ANTIBACTERIAL AND CENTRAL NERVOUS SYSTEM ACTIVITY OF (4,5-DIARYL-4H-1,2,4-TRIAZOL-3-YL)METHACRYLIC ACID DERIVATIVES.

The series of 1,2,4-triazole derivatives containing methacrylic acid moiety were synthesized in reaction of N3-substituted amidrazones with itaconic anhydride. Preliminary calculated bioavailability parameters of obtained compounds suggested good penetration via cell membranes and their good absorption after oral intake. Antimicrobial evaluation in vitio showed diverse activity of obtained triazoles mainly on Gram-positive bacterial strains. One derivative was also examined to determine the effect on the central nervous system of mice.

Impact of combined treatment with rosuvastatin and antidepressants on liver and kidney function in rats.

Depression is among the most prevalent and life-threatening forms of mental illness, and is also a risk factor for cardiovascular disorders, diabetes and metabolic syndrome. Elderly patients commonly receive statins for the prevention of cardiovascular diseases, and antidepressant drugs for the treatment of depression. It should be noted that long-term polypharmacotherapy may lead to potential drug interactions and disorders of the organs. The aim of the present study was to determine whether, and to what extent, combined treatment with rosuvastatin and antidepressants (amitriptyline or fluoxetine) influences the biochemical markers of liver and kidney function in a rat model. For this purpose, the activity levels of aspartate aminotransferase, alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and the concentrations of total protein, urea, creatinine and ß2-microglobulin were determined. The results of the study indicated that combined treatment with rosuvastatin and the antidepressants amitriptyline and fluoxetine for 14 days altered the activity levels of ALT and GGT, and the concentrations of urea and creatinine in the serum compared with groups of rats receiving rosuvastatin or either antidepressant alone. These observed changes in biochemical parameters may suggest the possibility of impaired liver and kidney function during the continuous combined exposure to the drugs. However, further clinical and animal studies are required in order to further elucidate this process.

Preliminary Pharmacological Screening of Some Thiosemicarbazide, s-triazole, and Thiadiazole Derivatives.

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.

Estimation of oxidative stress parameters in rats after simultaneous administration of rosuvastatin with antidepressants.

BACKGROUND: Patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular events and also commonly receive antidepressant drugs for the treatment of depression. A many-year polypharmacotherapy can lead to increased side effects of these drugs. It may lead to an oxidation-reduction imbalance and the growth of a generation of reactive oxygen species (ROS) which may induce cellular dysfunctions. METHODS: The aim of this study was to assess oxidative stress parameters in the blood of rats after simultaneous administration of rosuvastatin (10mg/kg) with paroxetine (10mg/kg) or citalopram (10mg/kg). The activity of glutathione peroxidase (GPX) was determined in whole blood, and the activity of glutathione reductase (GR) and the total antioxidant status (TAS) were determined in the serum. RESULTS: The 14-day simultaneous administration of rosuvastatin with paroxetine or citalopram caused an increase in glutathione peroxidase and glutathione reductase activity and did not influence the level of the total antioxidant status. Rosuvastatin (10mg/kg) or citalopram (10mg/kg) administered alone to rats for 14 days did not affect the examined parameters. The 14-day application of paroxetine (10mg/kg) significantly decreased a glutathione peroxidase activity, increased a glutathione reductase activity and did not affect the level of TAS. CONCLUSIONS: The observed changes may indicate an increased activity of the enzyme system preventing oxidation, which appears to be the effect of the reaction on the severity of oxidative stress during the combined treatment with rosuvastatin and antidepressants.

SYNTHESIS, STRUCTURE AND PHARMACOLOGICAL EVALUATION OF 1-(1H-PYRROL-1-YLMETHYL)-4-AZATRICYCLO[5.2.1.0(2,6)] DEC-8-ENE-3,5-DIONE.

A set of arylpiperazine derivatives with imide fragments, 1-(1H-pyrrol-1-ylmethyl)-10-oxa-4-azatricyclo[5.2.1.0(2,6)-]dec-8-ene-3,5-dione connected by propyl and butyl linkers, were synthesized and tested for the potential anxiolytic and antidepressant activities. Compounds 3a and 3b demonstrated antidepressant activity in the forced swimming tests in mice and were devoid of neurotoxic effects. (chimney test in mice).

EVALUATION OF SELECTED BIOCHEMICAL PARAMETERS OF OXIDATIVE STRESS IN RATS PRETREATED WITH ROSUVASTATIN AND FLUOXETINE.

The aim of this study was to assess the effect of a combined 14-day treatment with rosuvastatin (10 mg/kg) and fluoxetine (10 mg/kg) on selected biochemical parameters of oxidative stress in the blood of rats. The activity of glutathione peroxidase (GPX), glutathione reductase (GR) and the total antioxidant status (TAS) were determined. A combined 14-day treatment with rosuvastatin and fluoxetine significantly increases glutathione peroxidase and glutathione reductase activity and decreases the level of TAS. Rosuvastatin administered to rats caused a decrease in the glutathione peroxidase activity and an increase in the glutathione reductase activity but did not affect the level of TAS. A 14-day treatment with fluoxetine exerted practically no effect on the investigated parameters of oxidative stress in rats. The abovementioned changes in the biochemical parameters after the combined treatment with rosuvastatin and fluoxetine may imply an imbalance in prooxidant and antioxidant levels in the combined treatment with rosuvastatin and fluoxetine.

Preliminary studies evaluating cytotoxic effect of combined treatment with methotrexate and simvastatin on green monkey kidney cells.

Patients, affected by neoplastic disease, take usually other drugs and this may lead to a number of often rather unpredictable interactions. The statins are among the most commonly prescribed drugs in medicine but have also adverse side effects and come into interactions with other drugs. The aim of this study was to investigate the cytotoxic effect of methotrexate (5.5 or 16.5 micromol/L), simvastatin (100 or 300 micromol/L) and their combination on green monkey kidney (GMK) cells culture using cytotoxicity detection kit LDH. Besides, the effect of above drugs on the cells viability was estimated by MTT test. After 6, 12 or 24 h of simultaneous incubation of GMK cells with methotrexate (5.5 micromol/L) and simvastatin (100 micromol/L) the cytotoxicity (about 10%) of the drugs was found in LDH test. Cytotoxicity of combination: methotrexate (5.5 micromol/L) with simvastatin (300 micromol/L) after 6 or 12 h of incubation with GMK cells was similar (about 10%), but after 24 h of incubation, cytotoxicity increased to 21%. The significant increase of the cytotoxicity (about 30%) was found after 24 h incubation of GMK cells with methotrexate (16.5 micromol/L) and simvastatin (100 micromol/L). In the MTT assay, the decrease in the cells viability was found also after 12 and 24 h of GMK cells incubation with methotrexate (5.5 or 16.5 micromol/L) and simvastatin (100 or 300 micromol/L). These results suggest the adverse effect of combined application of both drugs on GMK cells especially after 24 h of incubation.

The influence of lead on the biomechanical properties of bone tissue in rats.

INTRODUCTION AND OBJECTIVE: Environmental lead (Pb) is a serious public health problem. At high levels, Pb is devastating to almost all organs. On the other hand, it is difficult to determine a safe level of exposure to Pb. More than 90% of the Pb in the adult human body and 70% in a child's body is stored in the bones. In the presented study, the effects of lead exposure on bones were studied for rats treated orally with Pb acetate in drinking water for 14 days. The hypothesis was tested that lead exposure negatively affects bone structure. MATERIALS AND METHODS: Femur strength was measured in a three-point bending test, whereas infrared spectroscopy (FTIR) was used to measure molecular structural changes. RESULTS: Lead significantly decreased the ratio of area of two types of vibrational transitions, which are highly specific to mineral to matrix ratio. The results of the biomechanical study show that femurs of rats treated by Pb-acetate appeared to be weaker than bones of the control group, and may produce a condition for the development of higher risk of fractures. Additionally, a great difference in body mass was observed between control and the Pb acetate-treated groups. CONCLUSIONS: The lower bone mineral content and the weaker mechanical properties of bones from Pb-treated rats are associated with the pathologic state dependent of the exposure of lead.

The problem of osteoporosis in epileptic patients taking antiepileptic drugs.

INTRODUCTION: Epilepsy is a common neurological disorder associated with recurrent seizures. Therapy with antiepileptic drugs (AEDs) helps achieve seizure remission in approximately 70% of epileptic patients. Treatment with AEDs is frequently lifelong and there are reports suggesting its negative influence on bone health. This is especially important in terms of general occurrence of osteoporosis, affecting over 50 million people worldwide. AREAS COVERED: This study refers to two main groups of AEDs: hepatic enzyme inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and topiramate) and non-inducers (clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, valproate, vigabatrin and zonisamide). Some reports indicate that enzyme inducers may exert a more negative influence on bone mineral density (BMD) compared to non-inducers. Bone problems may appear in both sexes during AED therapy, although women are additionally burdened with postmenopausal osteoporosis. Supplementation of vitamin D and calcium in patients on AEDs is recommended. EXPERT OPINION: Apart from enzyme inducers, valproate (an even enzyme inhibitor) may also negatively affect BMD. However, the untoward effects of AEDs may depend upon their doses and duration of treatment. Although the problem of supplementation of vitamin D and calcium in epileptic patients on AEDs is controversial, there are recommendations to do so.

Influence of combined therapy with rosuvastatin and amitriptyline on the oxidation-reduction status in rats.

The aim of the present study was to assess the impact of combined therapy with rosuvastatin (10 mg/kg) and amitriptyline (10 mg/kg) on oxidation-reduction status in the blood of rats. After 2-week application of drugs alone or their combination, the activity of glutathione peroxidase (GPX), glutathione reductase (GR) and total antioxidant status (TAS) were determined. It was noticed that combined therapy with rosuvastatin and amitriptyline significantly increased the activity of GPX in comparison to the group receiving only rosuvastatin and decreased the activity of GR in comparison to groups receiving only rosuvastatin or amitriptyline. However, the activity of these enzymes as a result of combined therapy was placed in the level of the control groups. Our studies indicated that the combined therapy with both drugs caused an increase of TAS compared to the groups of animals receiving only one of these drugs. The results indicate on the oxidation-reduction balance and increasing the antioxidant status in rats treated with rosuvastatin and amitriptyline.

Biological activity of novel N-substituted amides of endo-3-(3-methylthio-1,2,4-triazol-5-yl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and N-substituted amides of 1-(5-methylthio-1,2,4-triazol-3-yl)cyclohexane-2-carboxylic acids.

N-Substituted amides of endo-3-(3-methylthio-1,2,4-triazol-5-yl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid and 1-(5-methylthio-1,2,4-triazol-3-yl)cyclohexane-2-carboxylic acid were prepared by the condensation reaction of endo-S-methyl-N1-(bicyclo[2.2.1]hept-5-ene-2,3-dicarbonyl)isothiosemicarbazide and S-methyl-N1-(cyclohexane-2,3-dicarbonyl)isothiosemicarbazide with primary amines. The synthesized compounds were screened for their microbiological and pharmacological activities.

Pharmacological study on some new 3-[(1-methylpyrrol-2-yl)-methyl]-4-substituted 4,5-dihydro-1H-1,2,4-triazol-5-ones.

3-[(1-Methylpyrrol-2-yl)methyl]-4-substituted 4,5-dihydro-1H-1,2,4-triazol-5-ones were obtained by the cyclization reaction of 1-[(1-methylpyrrol-2-yl)acetyl]-4-substituted semicarbazides in alkaline medium. The effects of the synthesized compounds of the central nervous system of mice were studied.

Synthesis of amides of 2,4-dioxothiazolidin-5-yl acetic acid with 1,2,4-triazole substituents.

In the reaction of (2,4-dioxothiazolidin-5-yl)acetyl chloride with 1,2,4-triazole, 4-phenyl-1,2,4-triazolin-5-one and 4-phenyl-1,2,4-triazolin-5-thione, the new corresponding amides (2-4) were obtained. For compounds 2 and 4 effects on central nervous system (CNS) of mice were studied.

Cyclization of thiosemicarbazide derivatives of 5-arylidene-2,4-dioxothiazolidine-3-acetic acids to 1,3,4-thiadiazoles and their pharmacological properties.

By the reaction of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetyl chlorides with 4-phenylthiosemicarbazide, acylthiosemicarbazide derivatives 4-6 were obtained. The cyclization of 4-6 in acid medium led to 1,3,4-thiadiazole derivatives 7-9. The structure of the compounds was confirmed by elemental analysis and IR, H NMR, 13C NMR and MS spectra. The effects of compounds 7 and 9 on the central nervous system (CNS) of mice were studied.

[Imbalance of oxidoreductive status in suicidal antidepressant drugs poisoning]. / Zachwianie równowagi oksydoredukcyjnej w samobójczych zatruciach lekami przeciwdepresyjnymi.

The aim of this study was to examine the association between suicidal poisoning with antidepressants and the oxidoreductive balance by evaluation of changes in activity of glutathione reductase (GR) and total antioxidative status (TAS) in serum. GR activity and TAS were determined in 29 patients hospitalized after suicidal poisoning with antidepressants and compared with the results of the control group consisting of 16 healthy people. For this purpose, RANDOX diagnostic sets were used. The GR activity and TAS were significantly lower in the examined group, compared with the control group. The results obtained show a significant reduction of GR activity and TAS level in patients with suicidal antidepressants poisoning. It seems, that the oxidoreductive balance is shift towards the oxidative potential and leads to the decrease of the organism's antioxidative potential, which is manifested by the increase of oxygen free radicals and the intensification of the oxidative stress.

Synthesis and biological activity of new derivatives of 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid.

New 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid derivatives (8-14) were synthesized by condensation of N(3)-substituted amidrazones (1-7) with maleic anhydride. Molecular structure of obtained compounds was confirmed by an elemental analysis, IR and (1)H NMR spectra, and the X-ray crystallography for compound 11. The influence of the compound 9 on the central nervous system (CNS) of mice in some behavioural test was examined. The investigated compound showed anticonvulsive activity and potent antinociceptive action.

Synthesis and some pharmacological properties of 3-(piperidin-4-yl)-4-substituted-D2-1,2,4-triazoline-5-thione derivatives.

Synthesis of 3-(piperidin-4-yl)-4-substituted-D-2-1,2,4-triazoline-5-thione derivatives, AS-1-AS-4 is described. Results of a preliminary pharmacological screening of two compounds AS-1 and AS-3 are presented.

Synthesis and biological activity of new derivatives of 3-phenoxymethyl-4-R-D2-1,2,4-triazoline-5-thione.

New derivatives of 1,2,4-triazoline-5-thione system were obtained. The effects of both these compounds AP-I (3-phenoxymethyl-4-phenyl-D2-1,2,4-triazoline-5-thione) and AP-II (3-phenoxymethyl-4-ethyl-D2-1,2,4-triazoline-5-thione) on the central nervous system (CNS) of mice were studied.

Preliminary evaluation of CNS effects of 6-O-substituted chelidonine derivatives.

Eleven new derivatives of chelidonine I, obtained by functionalization of the alkaloid hydroxyl group, have been tested for CNS activity in mice exhibiting statistically significant effects.

[Activity of catalase after administration of some ADH and MEOS inhibitors: in vitro investigation in rat liver homogenates]. / Aktywnosc katalazy po zastosowaniu wybranych inhibitorów ADH i MEOS, badania in vitro w homogenatach watroby szczurów.

In the first pass methanol biotransformation three enzymatic systems: alcohol dehydrogenase (ADH), microsomal alcohol oxidising system (MEOS) linked with cytochrome P-450 and catalase are involved. Because of the toxicity of methanol, which is directly caused by its toxic metabolites, the major task in clinical toxicology is to inhibit each of these enzymes to protect human life. The aim of this investigation was to check the influence of some effective inhibitors of ADH and MEOS: 4-methylpyrazole, cimetidine, EDTA and 1,10-phenantroline on the activity of catalase with methanol as a substrate and the comparison with 3-amino-1,2,4-triasole. Catalase activity in rat hepatic homogenates was measured spectrophotometrically in vitro at physiological pH 7.4 and temp. 37 degrees C, assaying the degree of methanol oxidation according to Handler and Thurman. The quantity of arising formaldehyde was measured according with the method of Nash. Our results have shown that catalase activity was inhibited to different extents by all investigated compounds at concentrations of 10(-3) mol/l, 2 x 10(-4) mol/l, 10(-4) mol/l, 2 x 10(-5) mol/l, 10(-5) mol/l. 1,10-Phenantroline was found to be a highly effective inhibitor in comparison with aminotriasole. 4-Methylpyrazole, EDTA, 1,10-phenantroline and aminotriasole are catalase competitive inhibitors and cimetidine is non-competitive inhibitor. 4-Methylpyrazole has shown higher affinity to the enzyme than aminotriasole.