Analysis of effective molecular diffusion rates for verteporfin in subcutaneous versus orthotopic Dunning prostate tumors

Photosensitizer biodistribution change inside tissue is one of the dominant factors in photodynamic therapy efficacy. In this study, the pharmacokinetics of a benzoporphyrin derivative (BPD), delivered in verteporfin for injection formulation, have been quantified in the rat Dunning prostate tumor MAT-LyLu model, using both subcutaneous and orthotopic sites. Blood plasma sampling indicated that BPD had a bi-exponential metabolic lifetime in vivo, with the two lifetimes being 9.6 min and 8.3 h. The spatial distributions in the tumor were quantified as a function of distance from the perfused blood vessels, using fluorescence histologic images of the tumor. A fluorescent vascular marker was used to obtain locations and shapes of perfused capillaries at a wavelength of emission different from that of BPD and to allow colocalized images to be acquired of vessel and BPD locations. Using the BPD fluorescence images obtained 15 min after intravenous administration, a forward finite-element solution to the diffusion equation was used to predict the drug distribution by matching the fluorescence intensity images observed microscopically. An inverse solver was used to minimize the root mean square error between the image of simulated diffusion and the experimental image, resulting in estimation of the diffusion coefficient of BPD in the tumor models. Effective diffusion coefficients were 0.88 and 1.59 microm2/s for the subcutaneous and orthotopically grown tumors, respectively, indicating that orthotopic tumors have significantly higher vascular extravasation rates as compared with subcutaneous tumors. This analysis supports the hypothesis that leakage rates of the photosensitizer vary considerably. Thus, although varying the time between injection and optical irradiation may be used to vary the targeting between vascular and less vascular areas, the precise time of treatment will depend on the nature of the permeability of the vasculature in the tissue being treated.     

Light Dosimetry for Intraperitoneal Photodynamic Therapy in a Murine Xenograft Model of Human Epithelial Ovarian Carcinoma

Few studies have been published to date measuring spatially resolved fluence rates in complex tissue geometries. Here the light distributions of three different intraperitoneal light delivery geometries in a murine ovarian cancer model were investigated to assess their influence on the tumorcidal efficacy of photodynamic therapy (PDT). In vivo fluence rate measurements in the peritoneal cavities of mice, with the light intensity being mapped in three transverse planes, were performed using fiber-optic detectors. Three different source fiber designs and placements were tested for their ability to provide uniform irradiation of the peritoneal cavity. The biological response to a PDT protocol comprising three separate treatments administered at 72 h intervals, each consisting of a 0.25 mg kg intraperitoneal injection of benzopor-phyrin derivative-mono acid ring A followed 90 min later by delivery of 15 J of 690 nm light, was measured. The tissue response was evaluated by measuring the number of remaining visible lesions and the total residual tumor mass. Fluence rate measurements showed large variations in the fluence rate distribution for similar intended treatments. The most uniform and reproducible illumination was achieved using two 18 mm long cylindrical emitting optical fibers. The biological response was comparable to that produced when a flat-cleaved end optical fiber is used to illuminate the four quadrants of the abdomen sequentially. While a good reproducibility in tumor induction in this animal model exists, no correlation was found between the fluence rate distribution measured in one group of animals and the biological response in a separate group of similarly treated animals. Due to the large intra-animal variability in fluence rate distribution, representative fluence rate mapping in complex tissue geometries is of limited value when applied to an individual PDT treatment. Thus, surveillance of the fluence rate during individual treatments will be required for acceptable PDT dosimetry. To improve the versatility of this particular animal model for PDT research, a large number of extended sources are required to increase uniformity of the illumination in order to reduce unwanted cytotoxic side effects resulting from foci of high fluence rates. In this way, subsequent increase of the total energy delivered to the tumor may be possible.     

Flow injection-spectrophotometric determination of cresol compounds in water by reaction withp-aminophenol

A spectrophotometric method has been developed for the simultaneous determination ofo-cresol andm-cresol in water by reaction withp-aminophenol (PAP). Three different methodologies have been assayed; (i) batch analysis, after reaction in an alkaline medium in the presence of dissolved molecular oxygen as oxidizing agent, (ii) a stopped-flow procedure, carried out in the presence of KIO₄ and (iii) a flow injection method based on the same approach. The batch procedure requires 22 min for the full development of colour witho-cresol and 12 min form-cresol. In the stopped-flow mode, using KIO₄ and a reaction time of 12 min, better sensitivity can be obtained for both compounds and limits of detection of 10 g 1^–1 foro-cresol and 30 g 1^–1 form-cresol were found. The flow injection method has a lower sensitivity but permits more than 80 injections per hour. Based on the different maximum absorbance wavelengths obtained for the reaction products of PAP witho-cresol (614 nm) andm-cresol (632 nm), both compounds can be simultaneously determined in water samples and recoveries of 90 to 115% were found in spiked water samples of different types.     

Soot deep oxidation catalyzed by molybdena and molybdates: a thermogravimetric investigation

Molybdena (MoO₃) and molybdates of bismuth (Bi₂Mo₃O₁₂), chromium (Cr₂Mo₃O₁₂), barium (BaMoO₄), manganese (MnMoO₄) and copper (Cu₃Mo₂O₉) were synthesized and characterized by X-ray powder diffractometry and infrared spectroscopy. They were then assessed as ‘loose contact' catalysts for soot deep oxidation (combustion) in air by thermogravimetry. A similar assessment was carried out on commercial chromia (Cr₂O₃) and tungsta (WO₃). Observed high oxidation activity of MoO₃, as compared to both Cr₂O₃ and WO₃, is attributed to the higher volatility (mobility) of MoO_x species. On similar grounds, observed high activity of MoO₃ and Cu₃Mo₂O₉, as compared to the other test molybdates, is explained. Relatively speaking, however, a higher activity was observed for Cu₃Mo₂O₉ than MoO₃, whereby soot ignition temperature decreased from 571°C (uncatalyzed oxidation) to 430°C, to occur within the temperature range of diesel exhaust (200–450°C). This observation is ascribed to copper-promoted redox conduct of Mo(VI) in the oxidation reaction of soot. Kinetics of the reaction was studied non-isothermally, and the kinetic parameters (A, k, ΔE and the reaction order) were calculated.     

Spectrophotometric determination of phenol and resorcinol by reaction with p-aminophenol

Based on the reaction with p-aminophenol, a series of procedures have been developed for the spectrophotometric determination of phenol and resorcinol. Three basic approaches have been studied: (i) a batch procedure, using the dissolved oxygen as oxidant, (ii) a stopped-flow procedure by use of KIO(4) as oxidant and (iii) a flow injection (FI) procedure developed in the presence of KIO(4). Phenol can be accurately determined at 626 nm, in the stopped-flow mode, after a reaction time of 45 min in 0.005M NaOH, 0.004M KIO(4) and 500 mug/ml of PAP. The development of a manifold, which incorporates a sample parking, is a convenient approach which makes it possible to measure, in the stopped-flow mode, four solutions in one hour. The limit of detection of this method corresponds to 64 ng/ml of phenol Resorcinol can be determined by FI at 540 nm in 0.006M NaOH, 0.0002M KIO(4) and 50 mug/ml PAP with a limit of detection of 6.6 ng/ml and a sample throughput of 300 injections per hour. A combination between the FI procedure for the determination of resorcinol and the stopped-flow procedure for phenol determination provides accurate results in the analysis of spiked samples containing both phenol and resorcinol.     

Physico-chemical properties of iron-tin mixed oxide catalysts in cyclohexane oxidation

The state of mixed iron-tin oxide catalysts with a variable ratio of their metallic components has been studied by Mössbauer and ESCA spectroscopy. The results are compared with the activity of these catalysts in cyclohexane oxidation.

---

- . .

     

Phenolic compounds from the aerial parts of Clematis viticella L. and their in vitro anti-inflammatory activities*

Phytochemical investigations on the EtOH extract of Clematis viticella led to the isolation of six flavonoid glycosides, isoorientin (1), isoorientin 3′-O-methyl ether (2), quercetin 7-O-α-L-rhamnopyranoside (3), quercetin 3,7-di-O-α-L-rhamnopyranoside (4), manghaslin (5) and chrysoeriol 7-O-β-D-glucopyranoside (6), one phenylethanol derivative, hydroxytyrosol (7), along with three phenolic acids, caffeic acid (8), (E)-p-coumaric acid (9) and p-hydroxybenzoic acid (10). The structures of the isolates were elucidated on the basis of NMR and HR-MS data. All compounds were isolated from C. viticella for the first time. Compounds 7 and 8 showed significant anti-inflammatory activity at 100 μM by reducing the release of NO in LPS-stimulated macrophages comparable to positive control indomethacin. Compounds 3 and 7 exhibited anti-inflammatory activity through lowering the levels of TNF-α while 1, 3 and 5 decreased the levels of neopterin better than the positive controls.     

Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes paragraph sign

Excessive exposure of solar ultraviolet (UV) radiation, particularly its UV-B component, to humans causes many adverse effects that include erythema, hyperplasia, hyperpigmentation, immunosuppression, photoaging and skin cancer. In recent years, there is increasing use of botanical agents in skin care products. Pomegranate derived from the tree Punica granatum contains anthocyanins (such as delphinidin, cyanidin and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose) and possesses strong antioxidant and anti-inflammatory properties. Recently, we have shown that pomegranate fruit extract (PFE) possesses antitumor promoting effects in a mouse model of chemical carcinogenesis. To begin to establish the effect of PFE for humans in this study, we determined its effect on UV-B-induced adverse effects in normal human epidermal keratinocytes (NHEK). We first assessed the effect of PFE on UV-B-mediated phosphorylation of mitogen-activated protein kinases (MAPK) pathway in NHEK. Immunoblot analysis demonstrated that the treatment of NHEK with PFE (10-40 microg/mL) for 24 h before UV-B (40 mJ/cm(2)) exposure dose dependently inhibited UV-B-mediated phosphorylation of ERKl/2, JNK1/2 and p38 protein. We also observed that PFE (20 microg/mL) inhibited UV-B-mediated phosphorylation of MAPK in a time-dependent manner. Furthermore, in dose- and time-dependent studies, we evaluated the effect of PFE on UV-B-mediated activation of nuclear factor kappa B (NF-kappaB) pathway. Using Western blot analysis, we found that PFE treatment of NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated degradation and phosphorylation of IkappaBalpha and activation of IKKalpha. Using immunoblot analysis, enzyme-linked immunosorbent assay and electrophoretic mobility shift assay, we found that PFE treatment to NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated nuclear translocation and phosphorylation of NF-kappaB/p65 at Ser(536). Taken together, our data shows that PFE protects against the adverse effects of UV-B radiation by inhibiting UV-B-induced modulations of NF-kappaB and MAPK pathways and provides a molecular basis for the photochemopreventive effects of PFE.