bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and Toxicodynamics of Cisplatin and Its Metabolites in Rats: Relationship between Renal Handling and Nephrotoxicity of Cisplatin
Authors: Hanada Kazuhiko , Ninomiya Kimie , Ogata Hiroyasu 
Published: October 2002

Abstract
The renal handling of cisplatin and its metabolites and the relationship between the pharmacokinetics of these platinum species in the kidney and nephrotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodynamic analysis.
Rats received cisplatin intravenously as a bolus (2–10 mgkg−1) or by constant infusion (55 and 140 μg min−1 kg−1). After intravenous administration of each platinum species, the platinum concentrations of unchanged cisplatin and its mobile and fixed metabolites were determined separately. Nephrotoxicity was estimated by measuring the blood urea nitrogen (BUN) levels and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administration.
Cisplatin and its mobile metabolites in plasma distributed more rapidly and extensively into the kidney (mean apparent kidney-to-plasma concentration ratios were 2.69 and 7.12 mL (g tissue)−1, respectively) than into the liver (less than 1 mL (g tissue)−1). Concomitant administration of mobile metabolites did not significantly alter the disposition of cisplatin. Nephrotoxicity, estimated by measuring BUN levels, appeared to be related to the plasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoid Emax model showed the maximum BUN level reached after cisplatin administration was related to the area under the renal cisplatin concentration-time curve (AUCk).
Solubilization of meso-Tetraphenylporphyrin Photosensitizers by Substitution with Fluorine and with 2,3-Dihydroxy-1-propyloxy Groups
Authors: Songca Sandile P , Mbatha B 
Published: October 2002

Abstract
The tetra(hydroxyphenyl)porphyrins (5,10,15,20-tetrakis(2-hydroxyphenyl)porphyrin (3), 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (4), and 5,10,15,20-tetrakis(4-hydroxy-phenyl)porphyrin (5) and the tetrahydroporphyrins (5,10,15,20-tetrakis(2-fluoro-3-hydroxy-phenyl)porphyrin (6), 5,10,15,20-tetrakis(2,4-difluoro-3-hydroxyphenyl)porphyrin (7), and 5,10,15,20-tetrakis(3,5-difluoro-4-hydroxyphenyl)porphyrin (8)) have been reported as potential photosensitizers for photodynamic therapy. In particular, the tetrahydropor-phyrin 7, which has been in Phase III clinical trials for three years in the USA and Canada, has shown great promise for primary and recurrent head and neck cancer. It is expected to be on the market soon. A potentially limiting property of compounds 3–8 is their hydrophobicity, which renders them insoluble in aqueous media. We therefore set out to develop an approach for their solubilization in aqueous media.
The first attempt was to prepare analogues with fluorine substituents at the positions ortho to each of the four hydroxy groups on the meso-phenyl rings. This was expected to increase the acidity of the ortho hydroxy groups, and therefore the solubility of the compounds in hydroxylic media. This structural alteration resulted in a slight but significant decrease in the partition coefficients.
The second attempt was substitution of each of the hydroxy groups on the phenyl rings with 2,3-dihydroxy-l-propyloxy groups. This structural alteration resulted in a substantial decrease in the partition coefficients.
To harness the combined effect of these two structural variations porphyrins were prepared containing both 2,3-dihydroxy-l-propyloxy and ortho fluorine groups on the meso-phenyl rings. The partition coefficients decreased by more than two orders of magnitude. The most significant decrease was due to the substitution with 2,3-dihydroxy-l-propyloxy groups, rather than the substitution with fluorine, although fluorination alone contributed significantly. The effect of this method was demonstrated most clearly by comparison of the partition coefficients of meta and para isomers of these porphyrins.
Time-dependent Nephrotoxicity Associated with Daily Administration of Cisplatin in Mice
Authors: To Hideto , Kikuchi Atsumi , Tsuruoka Shuichi , Sugimoto Koichi , Fujimura Akio , Higuchi Shun , Kayama Fujio , Hara Kyoko , Matsuno Koji , Kobayashi Eiji 
Published: October 2002

Abstract
The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6 mg kg−1) for 5 days at four time points (0400, 1000, 1600 and 2200h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared.
In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.
The results showed diurnal variations in cisplatin toxicity, with the 0400 and 1600h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 0400 and 1600 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 0400 and the 1600h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 1600h group than in the 0400h group after saline injection alone (P &lt; 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS.
Antihyperglycaemic effect of Diamed, a herbal formulation, in experimental diabetes in rats
Authors: Pari L , Ramakrishnan R , Venkateswaran S 
Published: October 2002

Abstract
Diamed is a herbal formulation composed of the aqueous extracts of three medicinal plants (Azardirachta indica, Cassia auriculata and Momordica charantia). We have investigated Diamed for its possible antihyperglycaemic action in rats with alloxan-induced experimental diabetes. Oral administration of Diamed (1.39 (0.25 g), 1.67 (0.30 g) or 1.94 (0.35 g) mL kg−1) for 30 days resulted in a significant reduction in blood glucose, glycosylated haemoglobin, and an increase in plasma insulin and total haemoglobin. The effect was highly significant after administration of the 1.94 mL (0.35 g) g−1 body weight dose. Diamed also prevented a decrease in body weight. An oral glucose tolerance test was performed in experimental diabetic rats in which there was a significant improvement in glucose tolerance in the animals treated with Diamed. The effect was compared with 600 μg kg−1 glibenclamide. The results showed that Diamed had antihyperglycaemic action in experimental diabetes in rats.
Discrimination between the functional and biochemical effects of two herbal oxytocics on the rat myometrium
Authors: Veale D J H , Du Preez J L , Havlik I , Oliver D W 
Published: October 2002

Abstract
This study on the rat myometrium is the first report where the effects of herbal extracts used as oxytocics in traditional medicine have been systematically analysed in the same preparation at the level of functional (contractile) and biochemical (second messenger generation) responses. Extracts of Agapanthus africanus and Clivia miniata (used in South African traditional medicine) were compared with other uterotonic agents with regard to their ability to stimulate phosphoinositide metabolism in the rat myometrium and cause accumulation of [3H]inositol phosphates. The maximal contractile response of the isolated rat myometrium in response to stimulation by the herbal extracts and agonists was compared with the maximal contractile response to cumulative addition of acetylcholine. The rank order of intensity of stimulation of [3H]inositol phosphate generation was: oxytocin &gt; Agapanthus &gt; prostaglandin F2α (PGF2α) &gt; serotonin &gt; acetylcholine &gt; Clivia &gt; ergometrine. This differed from the rank order of maximum contractile response: oxytocin &gt; acetylcholine &gt; PGF2α &gt; serotonin ≅ Clivia &gt; Agapanthus &gt; ergometrine. Activity was also identified in chemical fractions of the plants and components common to both plants have been identified in the isolated active fractions. These results have identified that the uterotonic activity of Agapanthus is linked to increased turnover of phosphoinositides as a signal transduction mechanism, whereas this appears to play a less significant role in the uterotonic activity of Clivia. This study illustrates the benefits of using the measurement of stimulation of phosphoinositide metabolism as a bioassay in phytomedical research.
Inhibition of NF-κB-mediated gene transcription by the human A2B adenosine receptor in Chinese hamster ovary cells
Authors: Combes Patricia , Dickenson John M 
Published: October 2002

Abstract
NF-κB is a transcription factor that plays a vital role in regulating inducible gene expression in immune and inflammatory responses. In view of the well documented effects of adenosine on immune and inflammatory responses, we have explored whether adenosine A1, A2B and A3 receptors regulate NF-κB activity in transfected Chinese hamster ovary (CHO) cells using a luciferase reporter gene construct. No increases in NF-κB activity were observed in CHO-A1,-A2B and -A3 cells stimulated with the non-selective adenosine receptor agonist 5′-N-ethyl-carboxamidoadenosine. Elevating intracellular cyclic AMP (cAMP) levels using forskolin (direct activator of adenylyl cyclase) and rolipram (type IV, cAMP-specific phosphodiesterase inhibitor), inhibited NF-κB activity in CHO cells. Adenosine A2B receptor stimulation also inhibited NF-κB activity, whereas adenosine A1 and A3 receptor activation had no effect. These data reflect the known coupling of adenosine A2B receptors to increases in cAMP. In conclusion, adenosine A1, A2B and A3 receptors do not directly activate NF-κB in CHO cells. However, adenosine A2B receptor activation significantly inhibited NF-κB activity. Inhibition of NF-κB activity by the adenosine A2B receptor may contribute to the anti-inflammatory effects of adenosine.
Sustained ocular delivery of tilisolol to rabbits after topical administration or intravitreal injection of lipophilic prodrug incorporated in liposomes
Authors: Kawakami Shigeru , Yamamura Kenzo , Mukai Takahiro , Nishida Koyo , Nakamura Junzo , Sakaeda Toshiyuki , Nakashima Mikiro , Sasaki Hitoshi 
Published: October 2002

Abstract
To improve the retention time of tilisolol in the precorneal area or vitreous body, we prepared liposomes incorporating the O-palmitoyl prodrug of tilisolol. O-Palmitoyl tilisolol was completely incorporated in the liposomes. After topical administration of O-palmitoyl tilisolol liposomes to the rabbit eye, O-palmitoyl tilisolol rapidly disappeared from the tear fluid. The inclusion of 2% carmellose sodium slightly prolonged the retention of O-palmitoyl tilisolol in the tear fluid. After intravitreal injection of O-palmitoyl tilisolol liposomes, there was a relatively prolonged retention of O-palmitoyl tilisolol in the vitreous body. At 24 and 48 h after intravitreal injection of O-palmitoyl tilisolol liposomes, the tilisolol concentration in the vitreous body was significantly higher compared with the concentration after intravitreal injection of tilisolol liposomes.
Effects of furocoumarins from Cachrys trifida on some macrophage functions
Authors: Abad M J , de las Heras B , Silván A M , Pascual R , Bermejo P , Rodriguez B , Villar A M 
Published: October 2002

Abstract
Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxide-synthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of &lt; 15 μM. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin.
Chitosan: some pharmaceutical and biological aspects - an update
Authors: Singla A K , Chawla M 
Published: October 2002

Abstract
Chitosan, a natural polysaccharide, is being widely used as a pharmaceutical excipient. It is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chitosan comprises a series of polymers varying in their degree of deacetylation, molecular weight, viscosity, pKa etc. The presence of a number of amino groups permit chitosan to chemically react with anionic systems, thereby resulting in alteration of physicochemical characteristics of such combinations.
Chitosan has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient, some of which include binding, disintegrating and tablet coating properties. The polymer has also been investigated as a potential adjuvant for swellable controlled drug delivery systems. Use of chitosan in novel drug delivery as mucoadhesive, gene and peptide drug administration via the oral route as well as its absorption enhancing effects have been explored by a number of researchers.
Chitosan exhibits myriad biological actions, namely hypocholesterolemic, antimicrobial and wound healing properties. Low toxicity coupled with wide applicability makes it a promising candidate not only for the purpose of drug delivery for a host of drug moieties (anti-inflammatories, peptides etc.) but also as a biologically active agent.
It is the endeavour of the present review to provide an insight into the biological and pharmaceutical profile of chitosan. Various investigations carried out recently are reported, although references to research performed on chitosan prior to the recent reviews have also been included, where appropriate.
Skin delivery of 5-fluorouracil from ultradeformable and standard liposomes in-vitro
Authors: El Maghraby Gamal M M , Williams Adrian C , Barry Brian W 
Published: October 2002

Abstract
The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 μL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes, the non-rigid preparation was the best. However, stabilization of the liposome membrane with cholesterol abolished the benefit of this non-rigid preparation. It was concluded that ultradeformable vesicles are promising agents for skin delivery of drugs.
Application of Eudragit P-4135F for the delivery of ellagic acid to the rat lower small intestine
Authors: Jeong Young-Il , Yv̄ Rama Prasad , Ohno Tomoya , Yoshikawa Yukako , Shibata Nobuhito , Kato Shinichi , Takeuchi Koji , Takada Kanji 
Published: October 2002

Abstract
Based on the assumption that the delivery of ellagic acid to its site of action would show an antiinflammatory activity in inflammatory bowel disease (IBD), we have prepared microspheres using a new pH-sensitive polymer, Eudragit P-4135F (P-4135F), to deliver ellagic acid to the lower small intestine in rats. The microspheres were spherical in shape and the mean diameters were approximately 100–150 μm. The amount of ellagic acid released from the microspheres decreased by increasing the formulated amount of P-4135F. The release characteristics of ellagic acid were pH-dependent. By considering the factors loading efficiency and microsphere particle size distribution, ellagic acid-2 microspheres (P-4135F/ellagic acid = 1.65) were selected for further investigation. In a dissolution study, more than 95% ellagic acid was released within 0.5 h in pH 7.4 and 8.0 buffers. The release percent of ellagic acid was less than 40% in pH 6.8 and 7.0 and was less than 10% in pH 5.6 and 5.9. To observe the dissolution sites of the microspheres in the rat small intestine fluorescein was formulated in the microspheres as a tracer drug along with ellagic acid (50 mg kg−1). After intraduodenal administration of fluorescein-labelled microspheres to rats, the plasma fluorescein level started to increase at 0.5 h, by which time the microspheres had reached the middle part of the ileum. Microspheres started to dissolve within 1.0 h and the peak plasma fluorescein concentration was observed at 3.0 h, when the majority of the administered microspheres were dissolved in the terminal ileum. These results suggested that P-4135F microspheres could deliver ellagic acid to the lower part of the small intestine, and that the released ellagic acid would be distributed into the caecum and the ascending colon.
A simple, predictive, structure-based skin permeability model
Authors: Buchwald Peter , Bodor Nicholas 
Published: October 2002

Abstract
By an extension of our simple, molecular size-based model recently developed to describe octanol-water partition coefficients, we were able to obtain an entirely structure-based model that seems well suited to describe human skin permeability data. The corresponding equations not only eliminate the physicochemical interrelatedness of the parameters of the original Potts & Guy approach that was obtained from similar considerations, but also maintain its elegant simplicity and are consistent with a basic physicochemical model of the related phenomena. As the new model is structure based and fully computerized, it allows direct estimation of skin permeability for any molecule of known structure without the need to obtain octanol-water partition coefficients or other experimental data.
Prevention of structural perturbations and aggregation upon encapsulation of bovine serum albumin into poly(lactide-co-glycolide) microspheres using the solid-in-oil-in-water technique
Authors: Castellanos Ingrid J , Cuadrado Wanda L , Griebenow Kai 
Published: October 2002

Abstract
Bovine serum albumin (BSA) was encapsulated into poly(lactide-co-glycolide) (PLG) microspheres by a solid-in-oil-in-water (s/o/w) technique. We tested whether perturbations in BSA secondary structure could be minimized during encapsulation by using trehalose and how this would influence BSA aggregation and release. BSA secondary structure was monitored non-invasively by Fourier-transform infrared spectroscopy. When BSA was co-lyophilized with trehalose, lyophilization-induced structural perturbations were significantly reduced. The formulation obtained (BSA-Tre) was encapsulated into PLG microspheres and, by optimizing critical encapsulation parameters, a loading efficiency of 85% was achieved. However, due to the loss of the excipient in the o/w emulsion step, the structure of BSA-Tre was more perturbed than before encapsulation. Excipient-loss and encapsulation-induced structural perturbations could be prevented by saturating the aqueous phase in the o/w step with trehalose and by using the organic solvent chloroform. This in turn reduced the formation of soluble BSA aggregates. BSA was released from PLG microspheres using the improved formulations with an initial release in 24 h of not more than 22%, followed by a sustained release over at least 2 weeks. In summary, optimization of the encapsulation conditions in the s/o/w procedure resulted in the encapsulation of BSA without procedure-induced structural perturbations and minimized the release of aggregated protein. This demonstrates that the s/o/w technique is an excellent alternative to the most common encapsulation procedure, namely the water-in-oil-in-water technique.
Solid state properties of pure UC-781 and solid dispersions with polyvinylpyrrolidone (PVP K30)
Authors: Damian Festo , Blaton Norbert , Desseyn Herman , Clou Katrien , Augustijns Patrick , Naesens Lieve , Balzarini Jan , Kinget Renaat , Van den Mooter Guy 
Published: October 2002

Abstract
The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbo-thioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by co-evaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be; a = 8.1556(7) Å, b = 17.658(2) Å and c = 23.609(2) Å; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50% w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.