Synthesis and anti-microbial activities of some pyridinium salts with alkoxymethyl hydrophobic group.

A novel class of functionalized cationic surfactant has been obtained. The work-up procedure of synthesis is very simple, the yield is high and the pyridinium salts with alkoxymethyl hydrophobic group are easily purified. All the salts examined showed anti-microbial activities. Some of them exhibited strong activity and wide anti-bacterial spectra similar to the activity of benzalkonium chloride. The relationship between chemical structure and anti-microbial activity was analysed by the QSAR method.

Molecular modeling of buspirone-serotonin receptor interactions.

Modern concepts of buspirone activity as an anxiolytic drug are reviewed. Particular attention is focused on the molecular aspects of buspirone interactions in the phases that simulate cellular environment. Three-dimensional models of buspirone-serotonin receptor complexes are discussed as well.

[Comparison of the therapeutic efficacy of spironolactone and furosemide in patients with severe congestive heart failure]. / Porównanie skutecznosci klinicznej spironolaktonu i furosemidu u chorych na ciezka niewydolnosc serca.

21 patients with NYHA class III to IV congestive heart failure were randomised to Aldactone (200 mg i.v., 11 pts) or furosemide (20 mg i.v., 10 pts). The mean urine volume in 24 hours in Aldactone group was 1145 ml (range 600 to 2500 ml) and 1678 ml (range 1000 to 3500 ml) in furosemide group (NS). Reduction of magnesium plasma level in furosemide group 24 hours after treatment (from 2.16 +/- 0.18 to 2.01 +/- 0.12 mg/dl, p < 0.05) and slight elevation in Aldactone group (from 1.96 +/- 0.3 to 2.11 +/- 0.18, NS) were observed. Ventricular arrhythmias detected on 24 hour Holter monitoring didn't differ between the study groups.

Synthesis and hypolipidemic and antiplatelet activities of alpha-asarone isomers in humans (in vitro), mice (in vivo), and rats (in vivo).

A series of alpha-asarone isomers was synthesized and investigated for their hypolipidemic and antiplatelet activity. Considering the hypolipidemic activity in rats at a dose of 80 mg/kg/day, some isomers were more potent than clofibrate at 150 mg/kg. Compound 3 was one of the most active agents elevating the HDL cholesterol level by 56% and lowering the LDL cholesterol level by 46.8% in rats after 7 days of administration. The activities of the platelet aggregation test in vitro were significant but lower than those of the reference substances (indomethacine and acetylsalicylic acid). In the pulmonary thromboembolic in vivo test in mice, two compounds (alpha-asarone (6) and compound 4) produced significant antithrombotic effects at 100 mg/kg, namely 44% and 52% protection against lung microembolia, respectively. alpha-Asarone derivatives form a new group of potential hypolipidemic and/or antithrombotic agents. The compounds 3, 4, and 6 may serve as lead substances whose structural modifications may result in original drugs.

Selective hydrolysis of nucleotides to nucleosides and free bases.

The kinetics of the hydrolysis of 2'-deoxyadenosine-5'-monophosphoric acid (dAMP), 2'-deoxycytidine-5'-monophosphoric acid (dCMP), 2'-deoxyguanosine-5'-monophosphoric acid (dGMP) and tymidine-5'-monophosphoric acid (dTMP) was studied in the presence of Xanthomonas maltophilia [1]. The reaction products are nucleosides: 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), 2'-deoxyguanosine (dG) and tymidine (dT), respectively, or the respective free bases. Hydrolysis of dTMP and dGMP proceeded stepwise according to the sequence: nucleotide-->nucleoside-->free base, whereas no accumulation of the free base was observed during the hydrolysis of dAMP and dCMP.

13C cross-polarization magic angle spinning NMR and gauge-independent atomic orbital, coupled Hartree-Fock calculations of buspirone analogues. Part 2. Hydrochlorides and perchlorates of 1-arylpiperazine-4-alkylimides.

13C cross-polarization (CP) magic angle spinning (MAS) solid state NMR spectra of hydrochlorides and perchlorates of buspirone analogues (2-5) were recorded. In the spectra for each compound, one set of signals appeared, in agreement with single crystal X-ray diffraction data indicating the presence of one molecule per crystal unit. The resonances of 2-5 hydrochlorides were assigned by comparison with the solution chemical shifts. For perchlorate 2b and diperchlorate 2c, the reasonable assignment of signals was made with the aid of the theoretical studies. Ab initio calculations of the carbon shieldings were performed by means of the GIAO-CHF method for two model systems: perchlorate and diperchlorate of quinoline-(N-methyl)piperazine. As no remarkable differences between carbon chemical shifts of hydrochlorides 3-5 in solid state and in solution were observed, it was concluded that in solution these compounds adopted the same conformation as in the solid state.

The ligand-binding site of buspirone analogues at the 5-HT1A receptor.

A three-dimensional model of the 5-HT1A receptor in man was constructed by molecular-modelling techniques and used to study the molecular interactions of a series of buspirone analogues with the 5-HT1A receptor by molecular-mechanical-energy minimization and molecular-dynamics simulations. The receptor has seven trans-membrane alpha helices (TMHs) organized according to the electron-density-projection map of visual rhodopsin, and includes all loops between TMHs and the N- and C-terminal parts. The best fit between the buspirone analogues and the receptor model was obtained with the quinolinyl part of the ligand molecules interacting with amino acids in TMH6, the imide group interacting with amino acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonded with Ser86 and Ser393. The ligand-binding rank order deduced from the experimentally determined inhibition constant was reproduced by calculation of receptor-binding energies of the buspirone analogues. The models suggest that steric hindrance and repulsive forces between the receptor and the imide group of the buspirone analogues are the most important determinants of ligand-binding affinity for discriminating between these ligands.

Conformational flexibility of serotonin1A receptor ligands from crystallographic data. Updated model of the receptor pharmacophore.

Preparation and affinity to 5-HT1A and 5-HT2A receptors of new buspirone analogues 7-17 are reported. The compounds possess high to low affinity to 5-HT1A and moderate to low to 5-HT2A receptors. The crystal structures have been determined for compounds 11, 12, 13, and 14. For low affinity ligand (15) of 5-HT1A receptor conformational analysis was performed and compared with similar analyses performed for know high (buspirone 1) and very high (WY-48,723 2) affinity ligands of the receptor. Structure-activity relationship is discussed for the affinity to 5-HT1A receptor. A three-point pharmacophore explaining interactions of buspirone-like molecules with the receptor binding site is proposed.

Some derivatives of 3-amino-2-oxazolidinone influencing neurotransmission of dopamine and serotonin.

The influence of 3-amino-2-oxazolidinone derivatives 1-9 on dopaminergic and serotoninergic neurotransmission was tested. It was found that all tested compounds exhibited modulating activity on one (or both) of the neurotransmissions, the effect being dependent on the aromatic ring substituent.

Buspirone analogues as ligands of the 5-HT1A receptor. II: Capacity factors as chromatographic parameter of lipophilicity evaluation in a series of 5-HT1A and 5-HT2A receptor ligands.

The lipophilicity of a series of buspirone related agents was studied by means of reversed-phase HPLC using an octadecylsilane stationary phase a mixture of aqueous solution of sodium phosphate and methanol as a mobile phase. Comparison of the measured capacity factors with log P values has shown very good correlations with regression correlation coefficients in the range of 0.994-0.996.

Effects of captopril on ventricular arrhythmias in the early and late phase of suspected acute myocardial infarction. Randomized, placebo-controlled substudy of ISIS-4.

The antiarrhythmic effect of oral captopril was studied during the early (day 3) and late (day 14) phase of acute myocardial infarction among 304 patients in a randomized placebo-controlled substudy of ISIS-4. Ventricular arrhythmias (ventricular ectopic beats per hour) occurred significantly less frequently among captopril-allocated patients than among those allocated placebo at day 3 (logarithmic scale: 0.48 +/- 0.8 captopril vs 0.84 +/- 1.3 placebo; P < 0.003) and at day 14 (0.51 +/- 1.0 vs 0.77 +/- 1.3; P < 0.05). The number of patients with frequent ventricular arrhythmias (more than 10 ventricular ectopic beats per hour) was also significantly lower among those allocated captopril at day 3 (7.3% vs 14.4%; P < 0.05) and at day 14 (7.3% vs 14.8%; P < 0.05). These results support the hypothesis that the activation of the renin-angiotensin-aldosterone and sympathetic system may underlie heart rhythm disturbances in acute myocardial infarction, and that early use of converting enzyme inhibitor therapy may ameliorate these disturbances.

Intravenous amiodarone is safe and seems to be effective in termination of paroxysmal supraventricular tachyarrhythmias.

BACKGROUND: Paroxysmal atrial fibrillation (PAF) and paroxysmal supraventricular tachycardia (PSVT) leading to hemodynamic compromise are among the most common reasons for admission to the coronary care unit (CCU) and need prompt and efficient therapy. Direct current cardioversion is the therapy of choice, but if found contraindicated or unavailable some antiarrhythmic agents are usually given to restore sinus rhythm. Many of these drugs have obvious limitations, especially in patients with acute myocardial infarction and/or heart failure. HYPOTHESIS: The aim of the present study was to assess the safety and efficacy of intravenous amiodarone in the acute termination of PAF or PSVT refractory to other antiarrhythmic agents in a large group of patients consecutively admitted to our CCU. METHODS: In the present study, we evaluated the safety and efficacy of amiodarone given intravenously in 142 consecutive patients with PAF or PSVT lasting < 24 h. In 37% of patients no evidence of underlying heart disease which may have caused arrhythmias were defined. A median of two other antiarrhythmic agents given prior to the first amiodarone injection had been ineffective. RESULTS: Sinus rhythm was restored in 91 patients (64%) (65% in the PAF group and 61% in the PSVT group). The mean time to rhythm conversion was 5.5 +/- 6.1 h for patients with PAF and 1.2 +/- 1.2 h for patients with PSVT. The mean dose of amiodarone administered up to conversion was 340 +/- 220 mg for PAF and 220 +/- 105 mg for PSVT. Except for transient first-degree atrioventricular block in two patients, no adverse effects possibly related to amiodarone were observed (including proarrhythmia and incidence or aggravation of heart failure symptoms). CONCLUSION: Amiodarone given intravenously for acute termination of supraventricular tachyarrhythmias is completely safe and seems effective. The results of this study, which is the largest ever made, indicate a need of randomized, controlled trials for the ultimate assessment of the efficacy of amiodarone in this clinical setting.

Structure-activity relationship in a series of new 1-(2-pyrimidinyl)piperazine derivatives with hypnotic activity.

Preparation, biological properties and QSAR of new derivatives of 1-[4-(2-pyrimidinyl)-1-piperazinyl]-1, 3-butandione (11-13, and 15-18) and 3-[4-(2-pirimidinyl)-1-piperazinyl]-3-oxopropanoate (20-22) exhibiting hypnotic activity in mice are reported. The best therapeutic indices (TI = LD50/ED50) 4.7 and 9.4 for po and ip administration, respectively, were found for 1-[4-(2-pyrimidinyl)-1-piperazinyl]-2-n-pentyl-1,3-butandione (15). QSAR studies showed that the biological activity grows initially with an increase in lipophilicity to drop dramatically for log P > 2.5.

Buspirone analogues as ligands of the 5-HT1A receptor. 1. The molecular structure of buspirone and its two analogues.

An interdisciplinary (X-ray, 1H and 13C NMR, IR, and theoretical quantum mechanical) study on the potent 5-HT1A receptor ligand buspirone (1) and its two structural analogues, mesmar (4,4-dimethyl-1-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) (2) and kaspar (8-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane - 7,9-dione) (3), has been reported. The results have shown that buspirone-like molecules should appear in an extended rod-shape form, possessing several potential interaction sites with the receptor.

Some analogues of 1,4-disubstituted piperazines as hypnotic and sedative agents.

Preparation, analytical data, and biological properties such as acute toxicity, influence on spontaneous and amphetamine induced locomotor activity, hypnotic activity, influence on hexobarbital narcosis and anticonvulsant activity of new analogues of pyrimidyl piperazines--ethyl 3-[4-(2-pyrimidyl)-1-piperazinyl]-3-oxopropanoate (4), 1-[4-(2-pyrimidyl)-1-piperazinyl]-1,3-butandione (5), ethyl 3-[4-(2-pyrimidyl)-1-piperazinyl]butanoate (6) and 1-[4-(2-pyrimidyl)-1-piperazinyl]-2-acetyl-1-hexanone (7)--are reported.

[The effect of work-related stress on the occurrence of increased blood pressure]. / Wplyw stresu zwiazanego z praca na wystepowanie podwyzonego cisnienia tetniczego krwi.

In 546 officials the arterial blood pressure was measured twice at the beginning and at the end of a working day, filling also an inquiry form. As hypertension systolic BP over 160 mm Hg (21.3 kPa) or more, and diastolic BP 96 mm Hg (12.7 kPa) or more were accepted. In 90 subjects (16.5%) above normal pressure values were found. Hypertension had been diagnosed previously in 50 subjects in this group (55.5%) but only 13 of them (26%) were treated systematically. Excessive stress of work was complained of by 62.6% of the subjects. Increased blood pressure was found significantly more frequently in the group perceiving excessive stress of work (19.9%) as compared to those not experiencing this stress (10.8%, p less than 0.1). In the group in managerial posts these proportions were 24.8% and 14.4% respectively (p less than 0.1). Blood pressure rise to abnormal levels during the working day occurred also significantly more frequently in the group experiencing it this was noted only in 1.6% of cases (p less than 0.5). The knowledge of own hypertension was very low in this group. These results indicate the necessity of increasing prophylactic measures in the form of greater frequency of control measurements of the blood pressure, better health education, and limitation of stress situations in working environment.

Brachydactyly, a possible inherited anomaly at prehistoric Prince Rupert Harbour.

Disproportionately short metacarpals or metatarsals in eight burial skeletons and three unusually short metapodials recovered as disturbed bones were identified in a 1500 B.C. to A.D. 500 skeletal series from eight archeological sites of the north mainland coast of British Columbia, Canada. At least ten people were affected from four sites for a minimum series frequency of 5.2%. Various factors clinically implicated in the occurrence of brachymetapody were investigated to account for the anomaly. Context-sensitive information suggested that trauma, infarction or infection, and individual or family-related malformation syndromes were unlikely possibilities. Some modern population data suggest that the series frequency was unusually high, particularly for fourth metatarsal involvement, the most commonly affected bone. Modern pedigree interpretations, ethnohistoric inferences, and the archeological contexts of the affected burial skeletons and site samples provide a framework for concluding that brachymetapody in the series was more likely due to the inheritance of an essentially isolated anomaly.