Biomedical subjects
Publications and source records attributed to P Svec.
A series of the new aminoalkyl esters of chlor-, methyl- and alkoxy carbanilates was synthesized. All the compounds prepared were found to exhibit antiarrhythmic activities comparable with those of mexiletine.
Within the framework of studying the influence of alterations of the connecting chain in the group of local anaesthetics a series of 24 compounds of 1-propoxymethyl-2-(1-pyrrolidinyl), 2-(1-piperidino)-, and 2-(1-perhydroazepinyl)-ethyl esters of o- and m-alkoxyphenylcarbamic acid were prepared. Studied compounds show a high index of relative local anaesthetic activity as compared to the standards cocaine and procaine, at a relatively low acute toxicity.
Our previous experiments have suggested that besides the receptor cont and/or sensitivity a decrease of intracellular calcium level significantly participates in the mechanism of beta-blocker withdrawal 'rebound' phenomenon. This suggestion initiated studies in which possible changes in myocardial responsibility to cardioactive drugs were investigated in the condition of withdrawal of treatment with calcium entry blockers. The results showed increased cardiotoxicity of ouabain, aconitine and CaCl2, as well as an increased response of the heart to isoprenaline 24 hours after sudden cessation of treatment with verapamil (2 mg.kg-1 x 12 hours-1), diltiazem (3 mg.kg-1 x 12 hours-1) and nifedipine (0.5 mg.kg-1 x 12 hours-1). These results support the hypothesis of a common mechanism of the withdrawal syndrome of beta-lytics and calcium antagonists involving changes in intra-cellular calcium level. (Tab. 2, Fig. 4, Ref. 33.).
The influence of cholesterol atherogenic diet on the acid-base balance and electrolyte profile was investigated in rabbit blood and the effect of simultaneous administration of verapamil and nifedipine on the induced changes was evaluated. Cholesterol diet resulted in significant metabolic acidosis, hyperkalemia, and a slight decrease in plasma ionized calcium. On the other hand, longterm treatment with verapamil and nifedipine exhibited their protective effect, with the acid-base status and electrolyte profile maintained within the normal range. The protective effect of verapamil and nifedipine against cholesterol induced acid-base and electrolyte disturbances appears to be associated with their antiatherogenic activity. (Fig. 5, Ref. 10.).
Changes in the ultrastructure of rat myocardial cells were investigated after withdrawal of therapy with the calcium entry blockers diltiazem, nifedipine, and verapamil. Two hours after the last administration the ultrastructure was without significant changes in comparison to the control group. However the incidence of contracture bands, dehiscence of intercalated discs and lesions of mitochondria observed 30 hours after therapy withdrawal demonstrated serious damage of myocardial tissue. The recorded changes, practically identical with changes associated with the calcium paradox, were the consequence of withdrawal of calcium entry blocker therapy. The reported morphological changes reflected biochemical and functional changes characteristic of the calcium entry blocker withdrawal syndrome.
Using screening methods, the anti-inflammatory and antipyretic activities of mononuclear otahedral complexes [composition:Cu(2,YDHB)2.H2O;dihydroxybenzoate ion - DHB; Y(n)-4(8).5(4) and 6(8)] and the corresponding carboxylic acids were studied. On paw dextran edema (rats, an effective dose of 10 mg/kg), a higher efficacy of the complexes was found as compared with the acids. All compounds significantly reduced the endotoxin pyretic reaction (rabbits, in a single dose of 20 mg/kg; in the case of the first two complexes half-dose was administered). Marked toxic effects were determined for Cu(II) salts when they were administered i.p. The observed biological activities of complexes are discussed in relation to their proposed structures.
The present paper describes the effect of six-week oral administration of verapamil and diltiazem (1 mg.kg-1 of weight two times daily in 12 hour intervals) on the content of fatty acids of the serum and myocardium of PHHC rats. A cholesterol diet changes the content of fatty acids of the serum and myocardium of PHHC rats in comparison with control rats without the cholesterol diet. A significant decrease in the content of palmitic acid, a decrease in the content of stearic acid, linoleic acid and arachidonic acid and a significant increase in the content of oleic acid were observed in the serum. Long-term administration of the slow calcium channel blockers produces another decrease in the content of the bound form of arachidonic acid. Changes in the representation of other fatty acids are not marked. Long-term administration of a cholesterol diet produces an increase in the content of palmitic acid and stearic acid and a decrease in the content of oleic acid, linoleic acid and arachidonic acid in the myocardium. Administration of verapamil results in a modification of the above-mentioned changes in all parameters excepting the content of arachidonic acid, the content of which was decreased in an even more marked manner. Administration of diltiazem produced an accumulation of both saturated and mono-unsaturated fatty acids (palmitic, stearic and oleic acids) and produced a significant decrease in the content of linoleic acid and mainly the bound form of arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effect of equitoxic doses of three carbamate local anesthetics (pentacaine, carbisocaine and heptacaine), and a derivative of lidocaine (trimecaine) on the acid-base balance of blood was studied in conscious rabbits. In addition, changes in arterial blood pH induced by local anesthetics in relation to lipophilicity of the respective drugs were evaluated. All the drugs administered at the dose of half of LD50 induced a significant decrease in the arterial blood pH as well as in the plasma bicarbonate level and in the blood base excess. The observed acidosis was compensated within a 60 minute period by hyperventilation. The local anesthetic-induced decrease in the blood pH, expressed as AUC, correlated to some extent with the partition coefficient of these agents. These findings suggest that the acidifying effect of local anesthetics may be dependent on their lipophilicity.
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This report describes the cloning and sequencing of a chromosomally encoded tetracycline resistance determinant from a clinical isolate of methicillin-resistant Staphylococcus aureus. On the basis of the sequence, the gene is in the tet(M) class, and it was shown that the S. aureus tetA(M) gene is induced at the level of transcription.
The basic relationship between the chemical structure and pharmacological activities of new alkylesters of 4-[(2-hydroxy-3-alkylamino)propoxy]phenylcarbamic acids were evaluated. The efficiency of compounds was compared with those of metipranolol and practolol, respectively. The majority of 4-substituted derivatives of aryloxypropanolamines have shown antiisoprenaline (beta-adrenolytic) and local anesthetic (membrane stabilizing) activities. The values of LD50 and/or partition coefficients have not differed significantly when compared with those of standard metipranolol.
The influence of phenylcarbamic acid basic esters with local anesthetic activity on the phase transition temperature (Tc) of a model dipalmitoylphosphatidylcholine (DPPC) membrane from gel to liquid crystalline state was studied. It was found that (Tc) in the presence of carbamate anesthetics decreases. The decrease of Tc (delta Tc) correlated well with the biological activity of the compounds studied.
The Escherichia coli rpsU-dnaG-rpoD operon contains an internal transcription terminator T1 located in the intergenic region between the rpsU and dnaG genes (Smiley et al. 1982). By cloning T1 as a small 127 bp fragment into the terminator probe plasmid pDR720 between the trp operator promoter and the assayable galK gene, it was shown that T1 acts as a strong transcription terminator, comparable in strength to the 3' operon terminator T2. However, an operon sequence that occurs 5' to T1 within the coding region of the rpsU gene and which has homology with the lambda nut site, (Lupski et al. 1983) when placed 5' to T1 in the pDR720 plasmid construct, modifies transcription through T1 allowing expression of the galK gene. This sequence, called the dnaG nut site also modifies the termination activity of the external operon terminator T2. It is proposed that the dnaG nut site is a cis-acting element of an antitermination system in E. coli.
The synthesis of 24 compounds belonging to the group of dibasic substituted alkoxy phenyl carbamic acids is described. The compounds are characterized by relatively low acute toxicity and good local anaesthetic as well as antiarrhythmic activity.
The complete nucleotide sequence of 5-kb DNA fragment immediately 5' to the rpsU-dnaG-rpoD macromolecular-synthesis operon in Escherichia coli has been determined. It encodes for six open reading frames. Transcriptional and translational analysis have shown that three of them (orfx, orfz1 and orfz2) are expressed in exponentially growing E. coli cells. The orfx, directly 5' to the rpsU gene but transcribed in the opposite direction, may be part of the rpsU-dnaG-rpoD macromolecular-synthesis operon.
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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.