bluuebunny/crossref_metadata_2025 huggingface dataset:
Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying
Authors: Izutsu Ken-ichi , Kojima Shigeo
Published: September 2002

The relationship between mannitol crystallization during freeze-drying and its effects on stabilizing protein structures was studied using lysozyme, bovine serum albumin, ovalbumin, β-lactoglobulin and lactate dehydrogenase as model proteins. FT-IR analysis of the protein secondary structure indicated perturbation of both α-helix and β-sheet regions in freeze-drying without cosolutes, whereas the proteins retained most of their native structure in co-lyophilization with sucrose. Mannitol protected the protein structure to different degrees depending on the crystallinity. The combination of mannitol with potassium phosphate buffer reduced the mannitol crystallinity and the structural changes occurring during freeze-drying, whereas mannitol by itself showed little stabilizing effect. Heat-treatment of the frozen solutions at −10°C resulted in a higher mannitol crystallinity and a smaller stabilizing effect in freeze-drying. The secondary structure perturbation was mostly reversible in rehydrated solutions. The varied structure-stabilizing effects of mannitol paralleled its effects on maintaining lower concentrations of enzyme activity during freeze-drying. These results confirm the contribution of molecular interactions between amorphous excipients and proteins (e.g. hydrogen bonding) to structure stabilization during freeze-drying.
Solvent change co-precipitation with hydroxypropyl methylcellulose phthalate to improve dissolution characteristics of a poorly water-soluble drug
Authors: Sertsou Gabriel , Butler James , Hempenstall John , Rades Thomas
Published: September 2002

Research compound GWX belongs to biopharmaceutical classification system type II, and hence shows dissolution-rate-limited absorption. To improve its dissolution performance, GWX was formulated as a co-precipitate with hydroxypropyl methylcellulose phthalate (HPMCP). Co-precipitates with various drug-HPMCP ratios were prepared and characterised using modulated differential scanning calorimetry (MDSC), X-ray powder diffraction, HPLC and dissolution testing. Co-precipitates with 1: 9 and2: 8 drug-HPMCP ratios showed the highest extent of dissolution after both 5 and 90 min, followed by 3: 7, 4: 6, and 5: 5 drug-HPMCP co-precipitates, in respective order. Co-precipitates with drug-HPMCP ratios of 6: 4 and greater showed no significant improvement in dissolution over crystalline drug alone. The amounts of crystalline and amorphous drug in co-precipitates, as determined by MDSC, and HPLC quantification of the total amount of drug in co-precipitates were used to determine the amount of drug incorporated into solid solution. It was found that dissolution rate and extent was correlated to the amount of drug incorporated into amorphous solid solution for the 1:9 to 5: 5 drug-HPMCP ratio co-precipitates. Amorphous drug alone and physical mixtures of drug and HPMCP showed very little and no significant improvement in dissolution rate or extent, respectively, above crystalline drug alone. Amorphous drug alone re-crystallized to a large extent within 1 min of contact with the dissolution medium, whereas 4: 6 drug-HPMCP co-precipitate showed a lower degree of re-crystallization and 2: 8 drug-HPMCP co-precipitate showed very little re-crystallization. It was concluded that the likely mechanisms of improved dissolution of low drug-HPMCP ratio co-precipitates were improved wetting or increased surface area for mass transfer, thermodynamically enhanced dissolution of a higher energy amorphous form and inhibition of re-crystallization, when drug was incorporated into solid solution.
Enhanced oral absorption of halofantrine enantiomers after encapsulation in a proliposomal formulation
Authors: Brocks Dion R , Betageri Guru V
Published: September 2002

In this study, we evaluated the ability of a coated, encapsulated formulation to increase the oral bioavailability of (±)-halofantrine (HF) enantiomers, a drug with low and erratic oral bioavailability. After encapsulation of HF in distearoylphosphatidylcholine, the dried particles were coated with cellulose acetate phthalate. A suspension of the product was made using methylcellulose as a dispersion agent, and the product was administered to Sprague-Dawley rats to provide a HF dose of 7 mg kg−1 as the HCl salt. HF HCl powder in 1 % methylcellulose with or without liposomal product excipients was also administered to separate groups of rats, which served as control groups. Serial blood samples were obtained from the rats and plasma was assayed by stereospecific high-performance liquid chromatography. There were no significant differences in the area under the concentration-time curve (AUC) or maximum concentration (Cmax) between the two control groups. Plasma concentrations of both HF enantiomers were significantly higher in the rats given HF as an encapsulated proliposomal formulation compared with the control groups. Compared with methyl-cellulose control, the encapsulation product resulted in increases of 41 to 47% in the AUC of HF enantiomers, and 90 to 100% in Cmax. The ability of an encapsulated proliposomal product to significantly increase the oral absorption of HF was clearly demonstrated.
Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier
Authors: Yamamoto Chika , Murakami Hideyasu , Koyabu Noriko , Takanaga Hitomi , Matsuo Hirotami , Uchiumi Takeshi , Kuwano Michihiko , Naito Mikihiko , Tsuruo Takashi , Ohtani Hisakazu , Sawada Yasufumi
Published: September 2002

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contributions of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LLC-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C] ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.
Lung surfactant phospholipids inhibit the uptake of respirable microspheres by the alveolar macrophage NR8383
Authors: Jones B G , Dickinson P A , Gumbleton M , Kellaway I W
Published: September 2002

Fluorescent poly(lactic-co-glycolic acid) microspheres of a respirable size were fabricated for use in a fluorescent activated cell sorting assay utilizing the continuous alveolar macrophage NR8383. This is a suitable model of alveolar phagocytosis, which permitted an investigation of the influence of phospholipid structure on the inhibition of phagocytosis of microspheres. Phospholipid inhibition was found to be independent of phosphatidylcholine alkyl chain length. Head group effects were investigated by studies employing phosphatidyl-choline,-serine, and -ethanolamine, and inhibition was shown to be independent of head group. Closer modelling of the lung environment by co-culturing NR8383 on A549 alveolar epithelium showed type II secretions to also down-regulate phagocytosis. In addition, pre-incubation with microspheres coated with dipalmitoylphosphatidylcholine reduced the uptake of a second microsphere (fluorescein isothiocyanate-labelled latex).
Synthesis and evaluation of a monoreactive DOTA derivative for indium-111-based residualizing label to estimate protein pharmacokinetics
Authors: Mukai Takahiro , Namba Shinji , Arano Yasushi , Ono Masahiro , Fujioka Yasushi , Uehara Tomoya , Ogawa Kazuma , Konishi Junji , Saji Hideo
Published: September 2002

The purpose of this study was to develop an indium-111 (111In)-based residualizing label for estimating the pharmacokinetics of proteins. 1,4,7,10-Tetraazacyclododecane-N,N′,N′,N″-tetraacetic acid (DOTA), which produced a highly stable and hydrophilic 111In chelate, was selected as the chelating site, and the monoreactive DOTA derivative with a tetrafluorophenyl group as the protein binding site (mDOTA) was designed to avoid cross-linkings of proteins. mDOTA was synthesized with an overall yield of 11%. The stability in murine plasma, the radioactivity retention in the catabolic sites of proteins and the radiochemical yields of 111In-labelled proteins via mDOTA were investigated using human serum albumin (HSA), galactosyl-neoglycoalbumin (NGA) and cytochrome c (cyt c) as model proteins. 111In-labelled HSA via mDOTA was highly stable for 5 days after incubation in murine plasma. Long retention of radioactivity in the catabolic sites was observed after injection of 111In-DOTA-NGA in mice, due to the slow elimination of the radiometabolite from the lysosome. At a chelator concentration of 42.2 μM, 111In-DOTA-cytc was produced with over 91 % radiochemical yield. On the other hand, 111In-DOTA-lysine and 111In-DOTA were obtained with high radiochemical yields at lower chelator concentrations. These findings indicated that mDOTA would be an appropriate 111In-labelling agent for estimating protein pharmacokinetics. These findings also suggested that the introduction of a protein binding site at a position distal from the unmodified DOTA structure would be preferable to preparing 111In-DOTA-labelled proteins with higher specific activity.
Effect of honey bee venom on proliferation of K1735M2 mouse melanoma cells in-vitro and growth of murine B16 melanomas in-vivo
Authors: Liu Xing , Chen Dawei , Xie Liping , Zhang Rongqing
Published: September 2002

Bee venom has been reported to exhibit antitumour activity in-vitro and in-vivo. Apoptosis, necrosis and lysis of tumour cells were suggested as possible mechanisms by which bee venom inhibited tumour growth. The aim of this study was to investigate potential mechanisms by which bee venom inhibits K1735M2 mouse melanoma cells in-vitro and B16 melanoma, a transplantable solid melanoma in C57BL/6 mice, in-vivo. The proliferation of K1735M2 cells in-vitro was inhibited by bee venom in a concentration- and time-dependent manner. The inhibition was indicated by the arrest of the cell cycle at the G1 stage, as detected by flow cytometric measurements. The bee venom induced apoptosis-like cell death as identified by histological observations and by DNA fragmentation. In the in-vivo experiments, the bee venom (1.0, 3.0, 9.0 mg kg−1 of body weight, on days 1–12) was injected intraperitoneally into mice 24 h after the mice were inoculated with B16 cells. Inhibition of the solid tumour was observed. Apoptosis of the K1735M2 cells was suggested as the possible mechanism by which bee venom inhibited cell proliferation and induced K1735M2 cell differentiation in-vitro. The in-vivo experiment indicated that bee venom could be used as a chemotherapeutic agent against malignant tumours.
Effect of a novel NSAID derivative with antioxidant moiety on oxidative damage caused by liver and cerebral ischaemia-reperfusion in rats
Authors: Kourounakis A P , Tsiakitzis K , Paramithiotis D , Kotzampassi K , Kourounakis P N
Published: September 2002

Tissue ischaemia-reperfusion evokes toxic and harmful biochemical processes such as oxidative stress and inflammation. The aim of this study is to investigate the indices of tissue damage in rat liver and brain after ischaemia-reperfusion injury of these organs, and to study prospective cytoprotection of molecules such as the novel anti-inflammatory N-(2-thiolethyl)-2-{2-[N′-(2,6-dichlorophenyl) amino] phenyl}acetamide (compound 1) and α-tocopherol. Two experimental models were studied: firstly, 30 min liver ischaemia via hepatoduodenal ligament clamping followed by 60 min reperfusion; and secondly, 45 min cerebral ischaemia via bilateral common carotid artery occlusion followed by 90 min reperfusion. Compound 1 and α-tocopherol were administered intraperitoneally before induction of ischaemia. We hereby report that compound 1, a molecule that combines potent in-vitro antioxidant and in-vivo anti-inflammatory activity with low gastrointestinal toxicity, offered protection in-vivo against liver or brain ischaemia-reperfusion-induced damage. Both compound 1 and α-tocopherol prevented changes in lipid peroxidation in the rat liver and brain tissue and in tumour necrosis factor (TNF-α) levels in brain. Also compound 1 attenuated glutathione depletion, evoked by ischaemia-reperfusion, in the rat brain but not in the liver. These results could be explained on the basis of the antioxidant/anti-inflammatory properties of compound 1 and suggest its beneficial effect and potential therapeutic use in post-ischaemic injury.
Effects of BDF 9198 on left ventricular contractility in advanced spontaneously hypertensive rats with heart failure
Authors: Doggrell Sheila A
Published: September 2002

In the first part of this study, we characterized 24-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), their heart weights, and the responses of the isolated left ventricles to electrical stimulation. In the main part of the study, we tested whether the positive inotropic effects of BDF 9198, which prevents the closure of the cardiac sodium channel, were present in senescence and heart failure. Thus, we studied the effects of BDF 9198 on the left ventricle strips of 24-month-old WKY rats (senescence) and SHRs using contractility methods. In comparison with WKY rats, the left ventricles of 24-month-old SHRs were hypertrophied and had prolonged times to peak contraction. BDF 9198 (10−8 to 10−6m) was a positive inotrope on the left ventricles of WKY rats, with a maximum augmenting effect of 122% with BDF 9198 at 10−7m. The magnitude of the augmenting effects of BDF 9198 were reduced in SHR heart failure, with a maximum augmenting effect of 26% at 10−7m. BDF 9198 at 10−6 m attenuated the responses of the SHR left ventricle to electrical stimulation. In conclusion, the potential of drugs that prevent closure of the sodium channel as positive inotropes in the treatment of heart failure should be further considered.
Effect of hr-IL2 treatment on intestinal P-glycoprotein expression and activity in Caco-2 cells
Authors: Belliard Anne-Marie , Tardivel Sylviane , Farinotti Robert , Lacour Bernard , Leroy Christine
Published: September 2002

Caco-2 cells were used to investigate the effect of human recombinant interleukin-2 (IL2) on intestinal P-glycoprotein (P-gp) transporter activity in-vitro. More specifically the efflux function of P-gp was studied by measuring the transepithelial transport of rhodamine-123, a fluorescent substrate of P-gp. Its transport was completely inhibited by two specific P-gp inhibitors, ciclosporin A and GG918, in our experiments. Conversely, these two specific P-gp inhibitors inhibited only 50% of transepithelial transport when [3H]vincristine was used as substrate. After Caco-2 cells were treated with 100 IU mL−1 (6.1 ng mL−1) IL2 for 24 h, a significant diminution (21%) of P-gp transporter function was observed with rhodamine-123 substrate. This effect was also confirmed after 48 and 72 h of exposure to IL2. However, for higher concentrations of IL2 (1000 and 5000 IU mL−1), diminution of P-gp function only occurred after a longer treatment period (48 h and more). The inhibitory effect of IL2 on P-gp activity was found to be independent of tight junction function as demonstrated by constant transepithelial electrical resistance (TEER) measurements for all experimental conditions encountered in this study (time and concentration of IL2 exposure). Furthermore, the MDR1 mRNA level was found to be strongly repressed in Caco-2 cells exposed with 1000 IU mL−1 IL2 for 72 h while the amount of MRP1 mRNA remained unchanged. In conclusion, acute incubation of Caco-2 cells with IL2 induced a decrease of P-gp transporter expression and activity.
Tachykinin-independent activity of capsaicin on in-vitro lamb detrusor
Authors: Tucci Paolo , Evandri Maria Grazia , Bolle Paola
Published: September 2002

The capsicum alkaloid capsaicin is an afferent fibre exciter. In the vesical bladder, capsaicin acts by releasing peptides stored in afferent fibres. The aim of this work was to verify the activity of capsaicin on in-vitro lamb urinary bladder and to ascertain whether this alkaloid evokes peptide release. Capsaicin relaxed about 80 % of the lamb detrusor muscle preparations tested and contracted about 20%. Whereas neurokinin A and substance P antagonists, administered alone or together, left the contractile responses to capsaicin unchanged, atropine and tetrodotoxin totally inhibited contraction. Ruthenium red and indometacin abolished contractions and relaxation. The substance P and neurokinin A antagonists and the NO-synthesis inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) left relaxation unchanged; conversely, the calcitonin gene-related peptide antagonist αh-CGRP (8–37) abolished this response. These results suggest that capsaicin relaxes lamb detrusor muscle not through tachykinins but by releasing CGRP from afferent fibres. Our observation that indometacin blocks the capsaicin response in in-vitro lamb urinary bladder also suggests a role of prostanoids.
Causative agent of vascular pain among photodegradation products of dacarbazine
Authors: Asahi Mariko , Matsushita Ryo , Kawahara Masami , Ishida Tomoyuki , Emoto Chie , Suzuki Nagao , Kataoka Osamu , Mukai Chisato , Hanaoka Miyoji , Ishizaki Junko , Yokogawa Koichi , Miyamoto Ken'ichi
Published: September 2002

The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo) imidazolium-5-olate and 2-azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo-IC clearly induced pain reaction in mice in a dose-dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL−1. While diclofenac sodium significantly reduced acetic-acid-induced pain reaction in mice, it did not influence those induced by Diazo-IC. This result suggests that the mechanism of Diazo-IC-induced pain is different from that of acetic-acid-induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration-dependent manner, but there was no difference between the activity of dacarbazine and its photo-exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo-IC generated by photodegradation of dacarbazine solution causes the side-effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo-IC is an intermediate in the formation of the reddish product, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo) imidazolium-5-olate. Drip infusion preparations of dacarbazine should be shielded from light.
AT-1015, a newly synthesized 5-HT2 receptor antagonist, dissociates slowly from the 5-HT2 receptor sites in rabbit cerebral cortex membrane
Authors: Rashid Mamunur , Watanabe Masatomo , Nakazawa Mikio , Nagatomo Takafumi
Published: September 2002

The purpose of this study was to investigate the association and dissociation kinetics of [3H]AT-1015 from 5-HT2 receptors in rabbit cerebral cortex membranes using a radioligand binding assay method and to make a comparison with those of [3H]ketanserin binding. Scatchard analysis of [3H]AT-1015 binding in rabbit cerebral cortex membranes indicated the existence of a single class of binding sites (dissociation constant, Kd = 2.18 nm). The specific binding of [3H]AT-1015 increased slowly with time and the association rate constant of [3H]AT-1015 binding (k1 = 0.1229 min−1 nm−1) was two times slower than that of [3H]ketanserin binding (k1 = 0.2451 min−1 nm−1). The dissociation rate constant of [3H]AT-1015 binding (t1/2 = 37.03 min) was six times slower than that of [3H]ketanserin binding (t1/2 = 6.29 min), when the addition of excess unlabelled ligands were AT-1015 and ketanserin, respectively. The dissociation rate constant of [3H]AT-1015 was slowed to a greater degree (t1/2 = 163.40 min and t1/2 = 198.12 min) by the addition of ketanserin and sarpogrelate as excess unlabelled ligands than was that of [3H]ketanserin (t1/2. = 17.76 min and t1/2. = 18.45 min) by the addition of AT-1015 and sarpogrelate as an excess unlabelled ligand, respectively. These findings on the dissociation kinetics of [3H]AT-1015 have confirmed and supported previously reported evidence of the slower dissociation of AT-1015 from 5-HT2 receptors.
Synthesis and properties of a naproxen polymeric prodrug
Authors: Wang L F , Chiang H N , Chen W B
Published: September 2002

A water-soluble polymeric prodrug containing a naproxen moiety was synthesized. The carboxylic groups of naproxen were condensed with the hydroxyl groups of 2-hydroxyethyl methacrylate (HEMA) to produce a drug-linked monomer, denoted HN. The polymeric prodrug was prepared by copolymerization of HN with methacrylic acid. The molar percentage of HN in the polymeric prodrug was 26 mol%, as determined by 1H NMR. To investigate the pertinence of this polymeric prodrug, the hydrolysis was studied in-vitro with or without esterase or lipase. The kinetics of enzymatic catalysis was calculated from a Lineweaver-Burk plot. The anti-inflammatory activity was evaluated using the carrageenan-induced oedema test. The polymeric prodrug released a major fraction of the free naproxen and a significant fraction of the hydroxyethyl ester derived-naproxen. The maximum hydrolysis rate Vmax, and the Michaelis constant Km were calculated to be 2.16 times 10−5 equiv. mol L−1 min−1 and 5.11 times 10−2 equiv. mol L−1. The maximum anti-inflammatory inhibition of free naproxen appeared at 2 h and quickly decreased thereafter. In contrast, the polymeric prodrug showed a maximum at around 2∼3 h and then slowly decreased. This indicates that the polymeric prodrug displays greater potency than free naproxen in the inhibition of acute inflammatory processes over long periods.
Topical anti-inflammatory activity of extracts and compounds from Thymus broussonettii
Authors: Ismaili H , Sosa S , Brkic D , Fkih-Tetouani S , Ilidrissi A , Touati D , Aquino R P , Tubaro A
Published: September 2002

The topical anti-inflammatory activity of four extracts from Thymus broussonetii Boiss (Labiatae) leaves, a herbal drug used in Moroccan traditional medicine, has been studied using the croton oil ear test in mice. A bioassay-oriented fractionation revealed that the pharmacological activity is mainly in the chloroform extract. Fractionation and analysis of this extract allowed the identification of ursolic acid and oleanolic acid as the main anti-inflammatory principles. Some flavonoids (luteolin, eriodictyol, thymonin) and glycosides (luteolin-7-O-glucoside, luteolin-3′-O-glucuronide, eriodictyol-7-O-glucoside) were also isolated from the methanol extract.
Discovery of novel inhibitors of inducible nitric oxide synthase
Authors: Kita Yasuhiro , Muramoto Masakazu , Fujikawa Akihiko , Yamazaki Takao , Notsu Yoshitada , Nishimura Shintaro
Published: September 2002

We have discovered three compounds, 5-chloro-1,3-dihydro-2H-benzimidazol-2-one (FR038251), 1,3(2H,4H)-isoquinolinedione (FR038470) and 5-chloro-2,4(1H,3H)-quinazolonedione (FR191863), which show inhibition of inducible nitric oxide synthase (iNOS). The iNOS inhibitory activity of the compounds was examined in comparison with that of aminoguanidine, a representative iNOS inhibitor. FR038251, FR038470 and FR191863 inhibited mouse iNOS, with IC50 values of 1.7, 8.8 and 1.9 μM, respectively, in an in-vitro enzyme assay. These inhibitory activities are comparable with that of aminoguanidine (IC50 = 2.1 μm). The three compounds had iNOS selectivity 38- and 8-times, >11- and 3-times, and 53- and 3-times compared with rat neuronal NOS and bovine endothelial NOS, respectively. These compounds concentration-dependently inhibited NO production in intact RAW264.7 mouse macrophages stimulated by lipopolysaccharide (LPS)/interferon-γ. At 100μM, FR038251, FR038470, FR191863 and aminoguanidine showed 81, 44, 54 and 78% inhibition of NO production, respectively. In an in-vivo experiment, FR038251, FR038470, FR191863 and aminoguanidine inhibited NO production in LPS-treated mice by 68, 40, 5 and 68% at an oral dose of 100 mg kg−1. The in-vivo inhibitory activity of FR038251 was almost identical to that of aminoguanidine. In conclusion, the three FR compounds are iNOS inhibitors with novel structures and may be candidate compounds leading to discovery of more iNOS inhibitors in the future.
Effect of the flavonoid galangin on urinary bladder rat contractility in-vitro
Authors: Capasso Raffaele , Tavares Ignatius A
Published: September 2002

Galangin is a flavanol with several biological activities. We have evaluated the effect of galangin on the contractile response elicited by electrical field stimulation (EFS) in the rat isolated urinary bladder. Galangin (10−8- 10−4m) produced a concentration-dependent inhibition of the EFS contractile response without modifying the contractions produced by exogenous acetylcholine (10−6 m). Blockade of adrenergic and cholinergic nerves with a combination of atropine (10−6 m), phentolamine (10−6 m) and propranolol (10−6 m) or blockade of tachykinin NK1 and NK2 receptors with SR140333 (10−7 m) and SR48968 (10−6 m) did not modify the inhibitory effect of galangin. However, verapamil (10−7 m) significantly reduced the inhibitory effect of galangin. It is concluded that the galangin inhibits EFS-induced contractions of the rat urinary bladder by acting on L-type calcium channels on presynaptic nerves.
1-Oxides and 1,1-Dioxides of Thiophenes and Selenophenes and Related Compounds
Authors: Nakayama Juzo
Published: September 2002

The first topic of the present article involves recent advances in the chemistry of thiophene 1-oxides. Next is the chemistry of the parent thiophene 1,1-dioxide, which is followed by that of congested thiophene 1,1-dioxides, where emphasis is placed on their syntheses and synthetic applications. The chemistry of 1-imino, 1,1-diimino, and 1-imino-1-oxo derivatives of thiophenes is then described. Finally, the newborn chemistry of selenophene 1-oxides and 1,1-dioxides is discussed.
Preparation of 2-Propanol Dehydrogenation Catalysts for Chemical Heat Pump System
Authors: Lee Hwaung , Song Hyung Keun , Na Byung-Ki
Published: September 2002

2-Propanol dehydrogenation catalysts were prepared using three types of preparation methods. The catalytic activities of these catalysts were compared through reaction experiments. A Ru catalyst, prepared by an incipient-wetness method followed by NaBH4 reduction, had the predominant reaction rate, and a Pt catalyst, prepared by an incipient-wetness method with H2 reduction at 400 °C, showed high activity. The Ru catalysts with high temperature reduction and Pt catalysts with NaBH4 reduction showed negligible reaction rates; Also, a catalyst supported on activated carbon had a better activity than that on alumina. The Ru on activated carbon was proper for a chemical heat-pump system because of higher activity and a lower reduction temperature than the Pt catalyst.
3,4′-Bis[bis(t-butyl- and methoxy-phenyl)amino]stilbene Bis(cation radical)s and Their Electrochemical and Magnetic Properties
Authors: Michinobu Tsuyoshi , Tsuchida Eishun , Nishide Hiroyuki
Published: September 2002

3,4′-Bis[bis(p-t-butylphenyl)amino]stilbene 1a and 3,4′-bis[bis(p-methoxyphenyl)amino]stilbene 1b were synthesized. The oxidation of 1 was analyzed by electrochemical measurements, which revealed the reversible formation of the bis(cation radical) 2 via a two-electron transfer reaction. The chemical oxidation of 1 with NOBF4 also gave the bis(cation radical) 2; UV/vis and ESR spectroscopies supported aminium radical formation without any side reaction. Magnetization, magnetic susceptibility, and the ESR ΔMs = ±2 signal of the biradicals indicated triplet ground states with a large triplet-singlet energy gap.
Characteristics of MoO3 Reduced with H2 at the Different Flow Rates of H2
Authors: Matsuda Takeshi , Hirata Yasuyoshi , Uchijima Fumiko , Itoh Hidenobu , Takahashi Nobuo
Published: September 2002

MoO3 was treated with H2 at 623 K for 12 h. The degree of reduction and the specific surface area of H2-reduced MoO3 were dependent on the flow rate of H2 in the reduction process. MoO3 with a surface area of about 5 m2 g-1 was transformed to a porous MoOx with a surface area of 180 m2 g-1 after reduction at a flow rate of H2 larger than 600 ml min-1 g-1. The MoOx was found to be stable at 623 K, even in the presence of H2O vapor. A study of reduction with a mixture of H2 and H2O showed that the degree of reduction and the surface area decreased with increasing partial pressure of H2O in the reduction process. We conclude from these results that the reduction of MoO3 to porous MoOx with a large surface area was prohibited by the action of H2O produced by the reduction.
Structures and Photodimerizations of 1-Alkylthymine Crystals Obtained from N,N-Dimethylformamide
Authors: Mochizuki Eiko , Yasui Nobuyoshi , Kai Yasushi , Inaki Yoshiaki , Tohnai Norimitsu , Miyata Mikiji
Published: September 2002

Single crystals of 1-alkylthymine (carbon numbers of the alkyl chain were 8, 11, 12, 13, 14, and 16) were obtained from N,N-dimethylformamide (DMF) solution as plates, and the crystal structures were determined by X-ray crystal analysis. The terminal methyl group of the alkyl chain was found to approach to the double bond of the thymine base in the crystal. The thymine bases in these crystals did not give the photodimer by UV irradiation, while the crystals obtained from ethyl acetate and acetonitrile gave the photodimer as reported previously. The terminal methyl group of the alkyl chain was concluded to inhibit the rotation of the thymine bases in crystal, which made the crystal from DMF inactive for the photodimerization.
Thiamine as a Cationic Host in Anion Coordination Chemistry. Crystal Structures of Five Anion Salts of Thiamine Monophosphate
Authors: Hu Ning-Hai , Liu Wen , Aoki Katsuyuki
Published: September 2002

Five anion salts of thiamine monophosphate {(TMP), TMP+·Cl-·2H2O (1), TMP+·NO3-·2H2O (2), TMP+·ClO4-·2H2O (3), TMP+·ClO4-·H2O (4), and TMP2+·2CF3SO3- (5)} have been prepared and structurally characterized by X-ray diffraction in order to examine the host-guest-like anion binding in TMP compounds. In each salt, the TMP molecule adopts the usually observed F conformation and, as a cationic host, captures anionic or electronegative guests ( = A) through three kinds of anion-bridging interactions: C2-H…A…pyrimidinium-ring, N4′1-H…A…thiazolium-ring, and C6′-H…A…thiazolium-ring. Compared with the thiamine system, the TMP system displays more varieties of self-assembled and higher-ordered structures, due to an additional involvement of the phosphate group: a dimeric structure is formed through both `head-to-tail' and `tail-to-tail' hydrogen bonds in 1, where `head' and `tail' refer to the pyrimidinium ring and the phosphate group, respectively; a `head-to-head' hydrogen-bonded dimer forms in 2; each TMP molecule being linked to two other TMP molecules to form a `head-to-tail' cyclic dimer for each neighbor, thus creating an infinite columnar structure in 3; each TMP molecule is linked to two neighbors, to one in the `head-to-head' fashion and to the other in the `tail-to-tail' fashion, producing an infinite chain structure in 4; and an anion-bridged `head-to-tail' macrocycle, [TMP-A-]2, is formed and linked to two neighboring macrocycles in the `tail-to-tail' fashion to generate an infinite columnar structure in 5.
Molecular Design of Prostaglandin Probes in Brain Research: High, Specific Binding to a Novel Prostacyclin Receptor in the Central Nervous System
Authors: Suzuki Masaaki , Noyori Ryoji , Långström Bengt , Watanabe Yasuyoshi
Published: September 2002

Molecular design to develop a stable biochemical probe for a study of the role of prostacyclin (PGI2) in the brain led to the discovery of (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacylin (referred to as 15R-TIC), that selectively bind to a novel PGI2 receptor, IP2, expressed in the central nervous system (CNS). This artificial prostaglandin with the 15R configuration exhibits high binding affinity for the IP2 receptor in the thalamus (IC50 = 32 nM) and weak affinity for the peripheral-type PGI2 receptor, IP1, in the NTS (IC50 = 1.2 μM). The length of the ω side-chain and the position of the methyl substituent on the aromatic ring strongly influence the binding characteristics. The features of the IP2 receptor were elucidated by quantitative mapping, specificity studies, and Scatchard analysis, as well as by a study using knockout mice with a tritium-labeled 15R-TIC and related radioligands. In order to conduct in vivo PET studies, a rapid methylation reaction using methyl iodide and an excess amount of an aryltributylstannane has been developed. This has successfully been applied to the synthesis of short-lived 11C-incorporated PET tracers, 15R-[11C]TIC and its methyl ester. The PET experiments accomplished the imaging of the IP2 receptor in the brain of living rhesus monkeys through intravenous administration. The elimination of the C(15) chirality results in 15-deoxy-TIC with ten-fold higher affinity and selectivity for the IP2 receptor than original 15R-TIC. Neither 15R-TIC nor 15-deoxy-TIC inhibit platelets aggregation, up to 400 nM, while PGI2 derivatives which bind with the IP1 receptor show a very potent inhibitory effect at a several nM level. Notably, these artificial CNS-specific PGI2 ligands, like the unstable natural PGI2 itself, prevent the apoptotic cell death of hippocampal neurons induced under high (50%) oxygen atmosphere and by xanthine and xanthine oxidase or serum deprivation. The difference in the binding potency between 15R-TIC and 15-deoxy-TIC for the IP2 receptor correlates well with the extent of the prevention of the neuronal cell death (IC50 values of 300 and 30 nM, respectively, under high oxygen atmosphere). 15R-TIC protects CA1 pyramidal neurons against ischemic damage in gerbils. Thus the designed TICs have neuronal survival-promoting activity both in vitro and in vivo, providing the possibility as a new type of chemotherapeutic agents for applications in neurodegeneration.
Effect of the Chain Length of Carboxylic Acids and Alcohols on the Extraction of Copper(II) with the Acids Using Alcohols as Solvents
Authors: Naito Tetsuyoshi , Yamada Hiromichi , Wada Hiroko
Published: September 2002

The solvent extraction of copper(II) with aliphatic carboxylic acids (CH3(CH2)nCOOH : n = 2—7) in alcohols (CH3(CH2)nOH : n = 4—7) was carried out at 25 °C and an aqueous ionic strength of 0.1 mol dm-3 (NaClO4). Each extraction equilibrium for these systems was determined in detail by a slope analysis and a curve-fitting method. In all of the extraction systems, except for butanoic acid ones, copper(II) carboxylates were found to be extracted as monomeric and dimeric species: CuA2, Cu2A4, and Cu2A4(HA)2. The dimerization and the adduct formation constants of copper(II) carboxylates in the organic phase were estimated. The dimerization and the adduct formation constants in the organic phase were found to be dependent on the chain length of the acids and alcohols, although the extraction constant of CuA2 were found to be independent of their chain length.
Lewis Acid-Catalyzed Hydrometalation and Carbometalation of Unactivated Alkynes
Authors: Asao Naoki , Yamamoto Yoshinori
Published: September 2002

Hydrosilylation, hydrostannation, carbosilylation, and carbostannation of unactivated alkynes with organosilanes, or organostannanes proceed effectively in the presence of catalytic amounts of Lewis acids to produce the corresponding vinylsilyl or vinylstannyl compounds in a highly regio- and stereoselective way. Although it is well known that transition metal catalyzed hydrometalations and carbometalations, in general, proceed in a cis-manner, the Lewis acid-catalyzed reactions proceed in a trans-manner exclusively. The coordination of a triple bond to Lewis acids is proposed as a key step for the Lewis acid catalyzed reactions.
Studies of Gel Structure and Thermal Deswelling on Poly(N-isopropylacrylamide) Gel Treated by Freeze-Drying
Authors: Kato Norihiro , Hasegawa Hiroto , Takahashi Fujio
Published: September 2002

Fast-responsive deswelling of poly(N-isopropylacrylamide) gel after a freeze-dry (FD) treatment was investigated by means of SEM images and a kinetic method using a N-isopropylacrylamide (NIPAAm) monomer from the viewpoint of the mesoscopic structure comprising a partitioned polymer-network.

It was deduced from SEM images that an elastic frame comprising a partitioned polymer-network is formed by a hydrophobic interaction between polymer chains in the FD-treated gel. Fast-deswelling of the FD-treated gel results from the elasticity of a partitioned polymer-network caused water to release. The kinetic parameters on deswelling of both the conventional gel and the FD-treated gel were determined in the presence of an NIPAAm monomer. This monomer in solution is considered to play two directly-opposed roles in making a skin on the surface of the conventional gel: One is for disturbing the formation of hydrogen bonding between amide groups in the polymer; the other is for accelerating the separation of hydrated water from isopropyl groups in the polymer. Cracking the surface of a conventional gel was investigated in connection with the monomer.
Complex Formation of Perfumes with Cationic Surfactants and the Enhanced Thermal Stability
Authors: Iimura Nahoko , Ohashi Yuji , Hirata Hirotaka
Published: September 2002

Seven crystalline molecular complexes were formed between perfumes such as guaiacol, 2-methylindole, and skatole and cationic surfactants such as hexadecyl-, tetradecyl-, dodecyl-, and decyltrimethylammonium bromide from an aqueous or methanol solution at low temperatures (< 10 °C). The crystal structures were determined by X-rays. The structures are very similar to each other, that is, the perfume molecules are packed in the layers of the alkyl chains of the surfactant molecules. Those packings are substantially the same as the common packing pattern observed in complexes between the surfactants and the aromatic compounds. The thermal analysis showed that the volatilization temperatures of the perfumes increased significantly when the perfumes are packed in the complex crystals. Moreover, the molar loss ratio of the perfume with increasing the temperature decreased with increasing the length of the alkyl chain of the surfactant. This suggests that thermal stability of the perfumes can be controlled by forming the complexes with the surfactants containing different alkyl chains.
Hydrogen-Bonded Structure in Concentrated Aqueous Phosphoric Acid Solutions
Authors: Kameda Yasuo , Sugawara Kentaro , Hosaka Takayoshi , Usuki Takeshi , Uemura Osamu
Published: September 2002

Polarized Raman scattering, X-ray, and time-of-flight (TOF) neutron-diffraction measurements were carried out for highly concentrated aqueous phosphoric acid solutions, in order to deduce detailed structural information on both the PO4-intramolecular geometry and intermolecular hydrogen bonds in the solution. Isotropic Raman spectra observed for (H3PO4)x(H2O)1-x with x = 0.1—0.6 exhibited a single band assigned to the symmetrical stretching vibrational mode of the PO4 structural unit, which suggests that all P-O bonds in the unit are spectroscopically equivalent. The results of X-ray and neutron-diffraction measurements for the 53 mol% phosphoric acid solution indicated that the structure of the PO4 unit is a regular tetrahedron with a P-O bond-length of 1.540(3) Å. From a least-squares fit to the observed X-ray and neutron intermolecular interference terms, the nearest-neighbor intermolecular distances, reflecting intermolecular hydrogen-bonded interactions in the solution, were determined to be r(O…D) = 1.77(1) Å and r(O…O) = 2.73(2) Å, respectively, which are both ca. 0.1 Å shorter than those observed for pure liquid water. Therefore, it has been clarified that a strongly hydrogen-bonded network exists in such concentrated aqueous phosphoric acid solutions.
Salt Effect on Stability and Solvation Structure of Peptide: An Integral Equation Study
Authors: Imai Takashi , Kinoshita Masahiro , Hirata Fumio
Published: September 2002

Salt effects on the stability and on the solvation structure of a peptide in a variety of aqueous solutions of the alkali-halide ions are studied by means of the reference interaction site model (RISM) theory. The order of salt effect on the peptide stability is consistent with the experimental results; the order follows the Hofmeister series. The results are further analyzed in order to clarify the nature of the salt effect which determines the Hofmeister series and to find the reason why the Hofmeister series applies so generally to a variety of solutes in aqueous solutions. A heuristic model for explaining salt effects on the solvation structure of the peptide is proposed based on changes in the peptide-water pair correlation functions due to the ion perturbation.
IR Characterization of Mesoporous Tantalum Oxide, Ta-TMS-1
Authors: Kondo Junko N , Lu Lianhai , Takahara Yoshiko , Maruya Ken-ichi , Domen Kazunari , Igarashi Naoko , Tatsumi Takashi
Published: September 2002

By IR observation, Lewis acid sites of medium strength were found by CO adsorption on a mesoporous Ta-TMS-1 while no basic sites were detected by CO2 adsorption. Methyl migration of methoxy species and formation of methoxy species from adsorbed dimethyl ether were quantitatively demonstrated.
pH-Dependence of the Fractionation of Boron Isotopes with N-Methyl-D-Glucamine Resin in Aqueous Solution Systems
Authors: Sonoda Akinari , Makita Yoji , Ooi Kenta , Takagi Norio , Hirotsu Takahiro
Published: September 2002

We have found a unique pH dependence of the fractionation of boron isotopes with N-methyl-D-glucamine resin in aqueous solution systems. The fractionation is due to the adsorption of 10B isotopes from the solution phase to the resin phase. For pH values less than 7, the boron-isotope separation factors are 1.027, indicating that 10B isotopes are concentrated in the resin more selectively than 11B isotopes. On the other hand, for the pH values greater than 11, the factors are 0.998, revealing no fractionation of boron isotopes. In the intermediate pH range, the factors are decreased significantly with an increase in pH. This finding confirms that 10B is fractionated as boron complexes with a tetrahedral coordination geometry in resin phase more selectively than as those with a planar trigonal coordination geometry in solution phase, while 11B exhibits the opposite relation. This finding will provide a very important basis for separation of boron isotopes with novel chelating resins in aqueous solution systems.
Isomer Distribution and Stereoselectivity in Electron Transfer Reactions of [Co(dien)2]2+ with Anionic Cobalt(III) Complexes
Authors: Tatehata Akira , Yamada Shigeo , Muraida Akira
Published: September 2002

The product distribution of the three geometrical isomers and the stereoselectivity of the u-fac isomer in the oxidation of [Co(dien)2]2+ (dien = diethylenetriamine) by optically active anionic cobalt(III) complexes were significantly influenced by the geometrical arragement of the coordinated atoms in the oxidants, reflecting the differences in the stabilization of the precursor assemblies due to the hydrogen bonding interactions between the reactants. Solvent effects on the isomer proportions and the stereoselectivity were examined in water, methanol, ethanol, formamide, dimethylformamide, and dimethyl sulfoxide. The results are explained in terms of the differences in the degree of oxidant-solvent interactions depending on acceptor number of solvents.
Synthesis and Structural Characterization of Silver(I) and Gold(I) Complexes with 2-Mercaptonicotinic Acid (H2mna) and Triphenylphosphine Ligands, and Their Antimicrobial Activities. Crystal Structures of Monomeric, 3- and 4-Coordinate Silver(I) Complexes [Ag(Hmna)(PPh3)2] and [Ag(Hmna)(PPh3)3] in the Solid State
Authors: Nomiya Kenji , Noguchi Ryusuke , Shigeta Takaye , Kondoh Yoshihiro , Tsuda Kazuhiro , Ohsawa Katsunori , Chikaraishi-Kasuga Noriko , Oda Munehiro
Published: September 2002

Two types of silver(I)-triphenylphosphine complexes with 2-mercaptonicotinic acid (H2mna) were prepared as [Ag(Hmna)(PPh3)n] (1, n = 2; 2, n = 3); their crystal structures determined by single-crystal X-ray diffraction. These complexes were obtained from reactions of the precursor, [Ag(Hmna)]n, with less excess (3 equiv) and large excess (20 equiv) amounts of PPh3, respectively. Complex 1 was also obtained from a reaction among another precursor [AgCl(PPh3)3], H2mna and aqueous NaOH. The coordination geometry of 1 was a trigonal pyramid with an AgSP2 core; there was a weak interaction between the silver(I) center and the pyridine nitrogen atom, while that of 2 was a distorted tetrahedron with an AgSP3 core. In both 1 and 2, the carboxyl group was protonated and its oxygen atoms did not participate in the coordination. In contrast to the formation of 1 and 2, a related complex, [Ag(Hmba)(PPh3)3] 4 (H2mba = 2–mercaptobenzoic acid), has been obtained from a reaction of [Ag(Hmba)]n with a stoichiometric amount (3 equiv) of PPh3. On the other hand, the gold(I) complex, [Au(Hmna)(PPh3)] 3, with a 2-coordinate AuSP core, was prepared by a stoichiometric reaction among [AuCl(PPh3)], H2mna and aqueous NaOH. Complex 3 in the solid state showed a supramolecular array based on a repetition of hydrogen-bonding interactions between the carboxyl group and the pyridine nitrogen atom, also being contrasted to the related complex, [Au(Hmba)(PPh3)] 5, with a hydrogen-bonding dimer structure in the solid state. In CHCl3, both 1 and 2 were present as several equilibrium species due to a successive dissociation of PPh3 ligands, while 3 was present as an almost monomer. The antimicrobial activities in aqueous media of 1—5, evaluated by minimum inhibitory concentration (MIC), were also tested.
Preparation of Ammonium Polyphosphate Form II from the System of Ammonium Orthophosphate-Urea
Authors: Watanabe Makoto , Watanabe Masami , Narita Noriaki , Sakurai Makoto , Suzuki Hirokazu
Published: September 2002

Ammonium polyphosphate (APP) form II was prepared by heating of a mixture of ammonium orthophosphates (triammonium, diammonium, and monoammonium orthophosphates) and urea at 280 to 300 °C under wet ammonia, which was made by passing air through 3 to 5% aqueous ammonia. The following reaction process is proposed:

Ammonium orthophosphate → APP form I → Amorphous APP → APP form II.

The addition of APP form II shortened the preparation time significantly. A wider range of concentrations (1 to 8%) of aqueous ammonia was available to prepare APP form II. The average particle size of the obtained APP form II was larger than 5 μm.