RESUMEN
The photobiological properties of 6-methoxy-2-naphthylacetic acid (6-MNAA) were studied using a variety of in vitro phototoxicity assays: photohemolysis, photoperoxidation of linoleic acid, photosensitized degradation of histidine and thymine and the Candida phototoxicity test. 6-MNAA was phototoxic in vitro. 6-MNAA reduced nitro blue tetrazolium (NBT) when irradiated with lambda > or = 300 nm in deoxygenated aqueous buffer solution (pH 7.4). NBT can be reduced by reaction with the excited state of 6-MNAA subject to interference with molecular oxygen. The photohemolysis rate was inhibited by the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO), sodium azide (NaN3) and reduced glutathione (GSH). Photoperoxidation of linoleic acid and photosensitized degradation of histidine and thymine were significantly inhibited by sodium azide and reduced glutathione. 6-MNAA was phototoxic to C. albicans, C. lipolytica and C. tropicalis. A mechanism involving singlet oxygen, radicals, and electron transfer reactions is suggested for the observed phototoxicity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Butanonas/farmacocinética , Dermatitis Fototóxica , Ácidos Naftalenoacéticos/farmacología , Fármacos Fotosensibilizantes/farmacología , Aerobiosis , Anaerobiosis , Candida/efectos de los fármacos , Candida/crecimiento & desarrollo , Candida/efectos de la radiación , ADN/efectos de los fármacos , ADN/efectos de la radiación , Eritrocitos/efectos de los fármacos , Eritrocitos/efectos de la radiación , Hemólisis/efectos de los fármacos , Hemólisis/efectos de la radiación , Histidina/química , Histidina/efectos de la radiación , Humanos , Técnicas In Vitro , Luz , Ácido Linoleico/química , Ácido Linoleico/efectos de la radiación , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/efectos de la radiación , Nabumetona , Nitroazul de Tetrazolio/química , Nitroazul de Tetrazolio/efectos de la radiación , Fotoquímica , Timina/química , Timina/efectos de la radiaciónRESUMEN
The isolation and identification of the photodegradation products of clomipramine (CIP) in phosphate buffered saline (PBS pH 7.4 and 6.0) solution and methanol under aerobic conditions were studied. Six compounds were identified and four of them were isolated and characterized by spectroscopic methods. A radical mechanism with the participation of the solvent is proposed for the photodegradation of CIP which undergoes homolytic cleavage of the carbon-chlorine bond and also photooxidation of the amine group. CIP was able to induce photohemolysis when it was irradiated in PBS pH 7.4 and in PBS pH 6.0 containing a suspension of human red blood cells (RBCs). The photohemolysis experiments in the presence of additives DABCO and GSH showed nearly total inhibition of drug-induced photohemolysis. The efficient inhibition of photohemolysis by the radical scavenger GSH compared with the inhibition show by DABCO suggests a moderate effect by singlet oxygen. Clomipramine-N-oxide was the unique photoproduct able to induce hemolysis and photohemolysis when it was incubated and irradiated with RBCs for 1 h. A mechanism involving singlet oxygen, radicals and photoproducts is suggested for the reported phototoxicity.
Asunto(s)
Antidepresivos Tricíclicos/química , Clomipramina/química , Dermatitis Fototóxica/sangre , Eritrocitos/efectos de los fármacos , Aerobiosis , Antidepresivos Tricíclicos/efectos de la radiación , Clomipramina/efectos de la radiación , Hemólisis/efectos de los fármacos , Hemólisis/efectos de la radiación , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Fotoquímica , Fotólisis , Rayos UltravioletaRESUMEN
The photolability of nabumetone (NB, 1, 4-[6-methoxy-2-naphthalenyl]-2-butanone) and its photobiological properties were studied under aerobic and anaerobic conditions using a variety of in vitro phototoxicity assays: photohemolysis, photoperoxidation of linoleic acid, and photosensitized degradation of histidine and thymine. The photodegradation rate of NB in methanol and phosphate buffered saline (PBS) was enhanced under oxygenated media. NB was phototoxic in vitro. The photohemolysis rate was enhanced by deuterium oxide and inhibited by the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO), butylated hydroxyanisole (BHA), sodium azide (NaN3) and reduced gluthathione (GSH). The induced photoperoxidation of linoleic acid was inhibited significantly by sodium azide and reduced gluthathione. Histidine and thymine were photodegraded by a photosensitized reaction induced by NB. A mechanism involving singlet oxygen, radicals and photoproducts is suggested for the observed photoxicity.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Butanonas/química , Dermatitis Fototóxica/patología , Aerobiosis , Anaerobiosis , Antiinflamatorios no Esteroideos/toxicidad , Butanonas/toxicidad , Dermatitis Fototóxica/sangre , Eritrocitos/efectos de los fármacos , Eritrocitos/efectos de la radiación , Hemólisis/efectos de los fármacos , Histidina/química , Ácido Linoleico/química , Peroxidación de Lípido/efectos de los fármacos , Peróxidos Lipídicos/química , Nabumetona , Fotoquímica , Espectrofotometría Ultravioleta , Timina/químicaRESUMEN
Aqueous solutions of the antihyperlipoproteinemic drug bezafibrate (CAS 41859-67-0) are photolabile towards UV-B light under aerobic conditions. Two compounds were isolated and identified spectroscopically as well as by alternative synthesis as the only photoproducts formed. Their formation involves primary cleavage of the aryloxy-carbon bond and decarboxylation followed by hydrogen abstraction or dimerization. Bezafibrate is phototoxic in vitro as indicated by the photohemolysis test. Furthermore bezafibrate photo-sensitizes peroxidation of linoleic acid as monitored by the UV detection of dienic hydroperoxides. Partial inhibition of these processes on addition of butylated hydroxyanisole (BHA), reduced glutathione (GSH), sodium azide (NaN3) or 1,4-diazabicyclo [2.2.2] octane (DABCO) suggests the involvement of type I as well as type II mechanisms.
Asunto(s)
Bezafibrato/química , Bezafibrato/efectos de la radiación , Hipolipemiantes/química , Hipolipemiantes/efectos de la radiación , Aerobiosis , Bezafibrato/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/efectos de la radiación , Humanos , Hipolipemiantes/farmacología , Técnicas In Vitro , Luz , Ácido Linoleico , Ácidos Linoleicos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Fotoquímica , Espectrofotometría Infrarroja , Espectrofotometría UltravioletaRESUMEN
First of all some general concepts are given on phototoxic activity of pharmaceutical products which full fill the structural characteristics required to decompose by light and to cause biological damage, either themselves, their photoproducts or the products of their metabolism. These considerations are important due to the fact that this field of research is fairly new. Next, a review is given on recent research carried out in this laboratory on the photochemistry and phototoxicity of fibric acid and their derivatives and finally a review is made as well on the photochemistry and phototoxicity of antibacterial quinolones. Mechanisms are postulated for the photochemical decomposition of the substances investigated and possible mechanism for the in vitro activity at cellular level are also presented.