The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. I. An experimental study in cats.
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Acid-Base Equilibrium↗
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Effects of some S-alkylthiouroniums and related compounds on the osmotic fragility and the membrane expansion of human erythrocytes.
1 Changes in the osmotic fragility and critical haemolytic volume of human erythrocytes produced by S-n-decylthiouronium (S-10) and related compounds have been studied. 2 S-10 had a biphasic action on osmotic fragility, protecting erythrocytes against lysis in low concentrations but producing lysis in a concentration of 1 mM or higher. 3 Some lower homologues of S-10 also protected erythrocytes against osmotic lysis, the degree of protection depending on the length of the alkyl chain. 4 Critical haemolytic volume was increased by antihaemolytic concentrations of procaine and chlorpromazine but not by antihaemolytic concentrations of S-10 and related amidines. 5 It is concluded that S-10 and its near homologues penetrate and stabilize erythrocyte membranes, potency increasing with the number of methylene groups in the side-chain up to about ten. The stabilization produced by S-10 apparently differs from that produced by many other lipid-soluble depressant drugs. It may be related to a drug-induced change in the ionic permeability of the membrane.
Chlorpromazine↗
The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. II.
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Acid-Base Equilibrium↗
[An experimental study on compound anisodine III for softening scar of mouse skin after burn].
OBJECTIVE: The aim of this study was to investigate the mechanism of compound anisodine (CA) III which can rapidly soften the cicatrized tissue in clinical practice. METHODS: 2 mol/L NaOH was applied onto the back of 36 mice for one minute to induce deep grade skin burn injury. After 1 week local cicatrization occurred. The mice were randomly divided into 3 groups: 1 ml saline was used in group I as control, hyaluronidase 150 U dissolved in 1 ml 2% procaine was used in group II and 0.005% CA 0.1 ml in 2% procaine 1 ml with hyaluronidase 150 U was used in group III. Subcutaneous injection once every other day for two weeks was the method of drug administration in all the 3 groups and then all the rats were euthanized. The burned skin was sectioned for HE and modified Masson's stains. RESULTS: Histopathology revealed there were epidermis proliferation, keratinization and fibrosis with disorderly arranged collagenous fibers invading into muscles and a large amount of inflammatory cells infiltrating the lesion in groups I and II. However, the skin was nearly normal in group III. CONCLUSIONS: CA III can inhibit the epidermic and collagenous proliferation, improve the tissue blood supply and have antiinflammatory effect to prevent scar formation and promote epidermic repair in the skin.
Animals↗
Temperature dependence of [3H]dihydroalprenolol binding in rat myocardium.
The beta-adrenergic antagonist, [3H]dihydroalprenolol, was used to label binding sites in crude rat myocardial plasma membranes. The specificity of binding was dependent on the temperature of the assay. Specific binding at 22 and 37 degree C and at concentrations of radioligand less than 5 nM was consistent with binding to the myocardial beta-receptor. Binding sites labeled at 4 degree C possessed quite different properties. Binding was non-stereoselective and of lower affinity. Agonist compounds were much less effective at competing for the labeled myocardial sites at 4 degree C than at 22 degree C. Those beta-antagonists which additionally possess pharmacological "quinidine-like' activity (e.g. propranolol, alprenolol) were potent competitors at 4 degree C, but competition was non-stereoselective. In contrast atenolol, a beta-antagonist devoid of "quinidine-like' activity was ineffective at 4 degree C. Furthermore, procaine, and quinidine itself were potent competitors of [3H]dihydroalprenolol binding at 4 degree C. Thus the specificity of [3H]dihydroalprenolol binding to rat heart membranes at 4 degree C appears to be directed non-stereoselectively at that portion of the competing molecule which recognized "quinidine-like' as opposed to adrenergic activity.
Alprenolol↗
Rapid substitution procedure for intravenous drug self-administration studies in rhesus monkeys.
Rhesus monkeys were trained to press a lever one hundred times (FR 100) to obtain either a food pellet or an intravenous drug injection. Two daily experimental sessions, one in the morning and one in the afternoon, were divided into three 15 minute periods each. In Periods 1 and 3 lever pressing behavior was maintained by the delivery of food. Period 2 lever pressing was maintained by the intravenous injection of a drug solution. The drug available each day followed a four day sequence of cocaine (30 microgram/kg/injection), saline (1.0 ml/injection), cocaine, and test compound. This four day sequence was repeated to test a series of 16 psychoactive compounds at two doses each. These drugs were compared to saline for their ability to maintain Period 2 responding during the afternoon session. Morphine, oxymorphone, codeine, pentazocine, d-amphetamine and methylphenidate all maintained responding at rates significantly greater than for saline. Cyclazocine, naloxone, levallorphan, scopolamine, chlorpromazine, fenfluramine, and (+/-)-9-nor-9-alpha-hydroxy-hexahydrocannabinol (alpha-HHC) did not maintain responding during Period 2. The results with procaine, beta-HHC and nalorphine were considered equivocal. The authors suggest the use of a rapid substitution procedure as a method of initial screening of drugs with potential reinforcement efficacy.
Animals↗
Local anaesthetics as hypoxic radiosensitizers, oxic radioprotectors and potentiators of hyperthermic killing in mammalian cells.
Local anaesthetics with well-known pharmacology are found to radiosensitize hypoxic and radioprotect oxic murine L5178Y cells. Under the specified experimental conditions, radiation-modifying effects exerted by local anaesthetics are dose-dependent. It appears that in order that the drugs should act as oxic radioprotectors or as hypoxic radio-sensitizers, the agent must be present during the period of irradiation. Local anaesthetics are also found to potentiate the hyperthermic killing of cells. The possibility of applying compounds with such dual radiation-modifying properties plus hyperthermia-potentiating capacity to enhance the therapeutic gains in tumour therapy is briefly discussed.
Anesthetics, Local↗
Spinal anesthesia in sheep with local anesthetic solutions at pH 4 and pH 7.
Spinal anesthesia was performed in sheep, using five widely-used local anesthetic agents. The durations of sensory and motor block were shortest with procaine and longest with bupivacaine and tetracaine. The durations of block with prilocaine and mepivacaine fell between those of procaine and bupivacaine. These results agree with what we know about the relative durations of action of these agents in man. All solutions were tested at pH 4 and pH 7, but, except for prilocaine, there were no differences in the mean durations of sensory and motor block at the two pH levels. Sensory block with prilocaine solution at pH 7 was about 20% longer than at pH 4. With all the compounds except prilocaine, the frequency of motor block in the hind limbs was lower at pH 7 than at pH 4. We conclude that single injections of unbuffered solutions of these agents at pH 4 are as effective in terms of onset and duration as solutions at pH 7. The results of this study reconfirm the usefulness and reliability of the sheep as a model for evaluating and comparing spinal anesthetics.
Anesthesia, Spinal↗
Ozonation of Procaine Penicillin G formulation effluent Part I: Process optimization and kinetics.
Ozonation characteristics of synthetic Procaine Penicillin G (PPG) formulation effluent were investigated in a semi-batch ozone reactor at different pH (3, 7 and 12), ozone feed rates (600-2600 mg h-1) and COD values (200-600 mg l-1). Ozonation of aqueous PPG effluent resulted in 37 (82)% COD removal after 60 (120) min ozonation when the reaction pH was kept constant at pH=7.900 mg l-1 (corresponding to 50% of the total introduced) ozone was absorbed during a reaction period of 1 h. The effects of increasing the applied ozone dose and the initial COD on the COD abatement rates of PPG effluent were also studied. Results have indicated that increasing the ozone dose and decreasing the COD content both have positive effects on COD removal rates. The significant contribution of the free radical (.OH) reaction pathway to PPG ozonation could be traced using tert-butyl alcohol as the .OH probe compound at varying concentrations. The bimolecular reaction rate constants for the direct reaction of PPG with ozone were found as 152 and 2404 M-1 h-1 at pH=3 and 7, respectively, using the gas phase ozone partial pressures determined from of the outlet gas stream analysis. It could be demonstrated that ozone decomposition to free radicals being triggered by increasing the pH from 3 to 7 is essential for the rate enhancement of PPG effluent ozonation.
Free Radical Scavengers↗
Mandibular actinomycosis: report of case.
A case of mandibular actinomycosis, secondary to a compound fracture in an alcoholic patient, is described. The factors that apparently enhance the development of this disease are discussed.
Actinomyces↗
The relaxant action of nicorandil in guinea-pig isolated trachealis.
Nicorandil (1-1000 mumol l-1) caused concentration-dependent relaxation of guinea-pig isolated trachealis. Propranolol (1 mumol l-1) did not modify the relaxant action of nicorandil but antagonized isoprenaline. Among K+-channel inhibitors tested, apamin (0.1 mumol l-1) and procaine (5 mmol l-1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol l-1) caused five fold antagonism. Trachealis exposed to K+-rich (120 mmol l-1) Krebs solution developed near-maximal tension. Nicorandil relaxed the K+-depolarized tissue though its concentration-effect curve was shifted markedly to the right. In tissues in which tone was induced by histamine, methylene blue (100 mumol l-1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. Intracellular electrophysiological recording showed that nicorandil (1 mumol l-1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10-1000 mumol l-1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. TEA (8 mmol l-1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. Procaine (5 mmol l-1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, nicorandil (1000 mumol l-1) increased the efflux rate constant, whereas isoprenaline (1 mumol l-1) was without effect. It is concluded that nicorandil-induced relaxation does not involve the activation of beta-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.
Aminophylline↗
Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger.
There is evidence that intracellular Na+ entry potentiates hypoxic-ischemic cell death by causing cytotoxic cell edema, intracellular acidosis, and gating of Ca2+ entry by reverse activation of the Na(+)-Ca2+ exchanger. In this study, we examined the role of Na+ in mediating traumatic injury to spinal cord axons. Dorsal column segments from adult rats (n = 87) were isolated and maintained in an in vitro recording chamber while being superfused with oxygenated Ringer's solution (95% O2/5% CO2, 25 degrees C). Selected experiments (n = 10) also were done at 33 degrees C. Compound action potentials (CAP) were recorded from microelectrodes. Injury was performed by compression of the dorsal column segment for 15 sec with a modified aneurysm clip exerting a closing force of 2 gm. With injury, the CAP decreased to 72.1 +/- 9.6% of baseline values. Removal of extracellular Na+ and replacement with the impermeant cation N-methyl-D-glucamine enhanced recovery of the CAP to 98.3 +/- 18.3% (p < 0.05) of baseline. The Na+ channel blockers tetrodotoxin and procaine also improved recovery of the CAP to 96.3 +/- 23.7% (p < 0.05) and 82.8 +/- 4.6% (p < 0.05) of baseline values, respectively. In contrast, increasing Na+ permeability with veratridine resulted in greater attenuation of CAP amplitude after 1 hr of trauma (60.1 +/- 8.4%, p < 0.05). Similarly, prevention of extrusion of Na+ from the intracellular compartment by inhibiting the Na(+)-K(+)-ATPase pump with ouabain resulted in greater attenuation of CAP amplitude at 1 hr after trauma (56.7 +/- 3.6%, p < 0.05). The Na(+)-H+ exchange blockers amiloride (100 microM) and harmaline (100 microM) significantly improved recovery after injury to 89.6 +/- 17.0% (p < 0.05) and 85.7 +/- 7.2% (p < 0.05) of baseline, respectively. However, administration of the Na(+)-Ca2+ exchange blockers benzamil (100 or 500 microM) and bepridil (50 microM) was ineffective. In summary, reduction of extracellular Na+ confers neuroprotection after spinal cord injury in vitro. Intracellular sodium rises appear to be mediated by voltage-gated Na+ channels. Blockade of the Na(+)-H+ exchanger also is neuroprotective, possibly by reducing intracellular acidosis. Furthermore, prevention of extrusion of intracellular Na+ by the Na(+)-K(+)-ATPase pump exacerbates the effects of compression trauma. However, reverse operation of the Na(+)-Ca2+ exchanger does not explain the injurious effects of Na+ in traumatically injured CNS white matter.
Animals↗
A comparative study of the effects induced by MCN-A-343 and acetylcholine on the isolated toad rectus abdominis.
McN-A-343 (McN), a non nicotinic ganglionic stimulant, induced slow contractile responses of the toad rectus abdominis. A relaxation was also observed when large doses were added in the presence of a contraction caused by acetylcholine (Ach). The relaxation induced by McN could not be overcome by increasing Ach concentration. Bell-shaped log dose-response curves were obtained for McN. d-Tubocurarine caused an unusual change on these curves, suggesting an indirect action of the agonist. This possibility was corroborated by the fact that hemicholinium, procaine, and cold storage of the muscle caused a marked decrease of the organ sensitivity to McN but not to ACh.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
Lectin-mediated agglutination of amphibian embryonic cells.
Dissociated blastula cells of Xenopus laevis are agglutinated with wheat germ agglutinin (WGA), Ricinus communis agglutinin (RCA), concanavalin A (Con A) and, to a lesser extent with soya bean agglutinin (SBA). They are not agglutinated with fucose-binding protein. Neuraminidase treatment of cells enhances their agglutinability with RCA and SBA, but has no effect on Con A- and WGA-mediated agglutinability. Treatment of cells with procaine, or xylocaine, has no effect on the cells' agglutinability or on the extrusion of lobopodia. Treatment with colchicine or cytochalasin B either separately or simultaneously has no effect on lectin-mediated agglutinability. Cells treated with cytochalasin B or colchicine and cytochalasin B simultaneously lack lobopodial extensions, while colchicine alone has no effect on these structures. Phenothiazine tranquillizers inhibit agglutination mediated by all of the above mentioned lectins. Lobopodial extensions are absent in cells treated with these compounds. Glutaraldehyde fixation inhibits RCA and WGA mediated agglutinability and reduces the Con A-mediated agglutinability. Results suggest that in this system microtubules and microfilaments are not involved in lectin-mediated agglutination.
Animals↗
Electrical responses to mechanical stimulation of the membrane of squid giant axons.
The mechano-electrical transduction in the squid axon was studied. A certain volume of solution was intracellularly injected, subsequently redrawn, by a microsyringe, and the resultant expansion and shrinkage of the cell was employed as the mechanical stimulus. Upon stimulation, two types of responses appeared: a depolarizing response and a hyperpolarizing response. The former appeared on large stimulation, but the shape and magnitude were variable even with the same stimulation, and the recovery was very slow. The latter appeared constantly on small stimulation. This hyperpolarizing response was associated with an increase in membrane conductance. Application of inward current through the membrane reversed the sign of the response. The reversal potential was 5-15 mV more negative than the resting potential. It was greatly affected by extracellular K+ concentration. Tetraethylammonium, applied intracellularly, reduced the amplitude of the hyperpolarizing response. However, 4-aminopyridine, tetrodotoxin, and procaine did not affect the response at all. The response became larger when the temperature was reduced. It is possible that the mechanically-induced hyperpolarizing response arises from an increase of potassium and leakage conductance.
Animals↗
Action of local anesthetics on basal tone of rat vas deferens and on response to norepinephrine and calcium.
The actions of three local anesthetics (cocaine, procaine and tetracaine) on basal tone of isolated vas deferens from control and reserpinized rats were studied. The influence of these anesthetics on responses to norepinephrine and calcium was also examined. Cocaine, procaine and tetracaine, in the order, induced phasic and tonic contractions, the latter ones probably due to catecholamine release. The local anesthetics, at the lowest doses, produced an elevation of the maximum response to norepinephrine, as well as a leftward shift of the dose-response curve. The highest doses of local anesthetics inhibited the response to norepinephrine in a non-competitive way, while the response to calcium was competitively inhibited. In this connection, tetracaine proved to be the most active compound. The distinction between destabilizing and stabilizing effects on membrane is pointed out and discussed.
Anesthetics, Local↗
[Reactions of the pulp-dentin system to drugs].
The healthy or previously damaged pulp responds to most of the drugs currently applied to the dentin with an inflammatory reaction. By means of a standardized biological screening test, the modes of action of hydrogen peroxide and of Falikain preparations are demonstrated on the pulp of the rat incisor. Hydrogen peroxide produces an emphysema of the pulp tissue associated with a slowing of the circulation and partly irreversible capillary stases, whereas Falicain compound preparations (Falicid, Myrex) cause, by way of haemolysis, injuries involving entire areas of the pulp. For this reason, hydrogen peroxide should not be used for cleaning cavities. Myrex is well suited for symptomatic treatment to relieve pain, if removal of the inflamed pulp ensues.
Dental Pulp↗
Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines.
DNA methyltransferase inhibitors represent promising new drugs for cancer therapies. The first of these compounds (5-azacytidine, Vidaza) has recently been approved as an antitumor agent, and others are presently in various stages of their preclinical or clinical development. Most of the archetypal inhibitors have been established and characterized in different experimental systems, which has thus far precluded their direct comparison. We have now established defined experimental conditions that allowed a comparative analysis of the six most widely known DNA methyltransferase inhibitors: 5-azacytidine (5-aza-CR), 5-aza-2'-deoxycytidine (5-aza-CdR), zebularine, procaine, (-)-epigallocatechin-3-gallate (EGCG), and RG108. Of these, 5-aza-CR, 5-aza-CdR, zebularine, and EGCG were found to exhibit significant cytotoxicity in human cancer cell lines. 5-aza-CdR and EGCG were also found to be genotoxic, as evidenced by the induction of micronuclei. In addition, 5-aza-CR, 5-aza-CdR, zebularine, and RG108 caused concentration-dependent demethylation of genomic DNA, whereas procaine and EGCG failed to induce significant effects. Finally, the experiments in cancer cell lines were complemented by a cell-free in vitro assay with purified recombinant DNA methyltransferase, which indicated that RG108 is the only drug capable of direct enzyme inhibition. These results show a substantial diversity in the molecular activities of DNA methyltransferase inhibitors and provide valuable insights into the developmental potential of individual drugs.
Azacitidine↗