RESUMEN
It is shown for the first time that the mammalian enzymes can cause the degradation of the C60 fullerene molecules. This biodegradation is caused by the action of а hypochlorite generated neutrophil enzyme myeloperoxidase of fullerene molecule and leads to the loss of the topology of the fullerene core.
Asunto(s)
Fulerenos/química , Peroxidasa/química , Línea Celular Tumoral , Cromatografía de Afinidad , Humanos , Peróxido de Hidrógeno/química , Ácido Hipocloroso/química , Neutrófilos/química , Peroxidasa/aislamiento & purificación , Soluciones , Análisis Espectral , Sulfitos/químicaRESUMEN
The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.
Asunto(s)
Encéfalo/efectos de los fármacos , Fulerenos/farmacocinética , Compuestos de Hexametonio/farmacocinética , Antagonistas Nicotínicos/farmacocinética , Aminocaproatos/química , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Fulerenos/administración & dosificación , Fulerenos/química , Compuestos de Hexametonio/administración & dosificación , Compuestos de Hexametonio/química , Locomoción/efectos de los fármacos , Masculino , Ratones , Nicotina , Antagonistas Nicotínicos/administración & dosificación , Antagonistas Nicotínicos/química , Ratas Wistar , Convulsiones/tratamiento farmacológicoRESUMEN
In view of contradictory data on the toxicity of fullerenes for live organisms we studied the effect of water-soluble complexes of C60 with N-polyvivyl-pirrolidone (C60/PVP) and gamma-cyclodextrine (C60/gamma-CD) on MA-104 cells in culture. Both complexes proved to be non-toxic for cultured cells in the dark in wide range of concentrations. Both complexes provoke changes of cellular ultra-structure which reflect the enhancement of metabolic activity. At the same time only the exposition with the complex C60/PVP leads to the essential growth of number and size of mitochondria. However, the effect of two studied water-soluble forms of C60 under intensive UV-irradiation of cells proved to be opposite: C60/PVP had a cyto-protective action while C60/gamma-CD caused a significant growth of photo-toxicity. Possible reasons of the differences in the action of different forms of C60 on living organisms are discussed.
Asunto(s)
Fulerenos/toxicidad , Mitocondrias/efectos de los fármacos , Animales , Línea Celular , Fulerenos/química , Macaca mulatta , Microscopía Electrónica , Mitocondrias/efectos de la radiación , Mitocondrias/ultraestructura , Povidona/metabolismo , Povidona/toxicidad , Solubilidad , Rayos Ultravioleta , gamma-Ciclodextrinas/metabolismo , gamma-Ciclodextrinas/toxicidadRESUMEN
Biological effects of water-soluble inclusion complexes of fullerene C60 with poly(vinyl pyrrolidone) (C60/PVP) and gamma-cyclodextrin (C60/g-CD) as well as solid C60 (C60-coated surface) on cell viability have been studied in vitro. It is established that both inclusion complexes (in a broad range of concentrations) and solid fullerene coatings are nontoxic in the dark for the cell of all lines tested. In contrast, under intense UV illumination, the C60/PVP complex reliably protected test cells from the UV radiation damage, whereas the C60/g-CD and fullerene-coated surface exhibited pronounced phototoxicity. Moreover, solid fullerene caused a photodynamic effect under irradiation with both UV and visible light. The radiation damage could be blocked by some antioxidants (e.g., hypoxen) and singlet-oxygen scavenger (sodium azide). This is evidence for the participation of 1O2 in phototoxicity manifestations. The results indicate that the biological properties of fullerene C60 in vitro depend on its aggregate state, form of solubilization, and, probably, the nature of solubilizing medium.
Asunto(s)
Fulerenos/toxicidad , Luz , Povidona , gamma-Ciclodextrinas , Animales , Antioxidantes/farmacología , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Cristalización , Portadores de Fármacos , Depuradores de Radicales Libres/farmacología , Fulerenos/administración & dosificación , Fulerenos/farmacología , Haplorrinos , Humanos , Éteres Fenílicos/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/toxicidad , Azida Sódica/farmacología , Rayos UltravioletaRESUMEN
Ionic currents elicited by N-phthalamoyl-L-glutamic acid (PhGA) were investigated on freshly isolated hippocampal neurons with the whole-cell voltage clamp and concentration clamp techniques. PhGA elicited desensitizing inward currents in Mg(2+)-free salines only in the presence of glycine. The dose-response relationship for PhGA was close to a Langmuir isotherm with Kd = 3.7 mM and saturating level 0.75 of that for L-aspartate (L-Asp). PhGA-activated currents were blocked by Mg2+, D-2-amino-5-phosphonovalerate and kynurenate, and had the same reversal potential as L-Asp-activated currents. Complete cross-desensitization was obtained between the responses to PhGA and L-Asp. We conclude that PhGA is a new selective 'superacidic' agonist of the N-methyl-D-aspartate type of glutamate receptor.
Asunto(s)
Glutamatos/farmacología , N-Metilaspartato/fisiología , Animales , Ácido Aspártico/farmacología , Ácido Glutámico , Hipocampo/citología , Hipocampo/metabolismo , Magnesio/farmacología , Neuronas/metabolismo , Concentración OsmolarRESUMEN
The effects of some dipeptides, analogues of N-acetyl-alpha-L-aspartyl-L-glutamate, were studied after i.c.v. administration into mice in acute experiments. N-Acetyl-alpha-L-aspartyl-L-glutamate itself did not induce seizures in animals, but prevented glutamate-induced convulsions. All other dipeptides possessed excitatory glutamate-like actions. Some structural requirements for the excitatory effects of the dipeptides are discussed.
Asunto(s)
Dipéptidos/farmacología , Convulsiones/inducido químicamente , Animales , Anticonvulsivantes/farmacología , Convulsivantes , Dipéptidos/administración & dosificación , Dipéptidos/química , Glutamatos/farmacología , Inyecciones Intraventriculares , Ratones , Receptores de Aminoácidos , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Superficie Celular/fisiología , Convulsiones/prevención & control , Relación Estructura-ActividadRESUMEN
The capacity of water-soluble complexes of fullerene C60-polyvinylpyrrolidone to inhibit the replication of influenza viruses was studied. In contrast to remantadine, these complexes inhibit the replication of both A and B viruses (including the remantadine-resistant strains). The complexes inhibit influenza virus replication at all stages of replication cycle.
Asunto(s)
Antivirales/farmacología , Carbono/farmacología , Fulerenos , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/fisiología , Povidona/farmacología , Antivirales/uso terapéutico , Carbono/uso terapéutico , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Povidona/uso terapéutico , Replicación Viral/efectos de los fármacosRESUMEN
Intraperitoneal NMDLA was pharmacologically studied in mice for effects by using the hot-plate test. The agent given in a subconvulsive dose of 50 mg/kg showed a biphasic action: 5 minutes after administration there was hyperalgesia (Phase I) followed by hypoalgesia (Phase II) 15 minutes later. The effects of phencyclidine, ketamine, morphine, naloxone, bromocriptine and isradipine on NMDLA's analgetic action were also examined. Bearing in mind the fact that the action of NMDLA is decreased by isradipine in Phase I and by receptor-acting agents in Phase II it is suggested that there is a great difference in the patterns of the two phases of the analgetic action of NMDLA systemically used.
Asunto(s)
N-Metilaspartato/farmacología , Dolor/tratamiento farmacológico , Animales , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Masculino , Ratones , N-Metilaspartato/uso terapéutico , Dolor/fisiopatología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Factores de TiempoRESUMEN
Phenamine (10(-12)-10(-5) M/l) increased by 20-60 per cent the input (sodium and calcium) currents (Iin), the output slow potassium (Ikm) and fast potassium (Ikb) ones, and decreased the currents in higher concentrations. The volt-ampere characteristics of the membrane (VAC) and the curves of stationary inactivation (CSI) shifted along the potentials axis. The phenamine analogue IEM 1365 only decreased the currents leaving the VAC and CSI unaltered. Another analogue IEM 1370 only decreased the Iin whereas VAC and CSI also shifted along the potentials axis. The ion channels seem to be blocked in a decrease of the currents and the membrane surface potential induced with fixed charges seems to change.
Asunto(s)
Anfetamina/farmacología , Anfetaminas/farmacología , Canales Iónicos/efectos de los fármacos , Lymnaea/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Canales Iónicos/fisiología , Potenciales de la Membrana/efectos de los fármacos , Neuronas/fisiología , Perfusión/métodosAsunto(s)
Antivirales/farmacología , Carbono/farmacología , Fulerenos , Povidona/química , Antivirales/química , Carbono/química , Células Cultivadas , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Pruebas de Sensibilidad Microbiana , Pase Seriado , Replicación Viral/efectos de los fármacosRESUMEN
The review covers the principles of creation of prodrugs as a chemical system for delivering drugs to targets. It presents the strategy of prodrug design and describes the main approaches to creation of prodrugs for drugs of different classes: antibiotics, anti-inflammatory and antitumour agents, corticosteroids, agents of the central action, etc.
Asunto(s)
Profármacos/uso terapéutico , Química Farmacéutica , Diseño de Fármacos , Humanos , Profármacos/síntesis química , Profármacos/farmacocinética , Profármacos/farmacología , Relación Estructura-Actividad , Terminología como AsuntoRESUMEN
The effects of four derivatives of imidazole-4(5)-carboxylic acid on the formation and extinction of the conditioned drinking reflex and the preservation of the conditioned response of passive avoidance after electroconvulsive shock or mechanic craniocerebral injury were studied during experiments on rats. N-methylamide of imidazole-4(5)-carboxylic acid exhibited the greatest psychostimulant and antiamnestic activity. Addition of beta-phenylisopropyl radical to NH2-group resulted in the appearance of depressant properties.
Asunto(s)
Amidas/farmacología , Imidazoles/farmacología , Memoria/efectos de los fármacos , Amidas/uso terapéutico , Animales , Lesiones Encefálicas/complicaciones , Condicionamiento Clásico/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Electrochoque , Reacción de Fuga/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Imidazoles/uso terapéutico , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Ratas , Ratas Endogámicas , Reflejo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Three amino-alkylated derivatives of the naturally occurring excitatory amino acid (EAA) receptor agonist ibotenic acid (Ibo) have been synthesized and tested pharmacologically. N-Methyl-Ibo (1a) and N-ethyl-Ibo (1b) were shown to be agonists at NMDA receptors (EC50 = 140 and 320 microM, respectively), though with activities considerably lower than Ibo (EC50 = 9.6 microM). N-Benzyl-Ibo (1c) was inactive at ionotropic EAA receptors and all three compounds were, in contrast to Ibo, inactive at metabotropic EAA receptors. Molecular mechanics calculations have been performed on Ibo, 1a-c and the potent NMDA agonist 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA) in order to elucidate the observed structure-activity data.
Asunto(s)
Agonistas de Aminoácidos Excitadores/química , Ácido Iboténico/análogos & derivados , Receptores de N-Metil-D-Aspartato/agonistas , Animales , Células CHO , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Cricetinae , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Iboténico/síntesis química , Ácido Iboténico/farmacología , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
In the present investigation the interaction of a novel selective NMDA receptors agonist, N-phthalamoyl-L-glutamic acid (PhGA), with the synaptic membranes preparation of human hippocampus was examined against NMDA. It was established that there are two binding sites of 3H-L-Glu, Kd1 = 0.35 +/- 0.11 nM, Bmax1 = 6.5 +/- 2.3 pmol/mg and Kd2 = 51 +/- 12 nM, Bmax2 = 98 +/- 17 pmol/mg. The inhibition constants (Ki) were calculated for NMDA and PhGA and were equal: Ki(NMDA) = 19 microM, Ki (PhGA) = 13 microM, respectively. It was concluded that PhGA is the partial agonist of the NMDA receptors.
Asunto(s)
Glutamatos/metabolismo , Glutamatos/farmacología , Hipocampo/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Membranas Sinápticas/metabolismo , Sitios de Unión , Humanos , Técnicas In Vitro , N-Metilaspartato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
It was found in experiments on rabbit platelets that isoptin and derivatives of N,N'-di(beta-phenylisopropyl)polymethylene diamines produce a dose-dependent decrease of the platelet aggregation activity. The effect correlates with a lowering of membrane-bound calcium level in platelets as shown by the fluorescent technique with the use of chlortetracycline probe. The results obtained demonstrate that the derivatives of alkylenediamines significantly suppress platelet aggregation and block membrane-bound calcium at the lower concentrations than those of isoptin.