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The aim of this study is to investigate the influence of flufenamic acid (FFA) on the solubility, dissolution and bioavailability of sorafenib (SFN) in the combined administration of the MSNM@SFN and FFA. The MSNM@SFN&FFA was prepared by mixing the MSNM@SFN with FFA. The solubility, dissolution and bioavailability of SFN in the MSNM@SFN&FFA complex was investigated in comparison with those of the MSNM@SFN. This study was performed following the National Institutes of Health guidelines for the use of experimental animals; all care and handling of animals were performed with the approval of the Experimental Animal Center of Peking University Health Science Center. The MSNM@SFN&FFA showed no significant influence on the solubility, dissolution and bioavailability of SFN when compared with the MSNM@SFN. These data indicated that FFA had almost no influence on the solubility, dissolution and bioavailability of SFN in the combined administration of MSNM@SFN and FFA, thus providing an experimental foundation for the subsequent formulation research on the combined usage of drugs.
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Objective To evaluate the inhibitory effect of butyl flufenamate (BT) on ultraviolet (UV)-induced acute skin phototoxic reaction,and to investigate its possible mechanisms.Methods Eight SKH-1 hairless mice were included in this study.The back of each SKH-1 hairless mouse was divided into six regions,which were then randomly classified into six groups:blank group receiving no treatment,UV group receiving UV radiation only,BT + UV group and vehicle + UV group topically treated with BT ointment and vehicle respectively followed by UV radiation,UV + BT group and UV + vehicle group topically treated with BT ointment and vehicle respectively after UV radiation.Skin samples were obtained from these mice at 24 hours after treatment.Subsequently,hematoxylin-eosin (HE) staining was performed,real-time PCR was carried out to detect mRNA expressions of caspase-3,p53,COX-2,PGER1,interleukin (IL)-1β,IL-6,and an immunofluorescence assay was conducted to observe the expression of caspase-3.Statistical analysis was carried out by repeated-measures analysis of variance (ANOVA).Results Compared with the UV group,both BT + UV group and UV + BT group showed a decrease in the degree of skin edema and number of apoptotic cells at 24 hours after UV radiation.Real-time PCR showed that the mRNA expressions of caspase-3,p53,COX-2,PGER1,IL-l β and IL-6 were significantly higher in the UV group than in the blank group (all P ＜ 0.05),but significantly lower in the BT + UV group than in the UV group (all P ＜ 0.05),and only the expressions of caspase-3 and p53 mRNAs were significantly decreased in the UV + BT group compared with the UV group (both P ＜ 0.05).The immunofluorescence assay revealed that the expression of caspase-3 increased in the UV group compared with the blank group,but decreased in both BT + UV group and UV + BT group compared with the UV group.Conclusion BT could partially inhibit UV-induced acute skin phototoxicity in SKH-1 hairless mice.
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Objective To investigate the influence of flufenamic acid (FFA) on gap junction intercellular communication in vascu-lar smooth muscle cells(VSMC) in situ of acutely isolated arteriole segments .Methods Whole-cell patch clamp recordings were used to study the effects of FFA on membrane input capacitance (Cinput ) ,membrane input conductance(Ginput ) or membrane input re-sistance(Rinput ) of VSMCs embedded in arteriole segments .Results FFA concentration-dependently and reversibly suppressed Ginput or increased Rinput ,with an IC50 of 56 and 33μmol/L in acutely isolated mesenteric artery(MA) and brain artery(BA) segments re-spectively .There was not significant difference between MA and BA (P> 0 .05) .After application of FFA (≥ 300 μmol/L) ,the Cinput ,Ginput and Rinput of the in situ cells were very close to the respective dispersed cell in MA and BA .Conclusion FFA is a reversi-ble gap junction blocker ,achieving a complete electrical isolation of the recorded VSMC at ≥300 μmol/L .FFA suggesting a homo-geneous property of the gap junctions between MA and BA .
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Objective To observe the suppressing effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on ultraviolet ray (UV)-induced erythema.Methods A solar simulator and an UV phototherapy device were used as light sources,respectively.Erythema reaction was induced on the back skin of 30 healthy volunteers by 1,2 and 3 minimal erythema doses (MED) of irradiation.Five preparations including butyl flufenamate 2.5％ ointment,butyl flufenamate 5％ ointment,the base of butyl flufenamate ointment,halometasone ointment,and diclofenac 1％ ointment,were applied to the irradiation sites respectively half an hour before or immediately after the irradiation.One irradiation site remained untreated and served as the control.The degree of erythema was evaluated by a chromameter at 4,24,and 48 hours after the irradiation.Intragroup and intergroup comparisons were done by t test and analysis of variance,respectively.Results When applied half an hour before solar-simulated irradiation,both 2.5％ and 5％ butyl flufenamate ointment totally suppressed the erythema reaction induced by 1-3 MED of UV irradiation,with no significant increase in erythema index at all the three time points after irradiation (all P ＞ 0.05); diclofenac 1％ only inhibited the erythema induced by 1 MED of UV irradiation at 4 and 48 hours,with no difference observed in erythema index between the baseline and these time points after irradiation; however,halometasone significantly aggravated the erythema reaction (P ＜ 0.05).Neither NSAIDs nor corticosteroids applied immediately after solar-simulated irradiation showed statistical effect on the degree of UV-induced erythema.When applied immediately after irradiation using the phototherapy device,butyl flufenamate 2.5％ ointment,butyl flufenamate 5％ ointment and halometasone ointment all induced a significant reduction in erythema reaction at 4 hours after 1 MED of irradiation (all P ＜ 0.05),and diclofenac caused a statistical decrease in erythema reaction at all the time points after 1-3 MED of irradiation (all P ＜0.05).Conclusions Topical use of butyl flufenamate before UV irradiation can effectively inhibit erythema reaction induced by 1-3 MED of irradiation.When applied immediately after irradiation,diclofenac shows the strongest erythema-suppressive effect,followed sequentially by butyl flufenamate and halometasone.
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El ibuprofeno (IB) es un antiinflamatorio no esteroideo (AINE) de amplio uso por su alta efectividad y buen margen de seguridad. Sin embargo, poco se conoce de sus posibles acciones cardiovasculares. Algunas evidencias clínicas sugieren que este AINE pudiera tener efectos adversos sobre el sistema cardiovascular. El objetivo de esta investigación fue estudiar las posibles acciones colaterales del ibuprofeno sobre corazón y músculo liso vascular, tomando como patrón de comparación el ácido flufenámico (AF), fármaco con probada acción inotropo negativa. Se utilizó la técnica clásica de corazón de rata aislado y perfundido (Langendorff), registrando electrograma superficial y la fuerza de contracción. También se estudió el efecto sobre la contracción de aorta abdominal de rata inducida por KCl isotónico y por fenilefrina (10 µmol/L). En comparación con el AF (IC50=9,5 µmol/L), el IB tuvo un pobre efecto inotrópico negativo (IC20=30 µmol/L). A la concentración máxima utilizada (100 µmol/L), el IB fue menos efectivo que el AF en reducir el intervalo QT (25 ± 7 ms vs. 60 ± 15 ms; N ³ 5) y alargar el intervalo RR (60 ± 10 ms vs. 145 ± 20 ms; N ³ 5). Mientras que el AF no tuvo acción sobre la contracción aórtica inducida por KCl o por fenilefrina, el IB provocó una vasorrelajación de » 30 por ciento de la contracción aórtica inducida por KCl o por fenilefrina aunque solo a la concentración máxima (100 µmol/L). Estos resultados sugieren que las acciones cardiovasculares directas del IB son mínimas lo cual contribuye al buen margen de seguridad para su uso en clínica en pacientes sin enfermedad cardiovascular
Ibuprofen (IB) is a non steroidal anti-inflammatory drug (NSAID) widely used because of its high effectivity and good safety margin. However, little is known about its possible cardiovascular actions. Some evidences in clinics suggest that this NSAID could have adverse side effects on the cardiovascular system. The aim of this investigation was to study the possible side effects of IB on the heart and vascular smooth muscle, taking as a reference the flufenamic acid (FA) a drug with known negative inotropic action. We used the isolated perfused rat heart (Langendorff) and recorded the surface electrogram and the force of contraction. We also studied the effects of IB on the KCl- or fenilephrine- (10 µmol/L) induced contraction of rat abdominal aorta. Compared to FA (IC50 = 9.5 µmol/L), IB showed a small negative inotropic effect (IC20 = 30 µmol/L). At the maximal concentration used (100 µmol/L), IB was less effective than FA in reducing the QT interval (45 ± 10 ms vs. 60 ± 15 ms; N ³ 5) and prolonging the RR interval (60 ± 10 ms vs. 145 ± 20 ms; N ³ 5). While FA had no effect on the aortic contraction (KCl or fenilepinephrine), IB relaxed aortic contraction (KCl or fenilephrine) by » 30 percent but only at the highest concentration (100 µmol/L). The present results suggest that cardiovascular actions of IB are minimal contributing to its good safety margin when used in clinics in patients not suffering from cardiovascular diseases