Biomedical subjects
Publications and source records attributed to M A Miranda.
The decarboxylation of naproxen (1H) and its salt (1-) was achieved by means of chemical [Ce(IV) or S2O8(2-)] and electrochemical oxidation. The product patterns were compatible with mechanisms involving single-electron transfer from the pi-system or the carboxylate moiety. The results are discussed in connection with the involvement of electron-transfer processes in the reported phototoxicity of naproxen.
BACKGROUND: The mechanism of piroxicam-induced photosensitivity is unknown. It was first attributed to metabolites of the drug produced in vivo but further photochemical studies disclosed that piroxicam was not stable to light, forming at least two photoproducts. Photosensitivity reactions to droxicam and tenoxicam have been not reported. OBJECTIVE: The aim of this study was to determine whether piroxicam photoproducts contribute to the light reactions induced by this drug, to describe a case of droxicam-induced photosensitivity and to study the in vivo photosensitizing potential of tenoxicam. METHODS: Patch and photopatch tests with two major photoproducts of piroxicam, with different preparations of UVA-preirradiated piroxicam, and with low and high concentrations of tenoxicam were performed in normal volunteers and in piroxicam-photosensitive patients. Phototesting studies were also performed before and after the oral administration of tenoxicam in both groups of subjects. RESULTS: Positive patch test responses were obtained in piroxicam-photosensitive patients only with the preirradiated piroxicam preparations. Phototesting studies with tenoxicam were normal in both groups. CONCLUSION: Minor or intermediate piroxicam photoproducts are more likely to be responsible for the photosensitivity reactions induced by this drug.
BACKGROUND: Photosensitivity reactions to fibric acid derivatives are not well understood and have been rarely reported. OBJECTIVE: The aim of this study was to describe two cases of photosensitivity, one induced by fenofibrate and one by bezafibrate; to study the in vivo photosensitizing potential of these drugs; and to evaluate the possibility of cross-reactivity between fenofibrate and ketoprofen. METHODS: Patch and photopatch tests with fibric acid derivatives and ketoprofen were performed in the patients, in 12 normal volunteers, and in 7 patients with photopatch-proven photocontact dermatitis to ketoprofen. Phototesting studies were performed both while the patients were taking the drugs and after withdrawal of them, as well as in a group of 18 hyperlipemic volunteers without history of photosensitivity who were taking therapeutic doses of fenofibrate or bezafibrate for 2 to 3 months. RESULTS: Positive photopatch test responses to ketoprofen and to fenofibrate were obtained only in the first patient, who also had a weaker positive ordinary patch test response to the latter. Five patients photosensitized to ketoprofen also had a positive patch test to fenofibrate. Phototesting studies were abnormal in both patients but normal in all volunteers. CONCLUSION: An association between systemic photosensitivity to fenofibrate and photocontact sensitivity to ketoprofen seems to exist. The structural similarities of these chemicals favor cross-reactivity.
Explore the source record for details and available documents.
Since nalidixic acid had been previously studied in acidic and basic media, nifedipine had been investigated in anaerobic conditions and under ultraviolet light and tiaprofenic acid had not been studied at all, their photodegradation was carried out in this laboratory under milder conditions, with methanol as the solvent and using visible light. The role of oxygen was demonstrated and the photoproducts were isolated and identified spectroscopically.
A photocontact dermatitis developed in three patients after the application of gel containing 0.5% piroxicam. Patch tests were positive to thiomersal and thiosalicylic acid. Photopatch tests with piroxicam at several concentrations were positive in the three patients but negative in 62 normal volunteer subjects. Patch tests performed on 14 patients with proved systemic photosensitivity to piroxicam were positive for thiomersal and thiosalicylic acid. Nine of 12 patients previously sensitized to thiosalicylic acid and with no history of exposure to piroxicam showed positive photopatch test reactions to this chemical. These results support a relation between piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. Contact allergic sensitivity to the latter is a marker for patients with a high risk of developing photosensitivity reactions to piroxicam. These reactions may be due to photoproducts of the drug rather than metabolites.
The photodegradation of benorylate [4'-(acetamido)phenyl-2-acetoxybenzoate], a drug frequently used in rheumatoid arthritis therapy, has been examined under different sets of experimental conditions. Several photoproducts have been isolated and identified on the basis of their IR, NMR, and MS spectra. The most significant photochemical process is the photo-Fries rearrangement of benorylate, leading to 5-acetamido-2'-acetoxy-2-hydroxybenzophenone (1). This compound undergoes a rapid transacylation to the isomeric 5'-acetamido-2'-acetoxy-2-hydroxybenzophenone (2). A primary culture of rat hepatocytes has been used to evaluate the possible toxicity of these two benzophenones, keeping in mind the following criteria: leakage of cytosolic enzymes, attachment index to culture plates, gluconeogenesis from lactate and fructose, glycogen balance, and albumin synthesis. At the concentrations assayed, neither of the two major photoproducts of benorylate (benzophenones 1 and 2) had significant toxic effects on liver cells in culture.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The photodegradation of chlorpromazine, a drug frequently used in psychotherapy, was examined under different sets of experimental conditions. A primary culture of rat hepatocytes was used to evaluate the possible hepatotoxicity of the chlorpromazine photoproducts, keeping in mind the following criteria: leakage of cytosolic enzymes; attachment index to culture plates, and albumin synthesis. Cells exposed to concentrations greater than 10(-4) M of the photomixtures showed extensive leakage of GOT and GPT into the culture medium and, at the same time, the cell attachment was seriously impaired. A concentration of 10(-7) M of the photoproducts proved capable of inhibiting the synthesis of albumin (20%). Photoproducts obtained after aerobic irradiations were as toxic for hepatocytes as those found in anaerobic conditions. The implications of our results in connection with the relevance of oxygen-dependent photoreactions of chlorpromazine to its phototoxicity, and the possible appearance of hepatic alterations in patients treated with the drug after exposure to the sunlight, are discussed.
Photobinding of drugs to biomolecules constitutes an important early event in the onset of photoallergy. In the present work, UV irradiation of human serum albumin in the presence of either suprofen (SUP) or its major photoproduct, decarboxylated suprofen (DSUP), has been studied as a model system for drug-photosensitised protein binding. Both dark binding and binding in the presence of light were investigated since this will affect the mode, site and mechanism of drug interaction with the protein. In order to determine the binding features of SUP to albumin, competitive binding experiments were carried out using fluorescent probes specific for site I and II. Suprofen was found to selectively dark bind to site II on HSA. Photobinding of DSUP to HSA was more efficient than SUP. Parallel to this, the intrinsic tryptophan fluorescence of HSA decreased when the protein was previously irradiated in the presence of the photoactive compounds, again being DSUP more efficient compared with SUP. As fluorescence quenching involves electron transfer from the excited Trp to the ground state DSUP, it follows that the photoactive compound binding to HSA must be on (or in close proximity to) site I Trp(214) residue. It appears that photobinding of SUP is largely preceded by its photodecomposition to DSUP which, in turn, associates and photobinds to HSA.
The possible stereoselectivity in DNA-photosensitization by carprofen (a NSAID drug) and ofloxacin (a fluoroquinolone agent) was investigated. The different drug stereoisomers or racemic mixtures were UVA-irradiated and the relaxation of the supercoiled circular pBR322 quantified by electrophoresis. Formation of single strand breaks was compared for each group of compounds. Moreover a mechanistic study by means of repair enzymes: T4 endonuclease V (specific of cyclobutane pyrimidine dimers), E. coli endonuclease III (revealing oxidized pyrimidines) and E. coli Formamidopyrimidine-DNA glycosylase (revealing oxidized purines) provided further insights into a possible stereoselectivity of the different reaction pathways in drug photosensitized-DNA damage. Ofloxacin and levofloxacin (its S stereoisomer) were responsible of single strand breaks formation as well as oxidation of pyrimidine and purine bases. No pyrimidine dimers were observed. Racemic, R and S stereoisomers of carprofen were less efficient than ofloxacin in DNA single strand breaks formation and did not induce enzyme-sensitive sites. The photoproducts distribution of drug-photosensitized reactions of 2'-deoxyguanosine and thymidine were established by HPLC as fingerprints for assignment of the DNA-photosensitization mechanism. Both Type I and Type II mechanisms were assigned to nucleoside-photosensitization by ofloxacin and levofloxacin. In the case of carprofen, a weak nucleoside degradation was obtained. The data suggest that levofloxacin, the (S) stereoisomer, might be slightly more efficient than racemic ofloxacin. In the case of carprofen the (S) isomer appears to be somewhat less active than its (R) enantiomer. However, due to the small differences found, the possible stereoselectivity has to be confirmed by future studies.