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.     

Kinetic studies on the solvolysis and axial ligand substitutions of bis-triphenylphosphine(cyclohexane-1,2-dione-dioximato)ruthenium(II) in non-aqueous solvents

Kinetic studies of ligand substitutions of the six-coordinated Ru^II pseudo-macrocyclic complex [Ru(CHDH)₂- (PPh₃)₂] (CHDH=cyclohexanedione-dioximato) have been spectrophotometrically investigated in a variety of solvents and at 70, 80, 85 and 90°C. The reactions studied are of the form:[(PPh₃)Ru(CHDH)₂(PPh₃)] + L =[(PPh₃)Ru(CHDH)₂L] + PPH₃ where L is imidazole, pyridine, piperidine or thiophene or a solvent molecule (PhCl, PhMe, MeCN, DMSO or DMF). The solvolysis reactions with chlorobenzene and toluene proceed to an equilibrium position favoring the bis-triphenylphosphine complex. All other reactions proceed to completion. From a mechanistic point of view the reactions were found to proceed through the formation of a five coordinate intermediate that possesses little or no discriminating ability towards the incoming nucleophiles. The rate data were thus interpreted in terms of a dissociative (D) or dissociative interchange (Id) mechanism. Activation parameters H and S are reported. Preliminary studies on the solvatochromic behavior of [Ru(CHDH)₂(PPh₃)₂] and the corresponding mixed complexes are discussed.     

Synthesis of new thiazole analogues of pyochelin, a siderophore of Pseudomonas aeruginosa and Burkholderia cepacia. A new conversion of thiazolines into thiazoles

Three pyochelin analogues and their methyl esters all containing a thiazole ring have been synthesised from the same Weinreb amide key intermediate. One of these analogues called HPTT-COOH, a molecule released in the course of pyochelin and yersiniabactin biosynthesis, was efficiently synthesised using a new base induced conversion of the key compound 2′-(2-hydroxyphenyl)-2′-thiazoline-4′-(N-methoxy,N-methyl) carboxamide into 2′-(2-hydroxyphenyl)-2′-thiazole-4′-(N-methoxy,N-methyl) carboxamide.     

Spectrofluorometric determination of certain quinolone antibacterials using metal chelation

Simple, rapid, reliable, and sensitive spectrofluorometric methods were developed for the determination of eight quinolone antibacterials namely ciprofloxacin, norfloxacin, lomefloxacin, difloxacin, amifloxacin, pefloxacin, ofloxacin, and nalidixic acid. The methods depend on the chelation of each of the studied drugs with zirconium, molybdenum, vanadium or tungsten to produce fluorescent chelates. Different factors affecting the relative fluorescence intensity of the resulting chelates were studied and optimised. At the optimum reaction conditions, the drug-metal chelates showed excitation maxima ranging from 274 to 295 nm and emission maxima ranging from 409 to 495 nm. The chelates were found to be stable at room temperature for 2 days and show good stability upon increasing temperature to 50 °C for about 1 h. Rectilinear calibration graphs were obtained in the range of 10-60 ng ml⁻¹ for each of the investigated drugs and the limits of detection and quantitation ranged from 1.214 to 2.046 and from 4.047 to 6.819 ng ml⁻¹, respectively. The molar ratios of the formed chelates were determined by Job's method and their association constants were also calculated. The developed methods were applied successfully for the determination of the studied drugs in their pharmaceutical dosage forms with a good precision and accuracy compared to official and reported methods as revealed by t- and F-tests. They were also applied for the determination of studied drugs in spiked urine and plasma samples.     

A novel strategy towards the asymmetric synthesis of orthogonally funtionalised 2-N-benzyl-N-alpha-methylbenzylamino- 5-carboxymethyl-cyclopentane-1-carboxylic acid

The asymmetric synthesis of the orthogonally funtionalised compounds tert-butyl 2-N-benzyl-N-alpha-methylbenzylamino-5-methoxycarbonylmethylcyclopentane- 1-carboxylate and methyl 2-N-benzyl-N-alpha-methylbenzylamino-5-carboxymethylcyclo- pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6- diendioate with lithium N-alpha-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid is reported.     

A study on the electronic spectra of vinylpyridines and 1,2-(dipyridyl)ethylenes. Molecular orbital calculations

The electronic absorption spectra of 2-, 3-, and 4-vinylpyridines and 1,2-(2,3-dipyridyl), 1,2-(2,4-dipyridyl), 1,2-(3,4-dipyridyl), and 1,2-(4,4-dipyridyl) ethylenes have been investigated in polar and nonpolar solvents. A correlation has been made between the geometry of the molecule and the observed spectrum. Molecular orbital calculations have been carried out using the INDO/S? CI procedure and a limited geometry optimization. The solvent effect at the MO level has been calculated. MO calculations predicted the existence of nπ* transitions that were not observed experimentally. The wave functions of the different CI states were calculated. The experimental transition energy as well as oscillator strength corresponded satisfactorily with the calculated ones. The observed transitions were assigned according to the results of MO calculations.     

Reactions with Carbo(heterylhydrazonoyl) Halides. I. Chemistry of Carbo(3-phenylpyrazol-5-yl-hydrazonoyl) Chlorides

The Carbo(3-phenylpyrazol-5-yl-hydrazonoyl) halides 1a , b react with active methylene compounds to yield the 1-(3-phenylpyrazol-5-yl)-pyrazole derivatives 2a – k (Scheme 1). The acyclic intermediates 3a , b could be isolated from reaction of 1a , b with acetylacetone, thus establishing the substitution mechanism for these reactions. Compounds 1a , b reacted with carbon disulfide, phenyl isothiocyanate, methyl cyanide, and with p-chlorobenzaldehyde to yield the corresponding heterocyclic derivatives 5 – 8 , respectively (Scheme 2). The behaviour of compounds 2 with hydrazine hydrate is reported.     

Microemulsion-based synthesis of CeO(2) powders with high surface area and high-temperature stabilities

Pure ceria powders, CeO(2), were synthesized in heptane-microemulsified aqueous solutions of CeCl(3) or Ce(NO(3))(3) stabilized by AOT (sodium bis(2-ethylhexyl) sulfosuccinate), DDAB (di-n-didodecyldimethylammonium bromide), or DDAB + Brij 35 surfactant mixtures. Micellar DTAB (n-dodecyltrimethylammonium bromide) and vesicular DDAB systems were also used as media for generating CeO(2). Characterization of the powders by X-ray powder diffractometry, laser-Raman spectroscopy, and Fourier transform infrared spectroscopy revealed that in the presence of surfactants almost-agglomerate-free nanosized crystallites (6-13 nm) of anionic vacancy-free cubic CeO(2) were produced. In the absence of surfactants 21-nm-sized crystallites were formed, comparing with the 85-nm-sized crystallites when cubic CeO(2) was created via thermal decomposition of cerium oxalate. Surface characterization, by X-ray photoelectron spectroscopy, N(2) sorptiometry, and high-resolution electron microscopy showed AOT- or (DDAB + Brij 35)-stabilized microemulsions to assist in formation of crystallites exposing surfaces of large specific areas (up to ca. 250 m(2)/g) but of low stability to high-temperature calcination (28-13 m(2)/g at 800 degrees C). In contrast, the double-chained DDAB was found to generate cubic CeO(2) crystallites of lower initial surface areas (144 (microemulsion) to 125 (vesicles) m(2)/g)) but of higher thermal stability (55-45 m(2)/g at 800 degrees C). Hence, the latter cerias could be considered as appropriate components for total oxidation (combustion) catalysts.