Design and evaluation of pharmacological properties of a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid

Introduction: The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic (valproic) acid in order to obtain new drugs. Materials and methods: In the experiments on mice, acute toxicity, neurotoxicity, antiepileptic activity and analgesic effect of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (valprazolamide) were evaluated. LD50 was determined by probit analysis. Neurotoxicity was determined in a rotarod test and a bar test in mice. The effects of valprazolamide on the exploratory behavior of mice in open field test and in a light/dark transition test were evaluated. Its antiepileptic activity was tested in mice against seizures induced by maximal electroshock, pentylenetetrazole (scPTZ); isoniazid, thiosemicarbazide, pilocarpine, and camphor. The analgesic effect was studied in a hot plate test. Results and discussion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide was obtained by introducing pharmacophores into the structure of 2-propylpentanoic acid: a substituted amide group and an electron-donor domain of 1,3,4-thiadiazole. The LD50 value for intraperitoneal administration of a new 2-propylpentanoic acid: derivative to mice was 924.8 mg/kg, and the TD50 value in the rotarod test and the bar test were 456.7 mg/kg and 546.7 mg/kg, respectively. The suppression of orienting responses in the animals was noted when it was administered in neurotoxic doses. Valprazolamide showed the most antiepileptic activity on models of MES, scPTZ and isoniazid antagonism tests. The ED50 values were 138.4 mg/kg, 74.5 mg/kg, and 126.8 mg/kg, respectively. The therapeutic indices for these models of epilepsy were 6.7; 12.4; 7.3, and protective index – 3.3; 6.1 and 3.6, respectively. In the hot plate test, valprazolamide increased the latency period before a defensive response to a thermal stimulus (ED50 165 mg/kg). Conclusion: N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide is a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid with antiepileptic and analgesic activities, which belongs to the group of low-toxic agents. Graphic abstract N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (3D) LD50=924.8 mg/kg (mice, intraperitoneally) TD50=456.7 mg/kg (rotarod, mice, intraperitoneally) ED50=138.4 mg/kg (MES, mice, intraperitoneally) ED50=74.5 mg/kg (scPTZ, mice, intraperitoneally)

Evaluation of Betulinic Acid Effects on Pain, Anxiety, Catalepsy, and Oxidative Stress in Animal Model of Parkinson’s Disease.

BackgroundParkinson’s disease (PD) is known by motor impairments. Betulinic acid (BA) is a natural active compound with potent antioxidant activity. The present study addresses the question whether BA affects motor dysfunctions, pain, anxiety and molecular changes in the rat model of PD.MethodsRight medial forebrain bundle (MFB) was lesioned by injection of 6-OHDA in Male Wistar rats. BA (0.5, 5 & 10 mg/kg) and L-dopa (20 mg/kg) were administrated for 7 days. rigidity, anxiety, analgesia and memory, were assessed by bar test, open-field, elevated plus-maze (EPM), tail-flick and shuttle box. Additionally, the malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GPx) activity as well as Brain-derived neurotrophic factor (BDNF) and Interleukin 10 (IL10) levels in the brain tissue were measured.ResultsTreatment with BA significantly reversed the 6-OHDA-induced motor complication in the bar test, but it modified anxiety like behavior neither in open-field nor in EPM, it only decreased the time spent in open arms. Moreover no significant changes were found in the tail-flick between treatment and sham groups. On the other hand, the level of MDA & IL10 were decreased, and the activity of GPx, levels of SOD & BDNF in the rats brains were increased.ConclusionOur results showed that BA could affect as a potent natural free radical scavenger which removes brain tissue oxidants in PD. It can account a possible promise as a good therapeutic agent for motor and non-motor complications in PD.

Emergency Separation Simulation and Damage Prediction of an Airliner under Wheel-Up Landing Condition

To predict the damage to and response of aircraft structures during wheel-up crash landing, numerical simulations were performed using a constitutive and damage model for ductile metallic materials developed in the ABAQUS/Explicit environment. The model of an entire aircraft and detailed submodels were established. The Johnson–Cook and Gurson material constitutive models were validated by conducting Hopkinson’s bar test. A drop hammer test and a static test of the fuse pins were performed to determine and verify the response and strength of the structure. The experimental and analytical results indicate that the stain rate and damage parameters significantly influence the emergency separation load, fuse pin strength, and separation sequence. The analysis results were compared with the test results, and a close agreement was found in terms of the maximum load and deformation.

Influence of a multidimensional music-based exercise program on selected cognitive and motor skills in dementia patients—a pilot study

One of the most common causes of needing care in old age is dementia. In order to enjoy a pleasant retirement for people with dementia, it is essential for them to maintain their independence. Studies have shown that a combination of physical activity and music has positive effects on dementia patients. Therefore, this study aimed to investigate the feasibility of implementing a multidimensional music-based exercise program for dementia patients and the effects on an intervention group (IG) compared to a control group (CG, usual care). The study design was based on a 12-week intervention with two (IG/CG) by two (pretest/posttest) parallel groups and block randomization with unequal group sizes. Participants had to be able to move independently or with a walker and not have severe cardiovascular disease or cardiac arrhythmias. Fifty-three blinded dementia patients (age: 83.63 ± 6.03 years) from inpatient facilities participated in the study and were assigned from the exercise instructors to IG (n = 34) and CG (n = 19). The primary outcomes were feasibility (Observation sheet), modified Chair Rising test, Timed Up and Go test, hand dynamometer test, FICSIT‑4 (Frailty and Injuries: Cooperative Studies of Intervention Techniques), and drop bar test. Secondary endpoints included: verbal fluency (“animals”), the Mini-Mental State Examination, memory, Trail Making Test A, and Qualidem. Forty-nine subjects were analyzed (IG = 32; CG = 17). There were significant differences between the groups in the modified Chair Rising test (p = 0.033), FICSIT‑4 (p = 0.035), and Timed Up and Go test (p = 0.005) at posttest, which showed improved performance of the IG compared to the CG. The IG additionally showed improvements in the modified Chair Rising test (p = 0.000), drop bar test (p = 0.033), hand dynamometer test (p = 0.001), Timed Up and Go test (p = 0.000), verbal fluency (p = 0.002) and Trail Making Test A (p = 0.04) after 12 weeks. There were no adverse events or side effects. The multidimensional music-based exercise program could be performed by the dementia patients and was well received. The improved functional mobility could contribute to a lower risk of falls and thus maintain independence. For the follow-up study, the number of subjects, randomization, and parameters should be considered.

The Application of a New Oxidation Mortar Bar Test to Mixtures containing Different Cementing Systems

The effects of different cementing systems on the expansion of mortars containing iron sulphide-bearing aggregate was studied. Using a recently developed oxidation mortar bar test, the results showed that cementing systems containing low-calcium fly ash, metakaolin, slag, high-sulphate resisting Portland cement, or low heat of hydration Portland cement could reduce the expansion by 50–85%. The main suggested mechanisms behind the reduced expansion is the more refined pore structure of samples with SCMs, and the reduced C3A of low heat of hydration Portland cement. The refined pore structure reduces the permeation of the oxidizing solution into the samples. The similarity of this to penetration of oxygen into concrete under field exposure needs to be determined. Soaking the samples for >3 h in the oxidizing agent can produce excessive expansion – not related to oxidation of iron sulphide phases – in samples with cementing blends containing reactive alumina such as metakaolin.

The Efficacy of Accelerated Test Methods to Evaluate Alkali Silica Reactivity of Recycled Concrete Aggregates

The effectiveness of accelerated tests in evaluating the Alkali-Silica Reactivity of Recycled Concrete Aggregates was evaluated. The Accelerated Mortar Bar Test was found effective for evaluating potential alkali-reactivity when the test variables, such as crushing method and absorption, are carried out in a well-defined process. The method of crushing was found to have significant impact on the expansion. The Concrete Microbar Test (CMBT) provides good correlation to the expansion of Concrete Prisms incorporating Supplementary Cementing Materials when an expansion limit of 0.10% at 56 days or 0.04% at 28 days were used, based on the limited number of tests carried out here.

The Efficacy of Accelerated Test Methods to Evaluate Alkali Silica Reactivity of Recycled Concrete Aggregates

The effectiveness of accelerated tests in evaluating the Alkali-Silica Reactivity of Recycled Concrete Aggregates was evaluated. The Accelerated Mortar Bar Test was found effective for evaluating potential alkali-reactivity when the test variables, such as crushing method and absorption, are carried out in a well-defined process. The method of crushing was found to have significant impact on the expansion. The Concrete Microbar Test (CMBT) provides good correlation to the expansion of Concrete Prisms incorporating Supplementary Cementing Materials when an expansion limit of 0.10% at 56 days or 0.04% at 28 days were used, based on the limited number of tests carried out here.

The Application of a New Oxidation Mortar Bar Test to Mixtures containing Different Cementing Systems

The effects of different cementing systems on the expansion of mortars containing iron sulphide-bearing aggregate was studied. Using a recently developed oxidation mortar bar test, the results showed that cementing systems containing low-calcium fly ash, metakaolin, slag, high-sulphate resisting Portland cement, or low heat of hydration Portland cement could reduce the expansion by 50–85%. The main suggested mechanisms behind the reduced expansion is the more refined pore structure of samples with SCMs, and the reduced C3A of low heat of hydration Portland cement. The refined pore structure reduces the permeation of the oxidizing solution into the samples. The similarity of this to penetration of oxygen into concrete under field exposure needs to be determined. Soaking the samples for >3 h in the oxidizing agent can produce excessive expansion – not related to oxidation of iron sulphide phases – in samples with cementing blends containing reactive alumina such as metakaolin.