Pycnogenol efficiency on glycaemia, motor nerve conduction velocity and markers of oxidative stress in mild type diabetes in rats.

The aim of this study was to describe the effects of Pycnogenol at various doses on preprandial and postprandial glucose levels, the levels of thiobarbituric acid reactive substances (TBARs) and N-acetyl-beta-d-glucosaminidase (NAGA) and on motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-induced diabetic rats. Pycnogenol treatment (10, 20, 50 mg/kg body weight (b.w.)/day) lasted for 8 weeks after induction of diabetes. Pycnogenol significantly decreased elevated levels of preprandial glycaemia in treated animals at all doses. At doses of 10 mg/kg b.w./day and 20 mg/kg b.w./day it significantly decreased elevated levels of postprandial glycaemia compared with diabetic non-treated animals. Pycnogenol failed to induce a significant decrease of postprandial glycaemia at a dose of 50 mg/kg b.w./day. Pycnogenol improved significantly the impaired MNCV at doses of 10 and 20 mg/kg b.w./day compared with non-treated animals. The levels of TBARs were elevated in diabetic rats. The levels of NAGA increased gradually despite the treatment. Pycnogenol failed to affect the increased levels of TBARs and NAGA. Pycnogenollowered the elevated levels of glycaemia and reduced the decline in motor nerve conduction velocity in STZ-induced diabetic rats. The effect of Pycnogenol on postprandial glycaemic levels and MNCV was not dose-dependent.

[Synthesis of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxy-propoxy}-phenylcarbamic acid alkylesters and in vitro evaluation of their beta-antiadrenergic and vasodilatative activities]. / Syntéza alkylesteru kyseliny 2-{3-[4-(4-fluorfenyl)-piperazin-1-yl]-2-hydroxy- propoxy}-fenylkarbamové a in vitro : . ' hodnoceni jejich beta-antiadrenergní a vazodilatacní aktivity.

Synthesis of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxy-propoxy}-phenylcarbamic acid alkylesters and in vitro evaluation of their beta-antiadrenergic and vasodilatative activities In effort to obtain effective compounds able to favourably influence pathologically changed cardiovascular functions, such as hypertension and ischemic cardiac disease, a new series of aryloxyaminopropanols were synthesized. Four of the compounds, which differ in the alkyl substitution of phenylcarbamate (methyl, ethyl, propyl, butyl), were chosen for basic in vitro pharmacological analyses. In experiments on the isolated spontaneously beating guinea pig atria all compounds at conc. of 1.0.10(-6) mol.l(-1) decreased the basic heart rate (7.6-13.6%) and inhibited the positive chronotropic effect of isoprenaline (pA2 = 6.28-6.81). The compounds manifest only a slight relaxation effect on KCl pre-contracted aortal strips of rats (not until conc. of 1.0.10(-5) mol.l(-1)). The compounds with propyl and butyl substitution appear more effective than the methyl and ethyl derivatives.

Synthesis, pharmacological activity and chromatographic separation of some novel potential beta-blockers of the aryloxyaminopropanol type.

Following our previous structure-activity relationship studies, some novel compounds of the aryloxyaminopropanol type, derived from 2- or 4-hydroxyphenylalkanones, with phenethyl or 3,4-dimethoxyphenethyl groups in the hydrophilic part of the molecule were synthesized and pharmacologically evaluated. The compounds were prepared by means of two methods and their structures were confirmed by the interpretation of their IR, UV and 1H NMR spectra. The enantiomers were separated by HPLC on vancomycin (Chirobiotic V) and teicoplanin (Chirobiotic T) chiral stationary phases. The affinity of the prepared racemic compounds to beta1- and beta2-adrenergic receptors was pre-determined on isolated guinea pig atria and trachea. The assumed cardioselectivity was expressed as the beta1/beta2 ratio. Reciprocal changes in the position of the phenoxysubstituents did not influence the antiisoprenaline activity of the compounds. On the other hand, the increase of the N-substituent size in the hydrophilic part of molecule (3,4-dimethoxyphenethyl moietyled to a substantially higher affinity for cardiac (beta1) than for tracheal (beta2) tissue.

Synthesis and pharmacological evaluation of novel potential ultrashort-acting beta-blockers.

The basic relationship between chemical structure and pharmacological activity of eight newly developed potential ultrashort-acting beta-adrenergic blockers was evaluated. The compounds studied are derivatives of arylcarbonyloxyaminopropanols and were prepared by four-step synthesis. All the compounds evaluated showed weak antiisoprenaline (beta-adrenergic receptor blocking) activity and antiarrhythmic (antiouabain) activity.

[Effects of a (fluorophenyl) piperazine derivative (substance IIIv) on cardiovascular function]. / Ucinky (fluórfenyl)piperazínového derivátu (látka IIIv) na kardiovaskulárne funkcie.

The present paper links up with the study of principal pharmacological effects of newly synthesized aryloxyaminopropanols substituted with 1,4-piperazine derivatives in the hydrophilic moiety of the molecule. The substance with the working name IIIv showing the highest beta-adrenolytical and vasodilating effect underwent further pharmacological evaluations with the aim of contributing to the elucidation of the mechanism of its action. After 7-day administration of the substance in two doses (5 and 50 mg.kg-1), the changes in the reactibility of arterial preparations were investigated on three models of the contraction of the isolated rat aorta (KCl, noradrenaline, and PGF2 alpha) from both qualitative and quantitative views. The results were also supplemented with organometric studies of the effect of the substance in rats.

Can diastereoisomerism of alkoxyphenylcarbamates influence their local anesthetic activity?

The surface local anesthetic activity (LAA) in the homologous series of racemic (+/-)-cis- and (+/-)-trans-N,N-dimethyl-2- (2-alkoxyphenylcarbamoyloxy)cyclopentylmethylamonium chlorides was evaluated. The potency was expressed in rabbits as efficiency indices (EI) in comparison to the standard drug cocaine. All tested racemic mixtures of the phenylcarbamates were local anesthetically active and their potency increased with the size of alkoxysubstitution from the propyloxy- to the hexyloxyderivative and then decreased abruptly (cut-off effect). When different mixtures of both diastereoisomers were applied the synergistic effect--i.e. increase of the LAA of one diastereomer when adding the other--was observed. It seems that an optimal racemic ratio of the compounds could increase their local anesthetic efficiency.

[Preparation and anticonvulsant activity of new potential beta-adrenoreceptor blockers]. / Príprava a antikonvulzívna aktivita nových potenciálnych blokátorov beta-adrenoreceptorov.

Within the framework of a structure-effect relationships study in a group of new beta-adrenoreceptor blockers, a series of new derivatives derived from p-hydroxyacetophenone with modifications in the basic moiety of the side chain was prepared. The initial p-hydroxyacetophenone prepared by Fries rearrangement of phenylacetate in a reaction with 2-(chloromethyl)oxirane yields 1-[4-(2-oxiranylmetoxy)phenyl]-1-etanone, which combines with the appropriate amines to produce final substances. They were isolated either in the form of free bases, or salts with fumaric acid. Their structure was confirmed by interpretations of the IR, 1H-NMR and 13C-NMR-spectra. Within the framework of pharmacological evaluation of the prepared agents, the anticonvulsive effect as a protective effect against pentetrazole spasms was examined. The results of the evaluation were compared with the values of their distribution coefficients.

[Pharmaco-toxicologic evaluation of newly synthesized analogs of propafenone]. / Farmakologicko-toxikologické hodnotenie novosyntetizovaných analógov propafenonu.

The basic pharmacological evaluation of five analogues of propafenone was the aim of the present paper. Antiarrhythmic activity of the compounds at 10(-5) mol.kg-1 was established in guinea-pigs using experimental arrhythmias induced by ouabain and aconitine. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. All of the compounds studied were local-anaesthetically active and their indexes of efficiency were 1-5 fold higher in comparison with the standards cocaine and procaine. The acute toxicity of the compounds was within acceptable limits.

Comparative studies on beta-adrenolytic potencies of some new phenoxyaminopropanol derivatives and celiprolol.

The influence of different substitutions in 4-position of the phenyl ring of three recently developed l-alkylamino-3-phenoxy-2-propanol derivatives on the beta-adrenolytic potency and tissue specificity has been investigated and compared to the cardioselective beta-adrenoceptor antagonist celiprolol. The pA2 values against the isoprenaline tachycardia in isolated right atria (beta 1) and the relaxation of tracheal muscle (beta 2) both of guinea-pigs were expressed as beta 1/beta 2 selectivity ratio. The efficiencies and cardioselectivity of 4-propoxycarbonylderivative (BL 345 Ac) as well as celiprolol were similar, whereas 4-propoxymetylsubstitution (FoA 34t) decreased the inhibiting potency to the heart tissue nearly three times. The elimination of the 4-substitutent leads to the total loss of cardioselectivity (FoA 04). In addition, the character of the 4-substition has also influenced the nonspecific membrane activity expressed as local anesthetic efficiency in experiments on rabbit eyes and guinea-pig skin.

[Preparation and pharmacologic characteristics of aryloxyaminopropanol derivatives with an assumed cardiovascular effect]. / Príprava a farmakologická charakteristika aryloxyaminopropanolových derivátov s predpokladaným kardiovaskulárnym pôsobením.

In an attempt to prepare drugs favourably influencing pathologically changed functions of the cardiovascular system, such as hypertension and ischemic cardiac disease, several chemical compounds were prepared in which benzhydrylpiperazine, alkyl, or substituted phenylpiperazine (fragments of the structures of calcium antagonists) were bound to the fundamental aryloxyamino-propanol skeleton (the carrier of beta-adrenolytic effect). The selected four compounds underwent basic pharmacological analysis. In experiments on the isolated spontaneously beating guinea-pig atria (beta 1), three compounds competitively inhibited the positively chronotropic effect of isoprenaline (pA2 = 6.40-7.24) and in experiments on the isolated tracheal guinea-pig muscle they antagonised the relaxation effect of isoprenaline beta 2, the pA2 values ranging from 5.90-7.58. It follows from the experiments on the isolated guinea-pig aorta contracted with 50 mM KCl that all compounds under study possess mild relaxation effects, the intensity of which is, however, lower than in the used standards flunarizine and verapamil.

Synthesis of esters of aliphatic and aromatic carbamic acids. A comparative study of properties and local anesthetic activity of these compounds.

Four basic esters of cyclohexancarbamic acid and their salts with hydrochloride were synthesized and evaluated for local anesthetic activity. It was found that also aliphatic carbamates studied exhibit local anesthetic activity comparable with the activity of analogous esters of aromatic (2-methoxyphenyl) carbamic acid. Our comparative investigation shows that the presence of aromatic group in the ester of carbamic acid influences local anesthetic activity, however the occurrence of aromatic moiety is not necessary condition for their activity.

[Pharmacologic evaluation of p-hydroxyacetophenone derivatives as potential beta-adrenolytics]. / Farmakologické hodnotenie derivátov p-hydroxyacetofenónu ako potenciálnych beta-adrenolytík.

The anti-isoprenaline and negative inotropic activity in the electrically stimulated guinea-pig left atria as well as the local anaesthetic activity of three 4-(2-hydroxy-3-isopropyl-aminopropoxy)-3-(alkoxymethyl) acetophenone derivatives were evaluated. The efficiency of the compounds was compared with the beta-adrenolytic drug atenolol. All of the compounds tested exhibited a statistically significant anti-isoprenaline activity, which increased from the propoxy- to heptyloxyderivative. However, the nonspecific cardiodepressive and local anaesthetic effects of the drugs increased in the same order: propoxy- < pentyloxy- < heptyloxyderivative.

[Preparation and pharmacologic profile of derivatives of alkoxyphenylcarbamic acid with potential effects on the cardiovascular system]. / Príprava a farmakologický profil derivátov kyseliny alkoxyfenyl-karbámovej s potenciálnym úcinkom na kardiovaskulárny systém.

In a systematic study of the relationship between the chemical structure and beta-adrenolytic activity, eleven derivatives of the 4-alkoxysubstituted phenylcarbamic acids were prepared. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. Negative chronotropic and antidysrhythmic activity were also evaluated. All of the compounds studied were local anesthetically active and their indexes of efficiency were 3-50 fold higher in comparison with standards cocaine and procaine. The acute toxicity of the compounds was within the acceptable limits.

[Anti-inflammatory activity of aqua-(aryloxyacetate) copper complexes]. / Protizápalová aktivita niektorých akva-(aryloxyacetáto)mednatých komplexov.

The anti-inflammatory activity of selected mononuclear Aqua(aryloxyacetato)copper(II) complexes with the composition [Cu(R-O-CH2COO)2(H2O)n].mH2O (R = phenyl, n = 3; m = 0), 4-chlorophenyl (2; 0), 4-chloro-2-methylphenyl (2; 0) and naphthyl (2; 2) was examined using rat paw dextrano edema. The antiphlogistic effects of the tested complexes were compared to those for corresponding aryloxyacetic acids and salicylic acid and its Cu(II) salt. The compounds were administered i.p. in a single effective dose of 10 mg/kg. The complexes with R = phenyl, 4-chlorophenyl and 4-chloro-2-methylphenyl exhibited a biological activity comparable to that of copper(II) salicylate tetrahydrate.

[Changes in basic nitrogen in a group of potential new beta- adrenolytics--derivatives of p-hydroxyacetophenone and p-hydroxypropiofenone]. / Obmeny na bázickom dusíku v skupine nových potenciálnych betaadrenolytík--derivátov p-hydroxyacetofenónu a p-hydroxypropiofenónu.

Within the relationship of the structure and effect of new beta-adrenolytic agents derivatived from p-hydroxyacetophenone and p-hydroxypropiophenone with a propoxymethyl group in the lipophilic part of the molecule and with a propanamine, a butanamine and a pyrrolidine in the side-chain were studied. In order to prepare these substances, a procedure was selected from several tested ones, in which 4-hydroxy-3propoxymethylphenylketone were treated with chloromethyloxirane and subsequent reaction a hydrobromic acid were prepared 4-(3-brom-2-hydroxypropoxy)-3-propoxymethylalkylketone. Final substances were prepared reaction with amine. The structure of prepared compounds was confirmed on the basic interpretation of the IR, UV and 1H NMR spectra. The results of pharmacological evaluation of selected compounds showed a significant beta 1-blocking activity lower than acebutolol. Their local anesthetic activity is low according with their partition coefficients. The characteristic of the prepared compounds was supplemented by the determination of their partition coefficients, surface tension, dissociation constants and acute toxicity.