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Local anesthetics inhibit the exhange transport of glucose in human erythroytes. All compounds tested showed a competitive inhibition except lidocaine and baycaine causing a non-competitive one. Moreover the transport system can bind two inhibitor molecules to one transport site as described for tetracaine and oxybuprocaine.
Slow negative potentials, evoked by stimulation of the lumbar dorsal roots, have been demonstrated in the dorsal horn of an isolated, hemisected spinal cord preparation from golden hamsters. Paired stimuli revealed a period of partial suppression of this slow potential persisting for up to 2 s following the conditioning stimulus, but with high stimulation frequencies this effect was masked and above 20 Hz a tetanic train of stimuli produced a smoothly rising potential. The response evoked by tetanic stimulation was shown to consist of two components, a manganese-sensitive, synaptically generated component, and a manganese-resistant, frequency-dependent element. Treatment with 10(-4) M 4-aminopyridine blocked the manganese-resistant tetanic response but did not reduce the manganese-sensitive component. Bicuculline, picrotoxin and tubocurare had little effect upon the tetanic response, but 10(-3) M procaine blocked it completely. The possibility that the manganese-resistant response was due to the release of potassium ions is considered.
Effects of some metabolic inhibitors, as well as of biologically active compounds (diakarb, ethidium bromide and a phenanthridine alkaloid sanguinarine) on the formed novocaine and neutral red segregation zones were studied. The volume of granules diminished under the influence of a glycolytic inhibitor iodoacetate, uncouplers of oxidative phosphorylation (2,4-dinitrophenol and carbonyl cyanide trifluoromethoxyphenylhydrozone), and respiratory inhibitors (antimycin A and rotenone), as well as under the influence of cycloheximide - an inhibitor of protein synthesis. Diakarb, ethidium bromide or sanguinarine also provoked a regression of the segregation zones. It has been found that all these compounds are inhibitors of ATPase activity of the isolated segregation zones. A possible mechanism of volume decreasing in segregation zones under the influence of both the metabolic inhibitors and diakarb, ethidium bromide and sanguinarine is discussed.
The antiarrhythmic drug tocainide (5a) and some related chiral alpha-amino and alpha-imino anilides (5b-e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (-)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the alpha-iminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (-)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action.
The ionic mechanism of action of a spin-labeled local anesthetic (SLA), 2-[N-methyl-N-(2,2,6,6-tetramethylpiperidonooxyl)]-ethyl 4-ethoxylbenzoate, was studied by means of voltage clamp technique with squid giant axons in comparison with the parent compound without spin label moiety, 2-(N,N-dimethyl)ethyl 4-ethoxylbenzoate (GS-01). Like other local anesthetics, they suppressed both sodium and potassium conductance increases. However, three remarkable differences have been noted between SLA and GS-01: (1) SLA is more effective than GS-01 in suppressing the sodium and potassium conductance increases; (2) SLA induces a potassium inactivation, whereas GS-01 is lacking this ability; (3) SLA has no effect on the time to peak sodium current, whereas GS-01 prolongs it. GS-01 resembles procaine with respect to (2) and (3) above. SLA will become a useful probe for the study of the molecular mechanism of local anesthetic aciton and of ionic channel function.
The membrane response to mechanical stimulation was investigated under voltage-clamp conditions in the hypotrich ciliate Stylonychia mytilus (Protozoa). The mechanoreceptor current shows high ionic selectivity, unlike than in metazoans. It is exclusively carried by potassium ions and is selectively inhibited by tetraethylammonium and 4-aminopyridine. Procaine, tetramethylammonium, caesium and divalent cations have no or little effect on this receptor current. The ionic channels mediating the currents differ from voltage-dependent channels in the ciliate membrane in their low sensitivity to divalent cations, and their relatively high sensitivity to tetraethylammonium and 4-aminopyridine.
An approach is presented which allows the description of drug binding to lipid bilayers, when the drug is present in both charged and uncharged forms. Binding is described by Langmuir adsorption isotherms, with the maximum number of binding sites being 1/60 A2. An estimate of the change in drug pK on binding is necessary, and is close to zero for most drugs binding to dipalmitoyl phosphatidylcholine, although delta pK = 1.0 for procaine. From the binding curves it is possible to calculate the drug-induced decreases in lipid phase transition temperature, assuming ideal behaviour. Good fits between experiment and theory are possible, giving values for the dissociation constant describing drug binding to the membrane.
A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induce a low intensity hyperactivity but the introduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 3.4-25 mug dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradreline, d-amphetamine and alpha-methyldopamine, were all shown to induce marked hyperactivity at doses of 1.6-25 mug. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyl-dopamine, isoprenaline) (0.2-25 mug). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25-25 mug) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 mug propranolol or 50 mug piperoxan.
The preceding study of the effect of the branching of the connecting chain by the metoxymethyl-, ethoxymethyl- and propoxymethyl group on the alpha carbon on local anaesthetic activity was a stimulus for the preparation of 16 drugs of the group of 1-ethoxyethoxymethyl-2-(1-pyrrolidinyl-), 2-piperidino- and 2-(1-perhydroazepinyl) ethyl esters of o-, m- and p-alkoxyphenylcarbamic acids. The discontinuation of the substituent on the alpha carbon of the connecting chain by another oxygen atom (introduction of an ethoxyethoxymethyl group) has a positive effect on surface and infiltration anaesthesia. Of the prepared agents, 2-piperidino- and 2-(1-perhydroazepinyl-) derivatives with a hexyl or heptyloxy group in the o-position of the benzene ring were most effective; they exceeded the standards cocaine and procaine more than one hundred times. p-Derivatives were least effective; in some cases their indices of effectiveness did not achieve the effectiveness of the standards in both surface and infiltration anaesthesia under study. Acute toxicity of all drugs lies within the range of the toxicities of the standards.
Methylpentynol, paraldehyde, amylobarbitone and procainamide blocked transmission through the cat superior cervical ganglion, and antagonized the ganglion-stimulating actions of acetylcholine and carbachol injected intra-arterially to the ganglion. Comparison with the effects of tetraethylammonium indicated that the impaired response to acetylcholine could not wholly account for the failure of transmission, which suggested that an impaired release of transmitter substance was a contributory factor. Methylpentynol, paraldehyde and procainamide also blocked the ganglion-stimulating action of potassium chloride. In contrast, amylobarbitone and pentobarbitone did not block the stimulating action of potassium chloride, but antagonized specifically the actions of acetylcholine and carbachol. The anti-acetylcholine activities of the two barbiturate drugs at this site accord with their relative ganglion-blocking activities. It is concluded that the ganglion-blocking action of methylpentynol, paraldehyde and procainamide arises from a nonspecific depression of both presynaptic and postsynaptic elements in the ganglion, but that barbiturate compounds act more specifically on the acetylcholine receptor.
The rate of hydrolysis of chloroprocaine by human serum was studied in the presence and absence of a number of aminde local anesthetics and their metabolites. Bupivacaine (2.4 microgram/ml) and etidocaine (2.3 microgram/ml) caused 38% and 21% inhibition respectively of the rate of chloroprocaine hydrolysis. Circulating concentrations of these drugs have been reported in this range by several investigators following epidural doses of 150 to 400 mg of either drug. Mepivacaine, lidocaine, and two lidocaine metabolites (glycine xylidide and monoethylglycine xylidide) were only inhibitory at levels much greater than those seen in blood following the usual local anesthetic doses of the parent compounds. Since serum is an important site of chloroprocaine metabolism in man, the probability of chloroprocaine intoxication may be increased when it is administered with local anesthetics such as bupivacaine and etidocaine.
Many of the neurochemical changes associated with aging brain, particularly lower choline acetyltransferase and higher monoamine oxidase, occur with greater severity in senile dementia, Alzheimer's type (SDAT). These alterations correlate with neuropathologic indices, e.g., the number of senile plaques and tangles. Although many different treatment techniques have been used, most have been unsuccessful. No strong data have supported the use of stimulants, Gerovital H3, or hyperbaric oxygen. Among the vasodilators, cyclandelate and hydergine may be of value in some but not most patients. Much recent work has focused on techniques to increase acetylcholine brain concentrations. To date, precursors, such as choline, seem to have very limited value. Postsynaptic treatments, e.g., physostigmine, hold more hope for future benefit, if longer acting oral preparations are developed. Other compounds, such as ACTH, vasopressin, and piracetam, may have some value but need better definition and treatment indications. Recent discoveries on the influences of lecithin on membrane fluidity and receptor binding, may affect the focus of future pharmacologic investigation.
The influence of 12 cationic amphiphilic compounds on the equilibrium and kinetic characteristics of the binding of tritium-labelled ouabain to the lipoprotein Na+/K+-ATPase present in a crude membrane suspension of guinea pig myocardium was investigated. The drugs, e.g. local anaesthetic, antiarrhythmic and psychotropic agents, inhibited specific binding of ouabain in a concentration-dependent manner by reducing its affinity without affecting the number of binding sites. In the presence of chlorpromazine, propranolol and dibucaine, the decreased affinity of ouabain was due to both a diminished association rate and an increased dissociation rate, while in the presence of the weakly potent procaine only the association rate of ouabain was found to be reduced. The different potency of the catamphiphilic drugs was well correlated to the degree of their hydrophobicity. Evidence is presented that the protonized form of the drugs is the effective one. Concerning the mode of action, the catamphiphilic drugs are proposed to interact with the phospholipid part of the lipoprotein Na+/K+-ATPase, thereby indirectly altering the conformation of the embedded protein moiety and thus reducing the proper fit between ouabain and its receptor.
The preparation of stable composed eye drops with epinephrine, zinc sulfate and procaine was studied. It was proved that the preparation using Adrenalnum solutum Spofa does not guarantee sufficient stability. It follows from the results that the stability of eye drops can be prolonged from 2 or 3 d to 1 month by the addition of 0.05% L-cysteine, N-acetylcysteine and sodium metabisulfite respectively.
Ten beta-adrenoceptor blocking drugs varying in lipophilicity and beta-adrenoceptor blocking potency were examined for inhibitory effects on synaptosomal [3H]noradrenaline uptake. All compounds produced a concentration-dependent inhibition of noradrenaline uptake, but were at least one order of magnitude less potent than desmethylimipramine and cocaine. The order of potency was pronethalol greater than propranolol greater than betaxolol greater than alprenolol greater than oxprenolol greater than practolol greater than metoprolol greater than acebutolol greater than sotalol greater than atenolol, with IC50 values ranging from 4.0 X 10(-6) to 2.2 X 10(-3) M. Uptake inhibition was unrelated to beta-adrenoceptor blocking potency, but was highly correlated with drug lipophilicity. (+)-Propranolol was an effective uptake inhibitor, as was the local anaesthetic procaine. Kinetic analysis of uptake inhibition by propranolol, oxprenolol, metoprolol and procaine revealed a mixed inhibition for all four agents examined. It is suggested that this effect of beta-adrenoceptor blockers may be mediated, at least in part, by an action on membrane phospholipids associated with the noradrenaline carrier protein, and that noradrenaline uptake inhibition may underlie certain central side-effects observed with some drugs in this group.
During the systematic analysis of the relationship between chemical structure and local anaesthetic activity of basic esters of alkoxyphenylcarbamic acids, the diethylamino-isopropylester of 2-heptyloxyphenylcarbamic acid (carbisocaine) was synthesised and later extensively studied. This drug has been shown to be as active as procaine in skin anaesthesia in molar concentrations 416 times lower, and in corneal anaesthesia the drug parallels the standard agent cocaine in molar concentrations 251 times lower. The high relative local anaesthetic potency of carbisocaine and its low subcutaneous toxicity prompted wider pharmacological investigations in which the effects of carbisocaine on the central nervous system and the circulation were studied. The experiments showed that carbisocaine produced the typical effects of a local anaesthetic drug, i.e., stimulation of central nervous system, hypotension and a drop in the heart rate. The range of toxic doses and the cytotoxic activity of this interesting compound were also established.
The interaction between phospholipids and stabilizing lysosome agents such as acetylsalicylic acid (ASA), colchicine (CC), prednisolone (PD), etc., was studied using NMR spectroscopy. The peak intensity of protons arising from these compounds was reduced in liposomes containing lecithin and various agents with a molar ratio of 1:1 in D2O. The reduced percentage of protons in the agents differed due to their molecular structures: ASA was about 20%, CC about 30%, and PD about 100%.
Soman (pinacolyl methylphosphonofluoridate), a highly toxic organophosphate compound, has been found to be a strong inhibitor of hepatic microsomal carboxylesterase in vitro, but an enhancer of carboxylesterase when administered in vivo. In response to this paradoxical observation, the objective of this study was to determine if soman could cause true enhancement of the metabolism of drugs in the guinea pig and, if so, to characterize the enhanced enzyme activity. Following the pretreatment of guinea pigs with 90% LD50 soman, enhancement of microsomal esterase activity was noted 12 and 24 hr after pretreatment. Using Michaelis-Menten enzyme kinetic studies, enhancement was found to occur with liver carboxylesterase and procaine esterase, but not with aniline hydroxylase. Since the soman-enzyme complex was known to undergo aging with the release of pinacolyl alcohol and the subsequent formation of pinacolone, the effects of these metabolites on the activity of liver microsomal enzymes in vitro were explored. Pinacolone and pinacolyl alcohol produced enzyme enhancement in vitro in a manner similar to that produced by soman pretreatment. These effects were compared with those made by acetone in the same incubations, since the enhancing influence of acetone has already been well documented. Similarity was found between the in vitro effects of acetone and the effects of pinacolone and pinacolyl alcohol. Lastly, the in vivo effects of pinacolone on the activities of the same liver microsomal enzymes were studied following pretreatment of the guinea pigs with 90% LDLo (lowest published lethal dose) pinacolone. Pretreating guinea pigs with pinacolone prior to killing them enhanced liver microsomal carboxylesterase and procaine esterase activities, but had no effect on microsomal aniline hydroxylase activity. This pattern of enzyme enhancement was similar to that observed after soman pretreatment. Therefore, soman was found to enhance hepatic microsomal esterase activity in the guinea pig in a manner similar to that seen with its metabolites, as well as acetone. This information may give insight into how the efficacy and toxicity of therapeutic drugs, other xenobiotics, and endogenous materials may be altered in individuals who survive an exposure to soman.