piperidines and heptacaine

The aim of this review is to describe the pharmacology, toxicology and chemistry of the new group of local anesthetics of phenylcarbamic acid type.. Basic esters of alkoxy-substituted phenylcarbamic acid have shown high local anesthetic potency, while maintaining a relatively safe toxicity profile. Their potency uniquely increases with the decreasing pH of the external medium. This is of importance when using local anesthesics in inflamed tissues, where the action of common local anesthetics is often problematic.. The most potent phenylcarbamic anesthetics exceed the potency of the most common clinically used local anesthetics 100-300 times. Due to the unique pH dependency of these local anesthetics, further study of their action is required.

Topics: Amides; Anesthetics, Local; Animals; Carbamates; Dose-Response Relationship, Drug; Esters; Humans; Hydrogen-Ion Concentration; Lethal Dose 50; Molecular Structure; Phenylcarbamates; Piperidines; Sciatic Nerve; Structure-Activity Relationship

Micellization of selected quaternary ammonium compounds derived from heptacaine have been studied by absorption spectroscopy in the UV/VIS spectral region with the use of a pyrene probe. The compounds studied in the aqueous solution have been marked as H22, H26, H27, H29, H34, H + Al and H + B and the derivative marked as H34 was studied in a 3 mol/l ethanol solution at the temperature of 25 °C. In the homologous series of the studied bromides H22, H26, H27 and H29, cmc was observed to be dependent on the number of carbon atoms nc in the hydrophobic chain: ln (cmc) = -3.131-0.421nC. The Free Gibbs energy necessary for the transfer of a methyl group of the alkyl chain from the water phase to the inner part of the micelle at the temperature of 25 °C is (-0.421 ± 0.034)RT.

Topics: Anesthetics, Local; Hydrophobic and Hydrophilic Interactions; Micelles; Piperidines; Quaternary Ammonium Compounds; Temperature

The paper studies the kinetics of alkaline hydrolysis and stability under non-isothermal conditions of heptacainium chloride and carbisocainium chloride in the medium of aqueous-ethanolic solution of sodium hydroxide c = 0.1 mol/l and buffer solutions of values of pH 7.0 and pH 8.0. The results of the study of the kinetics of hydrolysis by means of a non-isothermal test - rate constants and activation energy values served as the basis for exact evaluation of the stability of these potential pharmaceuticals. The objective of the paper links up with the previous studies of these substances.

Topics: Anesthetics, Local; Carbamates; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Piperidines; Sodium Hydroxide; Solutions; Water

The study aimed to formulate the local anaesthetic heptacaine into hydrogels on the basis of chitosan. The gel-creating compounds used included natural polymers --three different types of chitosan, namely those of a medium molecular weight, from the shells of shrimp, and from the bumblebees species Bombus terrestris. The prepared hydrogels were evaluated on the basis of their rheological properties and drug liberation. From the point of drug liberation and flow properties, the optimal gel composition was as follows: 0.1% heptacaine + 2% chitosan (medium molecular weight) + 0.2% carbaethopendecinium bromide.

Topics: Anesthetics, Local; Chemistry, Pharmaceutical; Chitosan; Drug Compounding; Hydrogel, Polyethylene Glycol Dimethacrylate; Piperidines

The critical micellar concentration (CMC) of the local anaesthetic agent heptacainium chloride in the solution of KBr was determined by the spectrophotometric method in the UV region of the spectrum at the temperature range of t = 20-40 degrees C and pH = 4.5-5.0. The dependence of CMC on the temperature T turned out forming the U-shape with the minimum at the temperature of t = 25 degrees C. The parabolic dependence of CMC on the temperature T was drawn by the fitting of the values using the polynomial function and the so-called power law equation. The CMC dependence on the temperature T was fitted by the second degree polynomial function. The obtained parabolic equations were applied to the "phase separation model", so the following thermodynamic parameters could be calculated: standard Gibbs free energy (deltaG), enthalpy (deltaH degrees), and entropy (deltaS degrees). The thermodynamic parameters were further used to determine the so-called entropy-enthalpy compensation of the systems under study. The compensation temperature was in the following range: (301 +/- 1-303 +/- 3)K. Then the temperature dependence of the enthalpy (deltaH degrees) and entropy (-TdeltaS degrees) contributions to the standard Gibbs free energy (deltaG degrees) for all prepared concentrations of the compound were calculated.

Topics: Anesthetics, Local; Bromides; Chemistry, Pharmaceutical; Micelles; Piperidines; Potassium Compounds; Solutions; Thermodynamics

The critical micelle concentrations (CMC), of heptacainium chloride in various 0.5 M alcohols (methanol, ethanol and n-propanol) were determined using spectrophotometric measurements. CMC values were determined through the change in the slope when the absorbance versus surfactant concentration was plotted at 234 nm. The CMC values show that micelle formation occurred more easily in methanol than in other higher alcohols.

Topics: Alcohols; Algorithms; Anesthetics, Local; Micelles; Piperidines; Solvents; Surface-Active Agents; Thermodynamics

Effects of local anesthetics heptacaine and carbisocaine on mouse peritoneal macrophages after 5 days of peritoneal administration were observed. Both compounds in a daily dose 50 mg/kg caused significant decrease in phagocytic activity and index of phagocytosis (number of ingested particles). No significant effects on phagocytosis were observed when carbisocaine was administrated in a daily dose 5 mg/kg. No significant changes in weight gain and number of peritoneal macrophages were observed in all groups.

Topics: Anesthetics, Local; Animals; Body Weight; Carbamates; Female; Leukocyte Count; Liver; Macrophages; Mice; Mice, Inbred C57BL; Organ Size; Phagocytosis; Piperidines; Spleen

Topics: Algorithms; Anesthetics, Local; Micelles; Piperidines; Spectrophotometry, Ultraviolet; Temperature; Thermodynamics

Topics: Algorithms; Anesthetics, Local; Chemical Phenomena; Chemistry, Physical; Light; Lipid Bilayers; Liposomes; Nonlinear Dynamics; Phosphatidylcholines; Piperidines; Scattering, Radiation; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

We have studied the critical micellar concentration (c.m.c.) of the homologs of the local anesthetic heptacaine in the medium 0.1 mol/l NaCl, employing spectrophotometry in the UV region of the spectrum at T = 21 degrees C and pH = 4.5-5.0. On the basis of our experimental results, it is assumed that in the homologous series of amphiphilic compounds the quasi-parabolic dependence of biological potencies on the length of their hydrophobic substituent ("cut-off" effect) could be caused by c.m.c.

Topics: Anesthetics, Local; Micelles; Piperidines; Spectrophotometry

The present study aimed to find a suitable HPLC system for the determination of the values of the capacity factor of k' pentacaine, carbisocaine, heptacaine, and its 3-, and 4-positional isomers. The column Separon SG X C-18 and a mobile phase consisting of 90% methanol and 10% water (with 0.5 mol/l of sodium acetate) were demonstrated to be suitable for the separation of these potential local anaesthetics from the group of phenylcarbamic acid derivatives. In this system, k'o for pentacaine is 22.9, for carbisocaine 8.6, for heptacaine 8.1, and for 3-positional derivative of heptacaine, 13.0, and 4-isomer, 18.4. It results from the data that log k' of these drugs is in the interval 2-5 and even minor changes in the concentration of sodium acetate (c = 0.5 +/- 0.05 mol/l) do not change it markedly.

Topics: Anesthetics, Local; Carbamates; Chromatography, High Pressure Liquid; Isomerism; Piperidines

Within the framework of the study of the derivatives of phenylcarbamic acid with a local anaesthetic effect, one of them, a potential medicinal agent with the working name of XX B, chemically N-[2-(3-heptyloxyphenylcarbamoyloxy)-ethyl]-dimethylammoniumchl oride, was investigated. Linking up with the previous studies, the paper investigated the effects of two auxiliary substances--cellulose derivatives (hydroxyethylcellulose, methylcellulose)--and their concentration on the pharmaceutical availability of the potential drug XX B from the dosage form. At the same time the effect of the employed concentration of the macromolecular substances on the viscosity of the dosage form was examined. The study revealed that with the growing concentration of cellulose derivatives the viscosity of the prepared dosage forms was increased, and the release of the active ingredient was decelerated. Both auxiliary substances influenced the pharmaceutical availability of the potential drug XX B in an approximately identical manner, and thus both could be employed for the same purpose.

Topics: Anesthetics, Local; Cellulose; Dosage Forms; In Vitro Techniques; Macromolecular Substances; Pharmaceutic Aids; Piperidines; Viscosity

The molar partition coefficients of amphiphilic additives, e.g. local anesthetics, between the aqueous phase, the liquid crystal and the gel phase of lipid membrane can be determined based on a combination of phase transition data obtained at high and low concentrations of the lipid in aqueous phase. The data obtained at high lipid concentration allow to find the phase diagram lipid-additive in the aqueous environment. The combination of this diagram with data obtained at low lipid and additive concentrations provides direct information on the concentration of anesthetics in the lipid and thus allows the calculation of the partition coefficient.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Anesthetics, Local; Chemical Phenomena; Chemistry; Permeability; Piperidines; Solubility; Surface Properties; Temperature; Thermodynamics; Water

Interaction of the local anaesthetic heptacaine, monohydrochloride of [2-(heptyloxy)-phenyl]-2-(1-piperidinyl)-ethyl ester of carbamic acid, with multilamellar dipalmitoylphosphatidylcholine (DPPC) liposomes in aqueous solution with high excess of water has been studied by means of density measurements in the scanning regime in the main phase transition region. The anaesthetic decreased the temperature of main phase transition. The molar partition coefficients of heptacaine between aqueous phase, liquid crystal and gel phases of DPPC have been determined from a combination of phase transition data obtained by densimetry with a DPPC/heptacaine phase diagram published in the literature. The saturation of heptacaine concentration in liposomes has been observed at higher total amount of anaesthetic. The partial specific volume of heptacaine located in DPPC bilayers is slightly lower than in the aqueous phase.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Anesthetics, Local; Biophysical Phenomena; Biophysics; Chemical Phenomena; Chemistry, Physical; Liposomes; Piperidines; Thermodynamics; Water

Topics: Algorithms; Anesthetics, Local; Micelles; Piperidines; Temperature; Thermodynamics

Local anesthetic monohydrochlorides of [2-(alkoxy)phenyl]-2-(1-piperidinyl)ethyl esters of carbamic acid (CnA, n = 2, 3, 4, 6, 8, 10, 12 is the number of carbon atoms in the alkyloxy substituent) increase the probability of formation of gauche isomers p(g) and decrease the effective energy difference between gauche and trans conformation E(g) in egg yolk phosphatidylcholine (EYPC) acyl chains, as determined by electron spin resonance spectroscopy using dipalmitoylphosphatidylcholines labeled with the paramagnetic dimethyloxazolidinyl group on the 12-th or 16-th carbon atoms of their sn-2 acyl chain, and oriented EYPC bilayers hydrated at 81% relative water vapour pressure. CnAs also increase the hydration of EYPC in non-oriented bilayers at the same relative water vapour pressure. At the molar ratio of CnA:EYPC = 0.4:1, the maximum effect on p(g), E(g) and hydration has been observed for intermediate alkyloxy chain lengths n approximately 4/6.

Topics: Anesthetics, Local; Electron Spin Resonance Spectroscopy; Lipid Bilayers; Phosphatidylcholines; Piperidines; Spin Labels

The partition coefficient of the local anaesthetic heptacaine (monohydrochloride of [2-(heptaloxy)phenyl]-2-(1-piperidinyl)ethyl ester of carbamic acid) between unilamellar liposomes prepared from chromatographically pure egg yolk phosphatidylcholine and the aqueous phase (NaCl solution, ionic strength I = 0,1,pH 4,5, temperature t = 20 degrees C) was determined using UV-VIS spectrophotometry. The contribution to the anaesthetic spectra due to light scattering on liposomes was eliminated numerically using the scattering function. This procedure gave more precise results than the subtraction of liposomes spectra. The values of the partition coefficient defined with the use of molar concentrations, weight concentrations and molar fractions estimated at a wavelength of lambda = 292 nm were Kp = 1116 +/- 49, Kp(m) = 1098 +/- 48 and Kp(x) = 47575 +/- 2089, respectively.

Topics: Anesthetics, Local; Liposomes; Membranes, Artificial; Models, Biological; Phosphatidylcholines; Piperidines; Scattering, Radiation; Spectrophotometry, Ultraviolet; Surface-Active Agents

In the course of the drug form development of heptacaine potential local anaesthetic, the influence of auxiliary substances on the heptacaine release and its local anaesthetic effect was studied. The obtained results show that the following auxiliary substances are optimal: a) 0.3-1.2% solution hydroxypropylmethyl cellulose for 0.025% eye drops, which have the fastest onset of the local anaesthetic effect in the hamster's eye, b) hydroxyethyl cellulose containing 0.5% heptacaine and 10% glycerol or propylene glycol for hydrogels, c) cocoa oil without and with Dimodan S for suppositories.

Topics: Anesthesia, Local; Anesthetics, Local; Animals; Cellulose; Cricetinae; Delayed-Action Preparations; Hypromellose Derivatives; Methylcellulose; Ophthalmic Solutions; Piperidines; Solutions; Time Factors

In the course of the drug form development of substance XIX B (N-[2-(2-heptyloxyphenylcarbamoyloxy)-ethyl] dimethylammonium chloride [1]) the influence of auxiliary substance, namely glycerol (GL), propylene glycol (PG) and sorbitol (SO), used in the form of 5, 10, 15 and 20% solution, on the surface tension, partition coefficient, viscosity and liberation from aqueous solutions was studied. These parameters can influence the bioavailability. The obtained results show that as an optimal additive 5% SO may be used since this ensured maximal amount of liberated substance XIX B.

Topics: Anesthetics, Local; Biological Availability; Chemistry, Pharmaceutical; Glycerol; Piperidines; Propylene Glycol; Solutions; Sorbitol; Surface Tension; Viscosity

A HPLC method is described for the simultaneous determination of the phanylcarbamate type anesthetics heptacaine and carbisocaine and their metabolites. Using this method the in vitro degradation of these drugs in urine, human and rabbit serums was investigated. The slower degradation of carbisocaine was explained on the basis of steric hindrance.

Topics: Anesthetics, Local; Animals; Biodegradation, Environmental; Carbamates; Chromatography, High Pressure Liquid; Humans; Indicators and Reagents; Piperidines; Rabbits

Heptacaine (1), the monohydrochloride of [2-(heptyl-oxy)phenyl]-2-(1-piperidinyl)ethyl ester of carbamic acid, exerts a biphasic effect on the fluidity of egg yolk phosphatidylcholine (EYPC) model membranes as detected by the methyl esters of stearic acid spin probes with the paramagnetic doxyl group bound to the C-12 or C-16. The fluidity initially increases with an increase in the molar ratio of 1:EYPC, but a molar ratios above 1:EYPC = 0.5 a decrease of fluidity has been observed.

Topics: Adrenergic beta-Antagonists; Anesthetics, Local; Electron Spin Resonance Spectroscopy; Lipid Bilayers; Membrane Fluidity; Molecular Weight; Phosphatidylcholines; Piperidines

The aim of the study was to choose a suitable base for the topical application of pentacaine chloride and heptacaine chloride. Both local anaesthetics were processed into two hydrophilic creams, two hydrophobic creams and one hydrophobic ointment as well as into three hydrogel bases. The assumption that the rate of the release of both local anaesthetics from hydrogel bases is greater than from cream bases has been fully confirmed.

Topics: Administration, Topical; Anesthetics, Local; Carbamates; Kinetics; Ointments; Piperidines

Topics: Chemical Phenomena; Chemistry, Physical; Piperidines; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

During the course of study of variations in the basic moiety of heptacainium chloride 10 derivatives of 4-alkylpiperazinoethyl esters of o-heptyloxyphenylcarbamic acid were prepared. Pharmacological investigation indicated that practically all the new compounds were several times more active than standards (cocaine and procaine). The most effective compound was 1-[2-(o-heptyloxyphenylcarbamoyloxy)ethyl]-4-butyl-piperazinium dichloride, which was 142 times more active than cocaine and 266 times more active than procaine.

Topics: Anesthetics, Local; Animals; Carbamates; Cocaine; Guinea Pigs; Lethal Dose 50; Mice; Piperazines; Piperidines; Procaine

The potential mutagenic activity of three carbamate derivatives with local anaesthetic activity was investigated. Genotoxic activity was observed after application of Carbisocaine on Euglena gracilis, whereas no activity was detected by Carbisocaine, Heptacaine and Pentacaine on Salmonella typhimurium, Escherichia coli and Drosophila melanogaster.

Topics: Anesthetics, Local; Animals; Carbamates; DNA Repair; Drosophila melanogaster; Escherichia coli; Euglena; Genes, Lethal; Genes, Recessive; Mutagenicity Tests; Mutagens; Piperidines; Salmonella typhimurium

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a 60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of 3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.

Topics: Animals; Aspirin; Blood-Brain Barrier; Brain; Carbamates; Chloramphenicol; Cobalt Radioisotopes; Cranial Irradiation; Diazepam; Etimizol; Male; Piperidines; Rats; Rats, Inbred Strains; Regression Analysis

Topics: Anesthetics, Local; Humans; Piperidines; Spectrophotometry, Ultraviolet

The influence of local anesthetics (LA): tetracaine, lidocaine, cocaine, dibucaine and heptacaine derivatives on the gel to liquid crystalline phase transition temperature (Tc) of model dipalmitoylphosphatidylcholine (DPPC) membranes was studied using electron spin resonance (ESR) and polarization microscopy methods. The decrease of Tc in the presence of anesthetics (delta Tc) was found to be dependent on the [DPPC]/[H2O] molar ratio at constant [LA]/[DPPC] molar ratio. Hence, the parameter alpha = delta Tc/[( LA]/[DPPC]) in dependence on [H2O]/[DPPC] was extrapolated to zero concentration of water and compared with biological efficiency.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Anesthetics, Local; Cocaine; Dibucaine; Electron Spin Resonance Spectroscopy; Gels; Lidocaine; Lipid Bilayers; Microscopy, Polarization; Physical Phenomena; Physics; Piperidines; Tetracaine

Topics: Carbamates; Chemical Phenomena; Chemistry; Drug Stability; Hydrogen-Ion Concentration; Piperidines; Temperature; Time Factors; Ultraviolet Rays

Topics: Anti-Infective Agents; Chemical Phenomena; Chemistry; Microbial Sensitivity Tests; Piperidines

The newly synthesized carbamate local anaesthetics (heptacaine and BK-141) affected the NCNA responses of different segments of the guinea-pig small (jejunum, ileum) and large (colon, taenia coli) intestine in a similar manner to the classic local anaesthetics (procaine and trimecaine). The sensitivity of NCNA responses to the action of local anaesthetics was, in order: primary contraction greater than rebound contraction greater than primary relaxation. The action of the carbamate local anaesthetics resembled that of trimecaine more than that of procaine. The results presented suggest that different Ca2+ channels participate in primary and rebound contraction and that local anaesthetics affect the receptor-operated Ca2+ channels in lower concentrations than the voltage-dependent ones.

Topics: Action Potentials; Anesthetics, Local; Animals; Carbamates; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Intestines; Male; Piperidines; Procaine; Pyrrolidines; Sympathetic Nervous System; Trimecaine

Topics: Anesthetics, Local; Biotransformation; Chromatography, High Pressure Liquid; Humans; Piperidines

Pharmacokinetics of a local anaesthetic of the carbanilate type (Heptacaine; in the following briefly called HCP), was studied using a labelled product, N-[2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)ethyl]piperidinum++ + chloride. Determination of HCP in biological material was based on double extraction of HCP from alkaline media into n-heptane. The plasma concentration of HCP following i.v. administration to rats was approximated by a biexponential function. An open two-compartment pharmacokinetic model was conferred to the data. The model parameter estimates are as follows: terminal elimination half-life 3.80 +/- 0.15 h, distribution volume at steady state 9.31 l/kg, total body clearance 73.4 ml/min/kg, mean residence time 2.1 h. The systemic availability of the orally given HCP in solution was 35.8%. The HCP plasma AUC vs. dose relationship was linear within doses ranging from 2.78 to 4.33 mg/kg. The brain uptake index of HCP in comparison with 3H2O was 62.2%. Autoradiography in mice injected i.v. showed a heterogeneous distribution of the label in the tissues and its excretion by the urinary and biliary pathways. HCP showed strong affinity to the lung tissue. During 96 h after i.v. administration, 21% and 62% of the 14C dose was excreted into urine and faeces, respectively, and after oral administration, the excretion was 17% and 43%, respectively.

Topics: Administration, Oral; Anesthetics, Local; Animals; Autoradiography; Brain; Feces; Injections, Intravenous; Male; Mice; Piperidines; Rats; Rats, Inbred Strains; Species Specificity; Tissue Distribution

Electrophysiological investigations of new drugs with carbanilate structure (heptacaine, carbisocaine) on axons and sciatic nerves of the rat have shown their high local anaesthetic effect at physiological pH. This effect is not only maintained at acid pH (6.0); it even increases on shifting pH from basic to acid values. To study this unique pH dependence of the effect of new local anaesthetics, drug-lipid interactions were investigated in liposomes prepared from egg yolk phosphatidylcholine or dimyristoyl phosphatidylcholine. The effect of the local anaesthetics on the molecular ordering of lipids in the liposomes was measured from spectral anisotropy of spin-labelled fatty acid incorporated in the membrane. It was concluded that the change of pH from 9.5 to 6.5 not only sustains the disordering effect of heptacaine and carbisocaine; it even potentiates it with the maximum disordering effect recorded at pH 6.5. This trend towards pH dependence in the effect of the new local anaesthetics is similar to that observed in biological preparations and is quite unlike the case of classic local anaesthetics (procaine, lidocaine). The possible mechanism of pH dependence is discussed.

Topics: Anesthetics, Local; Carbamates; Chemical Phenomena; Chemistry, Physical; Electron Spin Resonance Spectroscopy; Hydrogen-Ion Concentration; Membranes, Artificial; Models, Chemical; Piperidines; Spin Labels

Topics: Anesthetics, Local; Animals; Carbamates; Escherichia coli; Female; Mice; Mice, Inbred C57BL; Mutagenicity Tests; Piperidines; Salmonella typhimurium

The action of newly synthesised basic esters of alkoxy-substituted derivatives of phenylcarbamic acid was compared with that of procaine and trimecaine in the guinea-pig small intestine. Some of the carbamate local anaesthetics, in concentrations high enough to markedly suppress cholinergic twitches, elicited regular rhythmic activity of the guinea-pig ileum. This effect of the carbamates was dependent on the position of the alkoxysubstituent and was independent of the basic group (pyrrolidine, piperidine or perhydroazepine) present. Only the ortho-substituted derivatives were active. It was also found that the rhythmic activity evoked was of myogenic origin, produced by rhythmic undulations of the sodium-pump activity, accompanied by a potential-dependent change in Ca2+ permeability. It is suggested that the mechanism by which carbamates reveal this endogenous rhythm in the guinea-pig ileum could be a selective block of noncholinergic, nonadrenergic innervation or the TEA-like activity of carbamates.

Topics: Anesthetics, Local; Animals; Carbamates; Cell Membrane; Colon; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Ouabain; Piperidines

Topics: Cell Line; Fibroblasts; Microscopy, Electron, Scanning; Piperidines

Topics: Anesthetics, Local; Animals; Blood Platelets; Carbamates; Histamine Release; In Vitro Techniques; Male; Mast Cells; Piperidines; Rats; Rats, Inbred Strains; Serotonin

Topics: Benzothiazoles; Escherichia coli; Euglena gracilis; Furazolidone; Mutagenicity Tests; Nitrofurantoin; Nitrofurazone; Piperidines; Salmonella typhimurium; Thiazoles

Topics: Acetanilides; Animals; Heart; Myocardium; Myofibrils; Piperidines; Rats; Trimecaine

In the present study effects of a new local anaesthetics, pentacaine (trans-2-pyrolidinocyclohexylester of 3-pentyloxyphenylcarbamic acid), and of some chemically related compounds on rat hepatic adenylate cyclase activity were studied under various experimental conditions. As compared with tetracaine, the local anaesthetics tested showed stronger inhibitory effects, regardless of the type of stimulating agents used to activate adenylate cyclase. The most potent effect was observed with pentacaine. Its inhibitory effects on glucagon, guanylylimidodiphosphate (Gpp/NH/p), sodium fluoride or forskolin stimulated activity suggest that it may directly act on the catalytic unit of adenylate cyclase. The same conclusion can be drawn based on its inhibitory effects on adenylate cyclase, regardless ATP concentrations used as the enzyme substrate, and on octylpyranoside solubilized enzyme activated by preincubation of the enzyme preparation with Gpp/NH/p. Structure-activity studies have suggested that the pentacaine molecule as a whole and none of its parts alone or its analogs are responsible for the inhibitory effect. However, the inhibitory effects of these compounds on the rat adenylate cyclase activity do not correlate with their local anaesthetic properties. The possibility of using adenylate cyclase inhibitors to decrease cyclic AMP production under pathological conditions, like in cholera, known to be due to a high adenylate cyclase activity, is discussed.

Topics: Adenylyl Cyclase Inhibitors; Anesthetics, Local; Animals; Carbamates; Colforsin; Glucagon; Glucosides; Guanylyl Imidodiphosphate; Liver; Piperidines; Rats; Structure-Activity Relationship

Stearic acids labeled with a doxyl group at the 5th, 12th and 16th carbon positions were used as the spin probes for an investigation of the perturbation effects of two local anaesthetics (the 2-piperidinoethylester of phenyl carbamic acid and the piperidinoethylester of 2-heptyloxyphenylcarbamic acid) on rat brain synaptosomes. For a quantitation of the perturbation effects we have studied the order parameter S of the spin probe, incorporated in the membrane, calculated from the ESR spectra as a function of temperature and concentration of local anaesthetics. The local anaesthetics had a different disordering efficiency at different depths of the membrane. It follows from our results that the perturbing effects of the anaesthetics increase relative to the depth of the membrane, and the extent of perturbation correlates with local anaesthetic activity.

Topics: Anesthetics, Local; Animals; Brain; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; In Vitro Techniques; Membrane Lipids; Phenylcarbamates; Piperidines; Rats; Spin Labels; Synaptosomes

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Anesthetics, Local; Animals; Cerebral Cortex; Guinea Pigs; Piperidines

Topics: Acetanilides; Antigens, Bacterial; Cell Membrane; Escherichia coli; Piperidines; Trimecaine

Topics: Anesthetics, Local; Animals; Chromosome Aberrations; Chromosomes; Cricetinae; Cricetulus; Male; Piperidines

Topics: Animals; Biotransformation; In Vitro Techniques; Male; Microsomes, Liver; Mixed Function Oxygenases; Piperidines; Rats; Rats, Inbred Strains

The membrane disordering efficiency of four local anesthetics, including lidocaine, tetracaine, dibucaine and heptacaine (piperidinoethyl ester of 2-heptyloxyphenylcarbamic acid) has been studied by spin-labeling methods. The disordering efficiency of the drugs in rat total brain lipid liposomes was quantitated with the initial slope value of the order parameter versus drug concentration curve, the so-called change-in-order parameter value. Using the positional isomers of m-doxyl stearic acids (m = 5, 12 and 16), it has been demonstrated that the tested drugs reveal quite different disordering efficiency. There is a clear tendency of increasing disordering efficiency towards the methyl terminal of the lipid acyl chains. By a comparison of order parameter versus drug concentration and temperature at three depths of rat brain total lipid liposomes and synaptosomes, it is shown that the 'fluidizing effect' of local anesthetics does not correspond to fluidization of membrane by temperature and that tetracaine and dibucaine do not have equal disordering efficiency as judged by their solubility in the membrane. The disordering efficiency of these drugs on the hydrocarbone core of a membrane qualitatively corresponds to their anesthetic potency. Similar results were obtained in liposomes and synaptosomes. It is assumed that there is a similar incorporation of the local anesthetics in the liposomes and in the lipid part of synaptosomes.

Topics: Anesthetics, Local; Animals; Cerebral Cortex; Dibucaine; Electron Spin Resonance Spectroscopy; Intracellular Membranes; Lidocaine; Liposomes; Membrane Lipids; Piperidines; Rats; Spin Labels; Synaptosomes; Tetracaine

Topics: Anesthetics, Local; Animals; Cell Nucleus; Chromosomes; Cricetinae; Cricetulus; Piperidines

Topics: Chemical Phenomena; Chemistry, Physical; Piperidines; Quaternary Ammonium Compounds; Staphylococcus aureus; Structure-Activity Relationship

Interaction of the local anesthetic 1[2-(2-heptyloxyphenyl-carbamoyloxy)-ethyl] piperidinium chloride (heptacaine hydrochloride) with a model membrane formed by phosphatidylcholine was studied using 2D-NMR spectra of heavy water and 31P-NMR proton-decoupled and undecoupled spectra of the lipid phosphate group. Heptacaine hydrochloride was found to increase the number of water molecules oriented over the polar region of the membrane, to increase the order parameter of the lipid phosphate group, as well as that of oriented water, and to increase the volume of unoriented water trapped between the bilayers. Heptacaine hydrochloride also affects the temperature dependence of quadrupolar splitting of oriented heavy water deuterons. Heptacaine hydrochloride is suggested to expand the membrane laterally and to charge the membrane surface electrostatically.

Topics: Chemical Phenomena; Chemistry, Physical; Deuterium; Magnetic Resonance Spectroscopy; Phosphatidylcholines; Phosphorus Isotopes; Piperidines; Temperature; Water

The newly synthetized local anaesthetics of the carbanilate type--pentacaine and heptacaine, and the currently used trimecaine have been previously found to exhibit markedly different effects on immune reactions in vitro and in vivo when administered in equitoxic doses. These compounds are now assayed for their influence on the weight and cell count in lymphoid organs, on peripheral blood leucocyte count and homing of 51Cr-labelled syngeneic lymph node cells. We have found that the weight and cell count in the thymus, spleen, lymph nodes, bone marrow and the levels of peripheral leucocytes are reduced after administration of pentacaine, whereas heptacaine and trimecaine have no effect on these parameters. In contrast to heptacaine and trimecaine, pentacaine significantly reduces also the homing of lymph node cells to the recipients' lymph nodes and increases their homing to bone marrow.

Topics: Anesthetics, Local; Animals; Carbamates; Cell Movement; Female; Leukocyte Count; Lymphocytes; Lymphoid Tissue; Male; Mice; Organ Size; Piperidines; Trimecaine

Topics: Anesthetics, Local; Escherichia coli; Mutagenicity Tests; Mutagens; Piperidines; Salmonella typhimurium

In the evaluation of experimental antiarrhythmic effect in guinea pigs, by a method of antagonizing ouabain arrhythmogenity, there was found a maximum effect of N-[2-(2-heptyloxy-phenylcarbamoyloxy)-ethyl]-piperidinium-chloride (heptacaine). The shortening or prolongation of the alkoxy substitution in the ortho-position, or the shift of hexyloxy substitution to the meta- or para-position, respectively, causes a decrease in activity. Negative chronotropic effect of heptacaine is increased and prolonged during the 5th min after acute i.v. application. The effect of lidocaine was short-lasting and decreased. In antagonizing experimental adrenaline (epinephrine) arrhythmogenity, heptacaine showed an important antiarrhythmic effect, too. In the relative hypotensive activity evaluation, there was an important effect in the 1st min after i.v. application and this decreased to the same values as those of lidocaine in the 5th min. Hypotensive effect evaluation of lidocaine and heptacaine after higher doses than therapeutic ones showed that the hypotensive effect of heptacaine takes place at the same rate as that of lidocaine and by the 10th min reaches control values. Values of experimental partition coefficient showed an increase in relation to prolongation of ortho-alkoxy substitution in the sequence: propoxy less than pentyloxy less than heptyloxy less than nonyloxy. Submaximal value by the heptacaine may reflect an optimal hydrophylic-lipophylic balance of its molecule. But in the evaluation on antiouabain effect and partition coefficient, there is no simple direct correlation in structure-activity relationship.

Topics: Animals; Anti-Arrhythmia Agents; Digoxin; Epinephrine; Female; Guinea Pigs; Male; Medigoxin; Ouabain; Piperidines; Rats; Structure-Activity Relationship

Topics: Electrochemistry; Humans; Piperidines; Polarography

Topics: Anesthetics, Local; Animals; Carbamates; Cornea; In Vitro Techniques; Piperidines; Proline; Rabbits; Thymidine; Trimecaine

The effects of pentacaine and heptacaine were compared with that of procaine on the isolated tracheal smooth muscle of guinea-pigs and anococcygeal muscle of rats. Pentacaine increased the initial tone of the tracheal smooth muscle. In higher concentration however pentacaine and heptacaine induced smooth muscle relaxation. Pentacaine diminished the action of histamine on the tracheal smooth muscle and both pentacaine and heptacaine depressed the effects of noradrenaline and acetylcholine on anococcygeal muscle.

Topics: Anal Canal; Anesthetics, Local; Animals; Carbamates; Female; Guinea Pigs; Histamine; Male; Muscle Contraction; Muscle, Smooth; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Trachea

Topics: Anesthetics, Local; Animals; Carbamates; Piperidines; Protein Binding; Trimecaine; Wool

The velocity of the release of heptacaine from selected ointment bases of the Csl. L. III has been studied in vitro with the aid of a dialysis technique. At three constant times the release rate could be brought in relation to the type of ointment base. Furthermore, the particle size of the suspended drug was estimated. It was found that the velocity of the release of heptacaine is influenced by its solubility in the outer phase of the ointment base.

Topics: Anesthetics, Local; Biological Availability; Diffusion; Ointment Bases; Piperidines

Topics: Anesthetics, Local; Azo Compounds; Chemical Phenomena; Chemistry; Hydrogen-Ion Concentration; Methods; Photometry; Piperidines

Topics: Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Blood Pressure; Heart Rate; Lethal Dose 50; Mice; Motor Activity; Muscle Contraction; Mutagens; Piperidines; Rats; Sleep

Topics: Anesthetics, Local; Chemical Phenomena; Chemistry; Piperidines; Quaternary Ammonium Compounds

Topics: Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Female; Guinea Pigs; Humans; Lidocaine; Male; Ouabain; Piperidines