In vivo and in silico pharmacological studies on some new 4-(1,3,4-thiadiazol-2-yl)benzene-1,3-diol analogues.

4-(1,3,4-Thiadiazol-2-yl)benzene-1,3-diols 5-substituted in the heterocyclic ring were obtained by the reaction of the commercially available hydrazides or thiosemicarbazides with sulfinylbis[(2,4-dihydroxyphenyl)methanethione]. The synthesized compounds were screened for their influence on CNS in the vivo model. Computer aided prediction tools were used for the evaluation of toxicological properties. Additionally, based on the Lipinski filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest favorable pharmacokinetics in the body after oral admission.

Synthesis and serotonin receptor activity of the arylpiperazine alkyl/propoxy derivatives of new azatricycloundecanes.

A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione, were synthesized and tested for their affinity for 5-HT(1A) and 5-HT(2A) receptors. The Fujita-Ban analysis showed that the influence of structural modifications on the affinity for both receptor subtypes is additive and that the activity of similar compounds could be predicted with high accuracy. Compounds 46, 48 and 18 out of 14 screened in a functional model of anxiety and depression demonstrated antidepressant activity in the forced swimming tests in mice, and were devoid of neurotoxic effects (chimney test in mice).

Relationships between characteristics of interfacial water and human bone tissues.

Water bound in human bone tissues healthy (sample S1) and affected by osteoporosis (sample S2) was investigated by using 1H NMR spectroscopy with layer-by-layer freezing-out of bulk and interfacial waters at T< 273 K. The 1H NMR spectra of the bound water include two signals which can be assigned to strongly associated typical water (chemical shift of the proton resonance at delta(H) approximately 5 ppm) and weakly associated water at delta(H) approximately 1.4 ppm. Approximately, half of the bound water is in the weakly associated state in S1. A fraction of similar water in S2 is smaller because of the structural difference of the studied samples. The pore size distribution of S2 (in aqueous medium) calculated using the cryoporometry method is characterized by much larger intensity of mesopores and macropores in comparison with that of S1. The total porosity and the surface area of the biostructures (accessible for water molecules and estimated on the basis of the cryoporometry data using a model of cylindrical pores) are larger for S2. Weakly polar chloroform-d has a significant influence on the organization of water in a spongy component of bone tissue. This effect depends on the porosity of the bone matrix and the amounts of CDCl3.

Weakly and strongly associated nonfreezable water bound in bones.

Water bound in bone of rat tail vertebrae was investigated by 1H NMR spectroscopy at 210-300 K and by the thermally stimulated depolarization current (TSDC) method at 190-265 K. The 1H NMR spectra of water clusters were calculated by the GIAO method with the B3LYP/6-31G(d,p) basis set, and the solvent effects were analyzed by the HF/SM5.45/6-31G(d) method. The 1H NMR spectra of water in bone tissue include two signals that can be assigned to typical water (chemical shift of proton resonance deltaH=4-5 ppm) and unusual water (deltaH=1.2-1.7 ppm). According to the quantum chemical calculations, the latter can be attributed to water molecules without the hydrogen bonds through the hydrogen atoms, e.g., interacting with hydrophobic environment. An increase in the amount of water in bone leads to an increase in the amount of typical water, which is characterized by higher associativity (i.e., a larger average number of hydrogen bonds per molecule) and fills larger pores, cavities and pockets in bone tissue.

Synthesis of 1-(3-aminopropyl)-4-phenyl-1,2,4-triazolin-5-one and 1-(3-aminopropyl)-3,4-diphenyl-1,2,4-triazolin-5-one.

The reaction of 4-phenyl-1,2,4-triazolin-5-one [Ia] and 3,4-diphenyl-1,2,4-triazolin-5-one [Ib] with 1-bromo-3-chloropropane was carried out. The obtained compounds [IIa, b] were subjected to the reaction with secondary amines and ethylenediamine with resulted in 1-(3-aminopropyl)-1,2,4-triazolin-5-one derivatives.

Synthesis and biological activity of O-acyl and O-alkyl chelidonine derivatives.

A group of 11 derivatives of chelidonine was obtained by acylations and/or alkylations of the secondary hydroxyl group with the aim of testing their biological activity. This paper focuses on the new derivatives influence on CNS in mice. The highest activity was observed for compounds 2c, 3c and 4, which produced antinociceptive and antiserotoninergic effects, not recorded for the parent alkaloid 1.

Synthesis of 1-(3-amino-2-hydroksypropyl)-4-phenyl-1,2,4-triazolin-5-one and 1-(3-amino-2-hydroksypropyl)-3,4-diphenyl-1,2,4-triazolin-5-one derivatives.

In the reaction of 4-phenyl-1,2,4-triazolin-5-one [Ia] and 3,4-diphenyl-1,2,4-triazolin-5-one [Ib] with 1-chloro-2,3-epoksypropane, the respective derivatives of 1-(2,3-epoksypropane)-4-phenyl-1,2,4-triazolin-5-one [IIa] and 1-(2,3-epoksypropane)-3,4-diphenyl-1,2,4-triazolin-5-one [IIb] were obtained. Then these compounds were converted into the corresponding aminoalkanol derivatives of 1,2,4-triazolin-5-one [IIIa, b-VIIIa, b] in reaction with secondary amines. The new compounds affected significantly the central nervous system of mice.

Synthesis and biological activity of BIS-1,2,4-triazole and BIS-1,3,4-thiadiazole derivatives.

Synthesis of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives via the condensation of N'-substituted amidrazones and p-phenylenediisothiocyanate (PPD) is presented. The reaction conditions are discussed. Results of a preliminary pharmacological screening are presented.

Synthesis of new derivatives of 3-benzyl-4-R-delta 2-1,2,4-triazolin-5-one and 3,3'-methylidyne bis(4-R-1,2,4-delta 2-triazolin-5-one).

In the reaction of phenylacetic acid hydrazide or malonic acid hydrazide with isocyanates, new derivatives of semicarbazide were obtained [I-VIII]. Cyclization of these derivatives with a aqueous 2% sodium hydroxide led to the formation of new derivatives of delta 2-1,2,4-triazolin-5-one [IX-XVI]. Some of them were investigated pharmacologically on the central nervous system in mice.

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part I: Effect on selected biomechanical parameters of the femur.

Ukrain, an acid alkaloid derivative from Chelidonium majus L., was administered intraperitoneally to intact and ovariectomized sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of this Ukrain treatment (24 h after the last dose of the drug), the right femora of the rats were harvested and a three-point bending test until shaft failure was performed under standard conditions. Assembled data, including ultimate strength, ultimate energy at failure and ultimate displacement, were assessed. Strength and energy were adjusted to accommodate differences between groups in the end body weight. These results showed a decrease in adjusted bone strength of ovariectomized rats as compared to sham-operated animals. None of the three long-term doses of Ukrain (i.e., 7 mg/kg, 14 mg/kg and 28 mg/kg) significantly altered the bone strength when it was adjusted to the end body weight of the ovariectomized animals. Intact rats that received a 28 mg/kg dose of Ukrain demonstrated decrease of bone strength of 13.5% when it was adjusted to the end body weight.

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part II: Effect on bone mineral density of the femur.

Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and control sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of the Ukrain treatment (24 h after the last dose of the drug) the right femora of the rats were harvested and the bone densitometric parameters of the whole bone and distal metaphysial and intertrochanteric subregions were assessed using the dual energy x-ray absorptiometry densitometric method. The results showed no apparent decrease in bone mineral density in groups of rats studied. A nearly significant (p = 0.08) decrease of bone mineral content was observed in ovariectomized rats treated with 14 mg/kg of Ukrain.

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part III: Effect on the native electron paramagnetic resonance signal intensity of the femur.

Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and sexually mature female control rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by a 10-day break. This procedure was repeated five times. At the end of the long-term treatment with Ukrain (24 h after the last dose of the drug) the left femora of the rats were harvested. Dried bones were studied by electron paramagnetic resonance (EPR) method. Significant changes in the intensity of the native signal were observed within the groups (ANOVA, p = 0.0001); the lowest value was observed in the ovariectomized rats treated with 28 mg/kg of Ukrain (decrease of 40.8% compared to the ovariectomized group, p = 0.005). A significant increase in the intensity of the signal was observed in the intact 7 mg/kg Ukrain-treated group (34.7% compared to controls, p = 0.004).

Effect of Ukrain on human liver alcohol dehydrogenase activity in vitro.

In the present study it was found that Ukrain inhibits the ethanol oxidation process catalyzed by human alcohol dehydrogenase (ADH). Ukrain at a concentration of 10(-6), 2.5 x 10(-6), and 5.0 x 10(-6) M decreased liver ADH activity in the presence ethanol (approximately 8.41%, 13.28%, 16.69%, respectively) as well as in the presence of methanol (approximately 13.29%, 19.07% and 42.20%, respectively).

High-performance liquid chromatographic assay of formycin A in plasma after solid-phase extraction.

A new, simple and accurate high-performance liquid chromatography (HPLC) method for the determination of formycin A in plasma is presented. The samples were chromatographed on a LiChrosórb RP-18 column after purification using a Bakerbond SPE column. The mobile phase was methanol-0.067 M phosphate buffer, pH 4.20 (1:4, v/v) containing 0.005 M sodium hexanesulfonate. Azathioprine was applied as an internal standard. UV detection was carried out at 293 nm. The method was tested for linearity (over the range 0.1-9.0 micrograms/ml). The recovery was 91.89% (mean). The described method has been successfully applied to the quantitative determination of formycin A in plasma and should be useful for clinical and bioavailability investigations.

Effect of amlodipine upon the protective activity of antiepileptic drugs against maximal electroshock-induced seizures in mice.

Amlodipine, a calcium channel antagonist of the dihydropyridine class, up to 10 mg kg(-1)(i.p.) did not significantly affect the threshold for electroconvulsions. However, this calcium channel antagonist (10 mg kg(-1)) enhanced the anticonvulsive activity of carbamazepine, valproate and phenobarbital against maximal electroshock-induced seizures in mice. Furthermore, amlodipine (5 mg kg(-1)) intensified the protection offered by carbamazepine. This effect was associated with the increased free plasma level of carbamazepine in the presence of amlodipine. Amlodipine did not influence the free or total plasma level of phenobarbital and valproate, so a pharmacokinetic interaction is not probable for valproate and phenobarbital. The anticonvulsive action and free plasma level of diphenylhydantoin was not modified by amlodipine. The combined treatment of the calcium channel antagonist and antiepileptics caused motor impairment (evaluated in the chimney test). Long-term memory (assessed in the passive avoidance test) in case of combinations of amlodipine with carbamazepine or diphenylhydantoin was not affected. The combination of amlodipine with valproate or phenobarbital significantly influenced the retention in this test. A possible usefulness of amlodipine as add-on therapy in epileptic patients may be limited by its considerable adverse effect revealed by behavioural tests. The pharmacokinetic interaction between carbamazepine and amlodipine might have some clinical importance for patients treated with these drugs.

Ukrain (NSC-631570) in experimental and clinical studies: a review.

The need to find a safe and highly effective cure for neoplastic disease remains a major challenge for modern pharmacology. This paper reviews the available literature on Ukrain (NSC631570), a novel semisynthetic drug obtained from Chelidonium majus L. alkaloids. Ukrain has been demonstrated to possess antineoplastic and immunomodulatory properties. Inhibition of the growth of cancer cell lines in vitro, tumor mass reductions in vivo, and partial and complete remissions in oncological patients, occur as a result of Ukrain application. The drug may interfere directly with the metabolism of cancer cells and it also improves the functioning of the host immune system. Diminished synthesis of DNA, RNA and proteins, the inhibition of cellular oxygen consumption, and the induction of programmed cell death in malignant cells have been described following Ukrain administration. The drug can also modify the immunological response via an increase in the number of total T-cells and a normalization of the T-helper/T-suppressor lymphocyte ratio. Ukrain therapy produces neither toxic consequences nor allergic reactions towards the drug. Several case reports and clinical trial data indicate that Ukrain may ameliorate effectively the progress of neoplastic disease and/or induce a total cure.

Six-week treatment with Ukrain in rabbits. Part I: Morphological parameters.

This study was performed to evaluate the effect of 6-week treatment with Ukrain in doses of 0.3, 1.5 and 3.0 mg/kg i.v. on the morphological and biochemical parameters of peripheral blood and morphology of body organs in rabbits. Ukrain application did not change the body organs and total body weight. The drug did not affect biochemical parameters of peripheral blood, except for a minor reduction in the total plasma level and increases in serum uric acid and urea indicating enhanced catabolism of proteins. The peripheral erythrocyte and leukocyte counts were not altered, whereas the percentages of lymphocytes, monocytes, and eozynophils were increased after higher doses of Ukrain. An increase in rod neutrophils and a decrease in the percentage of segmented neutrophils were also noted. These observations indicate a lack of organ toxicity following long-term treatment with Ukrain.

Six-week treatment with Ukrain in rabbits. Part III: Serum levels of thyroid hormones.

The influence of 6-week treatment with Ukrain at doses of 0.3, 1.5 and 3.0 mg/kg i.v. on serum levels of thyroid hormones, i.e., thyroxine and triiodothyronine, was studied in rabbits of both sexes. Ukrain affected the serum levels of both hormones in males. An increase in the thyroxine level was found after Ukrain used at a dose of 1.5 and 3.0 mg/kg i.v., whereas increased triiodothyronine was noted when Ukrain was given at all studied doses. In females the thyroxine level was not altered by Ukrain administration, whereas the triiodothyronine concentration was increased following Ukrain at 0.3, 1.5 and 3.0 mg/kg i.v. it is probable the altered thyroid hormone levels as a result of Ukrain application may contribute to the drug's potent immunomodulatory action.

Six-week treatment with Ukrain in rabbits. Part II: Serum levels of gonadal hormones.

The effect of 6-week treatment with Ukrain at doses of 0.3, 1.5, and 3.0 mg/kg i.v. on the serum levels of steroid hormones, i.e., estradiol, testosterone, and progesterone, was studied in rabbits of both sexes. It is demonstrated that Ukrain treatment exerts minor changes in serum hormone levels. The level of estradiol was increased in the serum of male rabbits following Ukrain treatment only at the dose of 1.5 mg/kg i.v. Similarly, the estradiol serum level was increased after Ukrain given at 1.5 mg/kg i.v. in female rabbits. In male rabbits Ukrain application at 0.3 mg/kg i.v. increased the serum testosterone level. Serum testosterone levels were not altered following Ukrain administration up to 3.0 mg/kg i.v. in female rabbits. Ukrain raised the serum progesterone levels in male rabbits at the doses of 0.3 and 3.0 mg/kg i.v. in females, only the highest dose of Ukrain produced a significant increase of serum progesterone.

Preliminary pharmacokinetic studies of Ukrain in rats.

Ukrain (thiophosphoric acid derivative of Chelidonium majus L. alkaloids) was administered to rats i.p. at a dose of 28 mg/kg (equivalent to 0.1 LD50). A high performance liquid chromatography (HPLC) method for rapid determination of Ukrain in plasma has been described. It was found that Ukrain rapidly penetrated into the plasma of the rats and the elimination of the drug from the plasma was slower. The results obtained were as follows: absorption rate constant ka = 0.0432 [min-1]; elimination rate constant K = 0.0113 [min-1]; drug half-life t1/2 = 61.32 min; actual concentration of Ukrain in the plasma C = 33 e-0.0113t - 39 e-0.0432t [microgram/ml]; and delay in drug absorption T0 = 5.23 min.