Reactive radical intermediates formed from illuminated nifedipine

Nifedipine, (1,4-dihydro-2,6,dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester) a calcium channel blocker widely used in treatment of hypertension, is strongly photolabile. This may represent a problem in patients taking nifedipine and in handling of nifedipine samples. Reactive radical intermediates were determined and characterized in the process of nifedipine illumination using EPR spectroscopy. On illumination of nifedipine by daylight or by a mercury lamp, a nitroxide radical, R^I_IL-NIFNO^.X was observed (in the first step), in various solvents like benzene, cyclohexane, methanol, acetonitrile, dimethylsulphoxide, or aqueous suspensions of liposomes. R^I_IL-NIF represents the nifedipine skeleton centered with phenyl group, and X is an EPR silent substituent. The generation of R^I_IL-NIFNO^.X is coupled with the formation of nitroso compound, R^I_IL-NIFNO, as characterized by UV-visible spectroscopy. In a further step, R^I_IL-NIFNO abstracts hydrogen from nifedipine skeleton under the formation of R^I_IL-NIFNO^.H radical. In addition to this, in system containing R^I_IL-NIFNO and unsaturated lipids, nitroxide radicals R_IL-INF^INO^.R_LIPIDS are formed probably via a pseudo Diels-Alder mechanism (R_LIPIDSrepresents lipidic skeleton). The unusually easy photochemical activation of nifedipine is probably stimulated by photosensitization of its nitro group interacting with suitably positioned hydrogen or carboxylic mehtyl ester group from the pyridynl ring.     

Nifedipine and phenytoin induce matrix synthesis,but not proliferation,in intact human gingival connective tissue ex vivo

Drug-induced gingival enlargement (DIGE) is a fibrotic condition that can be caused by the antihypertensive drug nifedipine and the anti-seizure drug phenytoin, but the molecular etiology of this type of fibrosis is not well understood and the role of confounding factors such as inflammation remains to be fully investigated. The aim of this study was to develop an ex vivo gingival explant system to allow investigation of the effects of nifedipine and phenytoin alone on human gingival tissue. Comparisons were made to the histology of human DIGE tissue retrieved from individuals with DIGE. Increased collagen, fibronectin, and proliferating fibroblasts were evident, but myofibroblasts were not detected in DIGE samples caused by nifedipine and phenytoin. In healthy gingiva cultured in nifedipine or phenytoin-containing media, the number of cells positive for p-SMAD2/3 increased, concomitant with increased CCN2 and periostin immunoreactivity compared to untreated explants. Collagen content assessed through hydroxyproline assays was significantly higher in tissues cultured with either drug compared to control tissues, which was confirmed histologically. Matrix fibronectin levels were also qualitatively greater in tissues treated with either drug. No significant differences in proliferating cells were observed between any of the conditions. Our study demonstrates that nifedipine and phenytoin activate canonical transforming growth factor-beta signaling, CCN2 and periostin expression, as well as increase collagen density, but do not influence cell proliferation or induce myofibroblast differentiation. We conclude that in the absence of confounding variables, nifedipine and phenytoin alter matrix homeostasis in gingival tissue explants ex vivo, and drug administration is a significant factor influencing ECM accumulation in gingival enlargement.