RESUMEN
Oxidation of derivatives and precursors of pantothenic acid was studied in alcohol dehydrogenase reactions. Despite the presence of free hydroxymethyl groups in a number of pantothenic acid derivatives only panthenol with Km = 8 x 10(-3) M was shown to serve as a substrate for alcohol dehydrogenase from horse liver tissue (EC 1.1.1.1) Pantethine, sodium phosphopantothenate, CoA and acetyl-CoA decreased the rate of ethanol oxidation, where pantethine and sodium phosphopantothenate were competitive inhibitors, while CoA and acetyl-CoA inhibited the enzyme noncompetitively Ki = 1.2 x 10(-2) M, 2.1 x 10(-2) M, 4.4 x 10(-4) M and 5.1 x 10(-4) M, respectively. Metabolic precursors, which were different from pantothenic acid in their structure, were not involved in the alcohol dehydrogenase reaction. Possible regulation of alcohol intoxication using derivatives and precursors of vitamin B3 is discussed.
Asunto(s)
Alcohol Deshidrogenasa/metabolismo , Ácido Pantoténico/metabolismo , Acetilcoenzima A/fisiología , Alcohol Deshidrogenasa/antagonistas & inhibidores , Animales , Coenzima A/fisiología , Caballos , Hígado/enzimología , Oxidación-Reducción , Ácido Pantoténico/análogos & derivados , Especificidad por SustratoRESUMEN
Pycamilon was shown to be rapidly absorbed in the blood (tmax = 0.23 h), to penetrate well through the blood-brain barrier and to be intensively uptaken by the animal organs and tissues and to be eliminated mainly in the urine (t1/2 = 0.51 h). The drug bioavailability at oral administration to mice is 21.9%, and to rats from 53 to 78.9% (according to the urinary excretion data).
Asunto(s)
Analgésicos/farmacocinética , Ácido gamma-Aminobutírico/análogos & derivados , Analgésicos/administración & dosificación , Analgésicos/análisis , Animales , Disponibilidad Biológica , Radioisótopos de Carbono , Relación Dosis-Respuesta a Droga , Ratones , Ratas , Factores de Tiempo , Distribución Tisular , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
Calcium pantothenate (CaP), calcium 4'-phosphopantothenate (CaPP), pantethine, panthenol, sulfopantetheine and CoA decrease acute toxicity of acetaldehyde in mice. All studied compounds diminish duration of the narcotic action of ethanol--ET (3.5 g/kg intraperitoneally) in mice and rats. In the latter this effect is realized at the expense of "long sleeping" and "middle sleeping" animals. CaP (150 mg/kg subcutaneously) and CaPP (100 mg/kg subcutaneously) prevent hypothermia and a decrease of oxygen consumption in rats induced by ET administration. Combined administration of ET, CaP and CaPP leads to a characteristic increase of acid-soluble CoA fractions in the rat liver and a relative decrease of acetyl CoA synthetase and N-acetyltransferase reactions. The antitoxic effect of preparations of pantothenic acid is not mediated by CoA-dependent reactions of detoxication, but most probably is due to intensification of ET oxidation and perhaps to its elimination from the organism.
Asunto(s)
Acetilcoenzima A/biosíntesis , Intoxicación Alcohólica/tratamiento farmacológico , Ácido Pantoténico/análogos & derivados , Acetaldehído/envenenamiento , Acetato CoA Ligasa/metabolismo , Acetilación , Intoxicación Alcohólica/enzimología , Animales , Arilamina N-Acetiltransferasa/metabolismo , Evaluación Preclínica de Medicamentos , Inducción Enzimática/efectos de los fármacos , Femenino , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Ácido Pantoténico/uso terapéutico , RatasRESUMEN
Calcium salts of pantothenate (CPN), 4'-phosphopantothenate (CPP), S-sulfopantetheine (CSP), as well as pantetheine and panthenol were administered to mice by various routes and the influence of the administration route on acute toxicity of streptomycin (500 mg/kg, subcutaneously) was studied. It was shown that with subcutaneous, intramuscular, intraperitoneal and intravenous administration of CPN, CPP and CSP the acute toxicity of streptomycin was lower. The value of ED50 and the ranges of the antitoxic action (LD50/ED50) were indicative of high efficacy of CPP on its intravenous administration. In rats all the tested compounds normalized the liver excreting function (bromsulphalein test) impaired by exposure to streptomycin in subtoxic doses (200 mg/kg). The lowest levels of acetylation of the sulfacyl sodium test dose were observed in the animals treated with streptomycin in combination with CPN, CPP or CSP which could be explained by increased excretion and acetylation (detoxication) of the antibiotic.
Asunto(s)
Ácido Pantoténico/análogos & derivados , Estreptomicina/envenenamiento , Acetilación , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Hígado/metabolismo , Pruebas de Función Hepática , Ratones , Ácido Pantoténico/administración & dosificación , Ácido Pantoténico/uso terapéutico , Ratas , Estreptomicina/toxicidadRESUMEN
The effect of calcium pantothenate (CPN)B 4'-phospho-CPN (PCP), pantetheine (PT) and calcium S-sulfopantetheine (SPN) on acute toxicity of kanamycin sulfate was studied on albino mice. The above derivatives of pantothenic acid except PT lowered the antibiotic toxicity. The coefficient of the antitoxic effect (LD50/ED50) of SPN and PCP was 1.3-1.4 times higher than that of CPN. The combined use of kanamycin (1/5 of the LD50) with CPN, PCP or PT (30 mg/kg bw was equivalent to CPN) for 15 days prevented the increase in the total content of CoA and in the content of the fraction of free CoA and the precursors of its biosynthesis participating in the reaction of N-acetylation in the liver and brain. The contents of these substances were within the normal during the whole experiment. A certain increase in the activity of pantothenate kinase in the liver cytosol due to the use of kanamycin was eliminated by the simultaneous use of PCP and PT. The vitamin-containing compounds PCP and SPN were recommended for the clinical trials as agents preventing complications of kanamycin therapy.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Coenzima A/biosíntesis , Kanamicina/antagonistas & inhibidores , Hígado/enzimología , Ácido Pantoténico/análogos & derivados , Animales , Antídotos , Encéfalo/enzimología , Evaluación Preclínica de Medicamentos , Femenino , Kanamicina/envenenamiento , Masculino , RatonesRESUMEN
The effect of calcium 4'-phosphopantothenate (CPP) on acute toxicity of streptomycin and the decrease by the antibiotic of the muscle working capacity, "holes" reflex, body temperature and oxygen intake was studied on 258 albino mice weighing 22-26 g. Medical calcium pantothenate (CPA) was used for control purposes. CPP is an antagonist of streptomycin sulfate. In a dose of 1/10 or 1/5 of the LD50 injected intraperitoneally CPP lowered acute toxicity of streptomycin and prevented its effect in a dose of 0.11--1.1 g/kg injected subcutaneously on the muscle working capacity, "holes" reflex and body temperature. The spectrum index of the CPP antitoxic effect was equal to 22.5. By its acute toxicity CPP (LD50 1.18 +/- 0.07 g/kg) did not differ from CPA (LD50 1.25 +/- 0.08 g/kg). The efficacy of CPP, by its antitoxic spectrum, was 1.8 times higher than that of CPA. CPA lowered the streptomycin effect on the "holes" reflex and body temperature, while CPP prevented it. Both the drugs did not influence the decrease in the oxygen consumption induced by streptomycin.