realized in temperature fields, as hierarchically superior to the fields of stress and current density, i.e. fields of physical properties of materials of the sheet and the electrode (superiority refers to the algorithm domain). Results of simulation for the non-stationary period of the welding process at two extreme discreet moments are presented at the end

Molecular Docking Analysis of Novel Thiourea Derivatives of Naproxen with Potential Anti-Inflammatory Activity

Administration of current non-steroidal anti-inflammatory drugs is often associated with serious adverse effects. Therefore, there is a constant need to develop new molecules with anti- inflammatory activity. On the other hand, thiourea derivatives of non-steroidal anti-inflammatory drugs demonstrated significant anti-inflammatory activity in numerous studies. To clarify anti- inflammatory mechanism of action, in silico study was performed on four thiourea derivatives of naproxen, which were selected from the initial group of compounds synthesized by our research group. Tested compounds contain p-fluoroaniline (16), p-methoxyaniline (17), p-ethoxyaniline (18) and aniline (19) in the side chains. Selected 3D structures of enzymes COX-2 (3NT1) and 5-LOX (6NCF) were taken from PDB database. MAKE Receptor 3.2.0.2 software (OpenEye Scientific Software, Inc, Santa Fe, NM, United States) was used for preparation of enzymes’ active sites, while ligands were prepared in OMEGA 2.5.1.4. FRED 3.2.0.2 software (OpenEye Scientific Software, Inc, Santa Fe, NM, United States) was employed for the analysis of binding poses into enzymes’ active sites. All tested compounds showed key binding interactions with both enzymes. The highest number of key binding interactions was observed during molecular fitting of derivative 19 into the active site of COX-2 and derivatives 16 and 18 into the 5-LOX. Derivative 17 had the lowest value of free binding energy for both target enzymes (−14.90 kcal/mol for COX-2 and −9.57 kcal/mol for 5-LOX). Therefore, all analyzed compounds represent potential dual inhibitors of mentioned enzymes.8th International Electronic Conference on Medicinal Chemistry, Online | 1–30 November 202

In silico prediction of pharmacokinetic properties and druglikeness of novel thiourea derivatives of naproxen

Masking the carboxyl group of naproxen with other functional groups may be a promising strategy to decrease its gastrointestinal toxicity. Thiourea moiety has been described as an important pharmacophore in a variety of pharmacologically active compounds, including anti-inflammatory, antiviral, anticancer, hypoglycemic and antimicrobial agents. Our research group has previously designed twenty novel thiourea derivatives of naproxen, containing amino acids (glycine, L-alanine, β-alanine, L-valine and L-phenylalanine - compounds 1,2,3,4 and 5, respectively), their methyl (6-10) and ethyl esters (11-15), as well as aromatic amines (16-20). Pharmacokinetic properties and druglikeness of these compounds were predicted using SwissADME web tool (http://www.swissadme.ch/). Predicted pharmacokinetic properties include potential for gastrointestinal absorption, blood-brain barrier permeability, skin permeability, transport mediated by P-glycoproteins and enzyme inhibitory potential. Druglikeness was evaluated using Lipinski’s, Ghose’s, Veber’s, Egan’s and Muegge’s rules, as well as on the basis of bioavailability score. All tested compounds had high-predicted gastrointestinal absorption and low blood-brain barrier permeability. Also, derivatives 2, 4, 7, 9, 10, 12, 14, 15 and 18 were predicted to be substrates for P-glycoprotein. Derivatives with aromatic amines (16-20) showed inhibitory potential against all tested CYP isoforms. Derivative 19 had the highest, while derivative 13 demonstrated the lowest predicted skin permeability. Finally, derivatives 1-12, except 5 and 10, have druglike structures, since they obey to all imposed rules

Fluoksetin ne remeti motornu funkciju kod bolesnika sa Parkinsonovom bolešću - korelacija raspoloženja i motorne funkcije sa koncentracijom fluoksetina/norfluoksetina u plazmi

Background/Aim. Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. Methods. In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 ≤ Hamilton Rating Scale for Depression (HDRS) ≤ 23)] without dementia [(25 ≤ Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. Results. Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 μg/L. Conclusion. Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted.Uvod/Cilj. Selektivni inhibitori ponovnog preuzimanja serotonina su antidepresivi koji se najčešće koriste u lečenju obolelih od Parkinsonove bolesti (PB). Cilj ovog istraživanja bio je da se proceni uticaj fluoksetina (Flu) na motorne funkcije bolesnika sa PB. Metode. U ovom prospektivnom, kontrolisanom, otvorenom kliničkom ispitivanju, 18 bolesnika sa PB i blagom depresijom [10 ≤ Hamiltonova skala za depresiju (10 ≤ HDRS) ≤ 23)], bez demencije [(25 ≤ Mini mental test (MMSE)] lečeni su primenom Flu. Procenjivana su dejstva kako pojedinačne, tako i ponovljene doze Flu od prvog do osamdesetog dana. Plazma koncentracije Flu i norfluoksetina (NORFlu) korelisane su sa rezultatima odeđenih testova za motorne funkcije: skala za procenu težine PB (UPDRS), test spretnosti kucanja (FTT) i Purdue pegboard Test PPT). Izraženost PD, depresije i demencije procenjivane su korišćenjem standardnih testova [(test dnevnih aktivnosti (ADL), Hoehn.-Yahr. stadijumi (HJ), HDRS, MMSE)]. Rezultati. Ravnotežno stanje za Flu/NORFlu postignuto je 18. dana lečenja. Takav plato u koncentraciji Flu/NORFlu bio je praćen značajnim poboljšanjem rezultata, kako testova za depresiju, tako i za izraženost PB (HDRS, UPDRS i ADL, sledstveno). Dodatno, rezultati FTT-a i PPT-a bili su u porastu do 18. dana, sa blagim fluktuacijama oko platoa. Optimalna motorna postignuća zabeležena su pri koncentraciji Flu od oko 60-110 μg/L. Zaključak. Flu (20 mg/dan) značajno redukuje depresiju kod bolesnika sa PB i ne remeti motorne funkcije. S obzirom na mogući placebo efekat u istraživanjima sa PB i depresijom, neophodna su obimnija, prospektivna, randomizovana, placebo- kontrolisana klinička ispitivanja

Cost-effectiveness analysis of preventing sudden cardiac death with an implantable cardioverter defibrillator versus amiodarone

Sudden cardiac death is natural death caused by previous heart disease, when within an hour from the onset of symptoms ensue loss of consciousness and cessation of circulation. Many studies have confirmed that malignant ventricular arrhythmias are the most common cause of sudden cardiac death. Alternatives for prevention of sudden cardiac death are antiarrhythmic drug treatment, primarily amiodarone, and implantation of cardioverter defibrillator. The aim of this pharmacoeconomic study was to compare the cost-effectiveness of implantable cardioverter defibrillator and amiodarone in preventing sudden cardiac death. The Markov model was designed based on data from the literature, and analyzed using the software TreeAge®. The time horizon was five years. The duration of one cycle was one month. Effect for each model state was expressed in quality-adjusted life years gained (QALYs). The Monte Carlo simulation was used for 1.000 hypothetical patients. Implantation of cardioverter defibrillator proved to be pharmacoeconomically inferior method of preventing sudden cardiac death, nearly twelve times more expensive than applying amiodarone, i.e. 621.833,18 dinars per QALY gained in comparison to 52.644,25 dinars per QALY gained for amiodarone. The study showed that the method with superior cost/effectiveness ratio was preventing sudden cardiac death by amiodarone. It is expected that further research will indicate a subpopulation in which the implantable cardioverter defibrillator will show better cost/effectiveness ratio than amiodarone

Transcranial parenhymal sonography in the diagnosis of Parkinson's disease

Bacground/Aim. Modern ultrasound systems allow highresolution transcranial sonography (TCS) of the brain structures. Enlargement of the echogenic signal (hyperechogenicity) of the substantia nigra (SN) has been reported as a highly characteristic finding in idiopathic Parkinson's disease (PD) and is thought to reflect increased amounts of iron, bound to proteins other than ferritin, in the SN in the course of neurodegeneration. The aim of our study was to investigate the prevalence of the SN hyperechogenicity in PD patients, as well as its possible clinical correlates. Methods. The study comprised 103 consecutive PD patients and 50 healthy age-matched controls. For TCS examination a color-coded, phased array ultrasound system equipped with a 2.5 MHz transducer was used (ESAOTE Technos MP, Italia). The examination was performed through a preauricular acoustic bone window with a penetration depth of 16 cm and a dynamic range of 45-50 dB. The SN was identified within the butterfly shaped structure of the mesencephalic brainstem, with scanning from both temporal windows. Results. The SN hyperechogenicity was identified in 95 out of 103 examined PD patients (92%), which was marked in 60 (63%), and moderate in 35 patients (37%). Median SN echogenic size was larger contralateral to the clinically more affected side of the body. Unilateral SN hyperechogenicity was also found in 5 out of 50 healthy controls (10%). No ventricular enlargements were notified in our study. Conclusion. Our study demonstrated SN hyperechogenicity in more than 90% of PD patients. In adult subjects without neurological symptoms, the TCS finding of at least unilaterally marked SN hyperechogenicity indicates a subclinical functional impairment of the nigrostriatal dopaminergic system.

Antibacterial and antibiofilm screening of new platinum(IV) complexes with some s-alkyl derivatives of thiosalicylic acid

The influence of 5 new Platinum(IV) (Pt(IV)) complexes with S-alkyl derivatives of thiosalicylic acid (C1-benzyl, C2-methyl, C3-ethyl, C4-propyl and C5- butyl) was studied on 16 strains of bacteria. Antibacterial activity was tested using microdilution method with resazurin while antibiofilm activity was observed by tissue culture plate method, using doxycycline as a positive control. The results were expressed as minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and biofilm inhibitory concentration (BIC). The best result on Gram positive bacteria exhibited C1 and MIC was <7.81μg/ml against Staphylococcus aureus ATCC 25923. Bifidobacterium animalis subsp. lactis (probiotic) was sensitive to C2 (MIC at 15.625 μg/ml). The highest sensitivity of Gram negative bacteria was observed in Escherichia coli ATCC 25922 treated with C1, C2, C3 and C4, in Proteus mirabilis ATCC 12453 treated with C1, and in Pseudomonas aeruginosa treated with C2, C3 and C5 (all MICs at 250 μg/ml). The C2 complex were more efficient as antibiofilm agents and the best results were obtained with C2 acting against S. aureus and S. aureus ATCC 25923 biofilms. In conclusion, we noticed that the tested compounds exhibited promising properties as antibacterial and antibiofilm agents

Fluoxetine does not impair motor function in patients with Parkinson's disease: Correlation between mood and motor functions with plasma concentrations of fluoxetine/norfluoxetine

Background/Aim. Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. Methods. In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 ≤ Hamilton Rating Scale for Depression (HDRS) ≤ 23)] without dementia [(25 ≤ Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. Results. Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 μg/L. Conclusion. Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted. [Acknowledgment. Projekat Ministarstva nauke Republike Srbije, br. 175090)

Interactions of binuclear copper(II) complexes with S-substituted thiosalicylate derivatives with some relevant biomolecules

Interactions of copper(II) complexes which contain S-alkyl derivatives of thiosalicylic acid (alkyl = methyl, ethyl, propyl and butyl; aryl = benzyl), marked as 1–5, with guanosine-5′-monophosphate (5′-GMP) and calf thymus DNA (CT-DNA) were studied. Kinetics of substitution reactions of 1–5 with 5′-GMP and CT-DNA were investigated under pseudo-first-order conditions at 310 K and pH = 7.2 in 25 mM Hepes buffer using stopped-flow method. All complexes have high affinity toward studied bio-molecules. Additionally, interactions with CT-DNA were followed by absorption spectroscopy and fluorescence quenching measurements. The results indicate that complexes bind to DNA exhibiting high binding constants (Kb = 104 M−1). During the examination of competitive reactions with ethidium bromide (EB), results showed that complexes can replace EB-bound DNA. In addition, a new crystal structure of the binuclear Cu(II) complex with S-substituted thiosalicylate derivative has been reported. In the present series of Cu(II) complexes the crystal structure is the first example of a complex comprising an S-aryl derivative of thiosalicylate ligand. Through comparative study of structural properties of six molecules from four crystal structures we examined the structural variations, potentially important for biological activity of these complexes. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group