Showing papers in "Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan in 1996"
TL;DR: The antihypertensive effect of tea-leaf saponin was examined in spontaneously hypertensive rats (SHR) and showed a long-lasting hypotensive effect and this effect was as potent as that of enalapril maleate at the dose of 3 mg/kg, p. o.o.
Abstract: The antihypertensive effect of tea-leaf saponin (the saponin mixture isolated from leaves of Camellia sinensis var sinensis) was examined in spontaneously hypertensive rats (SHR) Tea-leaf saponin reduced a time-dependent increase in blood pressure dose-dependently when it was administered orally to young SHR (7 weeks old) for 5 d Oral administration of tea-leaf saponin to elder SHR (15 weeks old) for 5 d decreased the mean blood pressure by 292 mmHg at the dose of 100mg/kg compared to the control group Single administration of tea-leaf saponin at 50mg/kg, po showed a long-lasting hypotensive effect and this effect was as potent as that of enalapril maleate at the dose of 3 mg/kg, po Tea-leaf saponin inhibited angiotensin I-induced contraction of the isolated guinea pig ileum in a dose dependent manner but little depressed angiotensin II-induced contraction On the other hand, in in vitro experiment using a synthetic peptide as a substrate, tea-leaf saponin showed almost no inhibitory activity against the angiotensin I converting enzyme (ACE) (IC50 > 10 mg/ml)
55 citations
TL;DR: It was found that tea-leaf saponin antagonized the action of leukotrien D4, one of the chemical mediators of inflammatory reactions, and showed relatively high antimicrobial activity against pathogenic dermal fungi.
Abstract: Antimicrobial and anti-inflammatory actions of tea-leaf saponin, which was a mixture of saponin separated from leaves of Camellia sinensis var. sinensis, were investigated. Tea-leaf saponin showed relatively high antimicrobial activity against pathogenic dermal fungi and its MIC value for Microsporum audouinii was 10 microgam/ml. On the other hand, tea-leaf saponin inhibited rat paw edema induced by carrageenin in a dose dependent manner. Activation of hyaluronidase, one of the enzymes involved in inflammatory reactions, was inhibited by tea-leaf saponin. It was also found that tea-leaf saponin antagonized the action of leukotrien D4, one of the chemical mediators of inflammatory reactions. Any symptom of toxic reaction was not observed when tea-leaf saponin was administered orally to mice at a dose of 2000 mg/kg.
48 citations
TL;DR: An ethanol extract of "Kijitsu" (Aurantii Fructus Immaturus, Citrus aurantium L.) collected in China was assessed for the antitumor activity using murine leukemia P388 in vivo and in vitro, and the extract was found to be active by the anti-tumor bioassay.
Abstract: An ethanol extract of "Kijitsu" (Aurantii Fructus Immaturus, Citrus aurantium L.) collected in China was assessed for the antitumor activity using murine leukemia P388 in vivo, and the extract was found to be active by the antitumor bioassay in vivo and in vitro. The extract was separated into a petroleum ether-soluble fraction and an ethyl acetate-soluble fraction. Fractionation was carried out using an index of cell-growth inhibitory activity against mouse leukemia L1210 cells to isolate antitumor active substances or compounds. The active compounds were purified employing silica gel column chromatography and HPLC. The antitumor effect of the isolated active compounds was studied. Five compounds, auraptene, marmin, tangeretin, nobiretin and 5-[(6',7'-dihydroxy-3',7'-dimethyl-2-octenyl)oxy]psoralen were isolated from Citrus aurantium L. Though they are all known compounds, 5-(6',7'-dihydroxy-3',7-dimethyl-2-octenyl)oxy-psoralen from this plants was first isolated. These compounds showed a cell-growth inhibitory effect against L1210 and K562 in vitro.
27 citations
TL;DR: Two biogenetically key compounds, acetylshengmanol xyloside and cimicifugoside H-1, were isolated and their chemical structures were elucidated by a group of scientists and described in this review.
Abstract: Cimicifugae Rhizoma have been used as an anti-inflammatory, analgesic and antipyretic remedy in the traditional Chinese medicines. Many 9,19-cyclolanostane glycosides have been isolated from Cimicifuga and related genera. Two biogenetically key compounds, acetylshengmanol xyloside and cimicifugoside H-1, were isolated and their chemical structures were elucidated by our group. The former compound seems to be the parent component of the other glycosides such as cimigenol xyloside from C. dahurica, C. iaponica and C. acerina. The latter glycoside, cimicifugoside H-1 was isolated together with cimicifugosides H-2-H-6 from commercial Cimicifugae Rhizoma. They are novel glycosides having a hydroxyl group ay C-11, and cimicifugosides H-3, H-4 and H-6 were trinor-triterpenol glycosides. Cimicifugoside H-1 changed into H-2, H-3 and H-4 under acidic or alkaline conditions. In this review, the structure elucidation of the above glycosides and their chemical transformation into other Cimicifuga glycosides are described.
23 citations
TL;DR: In this article, the relation between constituents and effects on hemorheology with processing of root of Rehmannia glutinosa was investigated, and the change of pharmacological activities with the processing was investigated.
Abstract: The relation between constituents and effects on hemorheology with processing of root of Rehmannia glutinosa was investigated. With the processing to dried or steamed root from crude root, the content of stachyose, which was the highest component in crude root, was decreased and the content of manninotriose was increased. Iridoid glycoside, catalpol, was gradually decreased with the processing. From these results, the content of carbohydrates and catalpol made it possible to estimate the quality of Rehmanniae Radix by processings. On the other hand, the change of pharmacological activities with the processing was investigated. The 50% ethanolic extract (BJ-ext) from steamed root of R. glutinosa increased erythrocyte deformability and erythrocyte ATP contents, inhibited polybrene-induced erythrocyte aggregation, and promoted an activity of fibrinolytic system. The extracts from crude or dried root had weak or no effect. The crude or dried root and steamed root of R. glutinosa showed the different pharmacological activities, and the quality of Rehamanniae Radix by processings may be estimated by investigation of correlation between the changes of constituents and improvable effects of hemorheology.
18 citations
TL;DR: In this article, the constituents of monoterpene in Paeoniae Radix were analyzed by means of high performance liquid chromatography (HPLC) using hitherto elucidated eight monotone glycosides.
Abstract: The constituents of monoterpene in Paeoniae Radix were analyzed by means of high performance liquid chromatography (HPLC) using hitherto elucidated eight monoterpene glycosides, paeoniflorin 1, oxypaeoniflorin 2, benzoylpaeoniflorin, 3, benzoyloxypaeoniflorin 4, galloylpaeniflorin 5, galloyloxypaeoniflorin 6, albiflorin 7 and lactiflorin 8 and a monoterpene paeoniflorigenone 9. In sixty seven kinds of Paeoniae Radix collected in Japan, China, and South and North Korea those monoterpene constituents 1-9 were found to exist in the amounts of ranging 0.12-9.61% 1, 0.06-10.8% 2, 0.02-0.79% 3, 0.24-0.47% 4, 0.25-2.53% 5, 0.05-2.86% 6, 0.09-2.76% 7, 0.35-0.64% 8 and 0.01-0.49% 9 respectively. In addition, these results obtained by the quantitative analysis were discussed from the viewpoint of the external figures and processing methods.
16 citations
TL;DR: The pathways by which cisplatin, one of most emetogenic drugs, induces emesis are proposed and scavengers of free radicals and antioxidants can be a new type of antiemetic drug.
Abstract: In this review, I have attempted to provide an overview of the pathways by which cytotoxic drugs induce emesis. The mechanisms of serotonin 5-HT3 antagonists and new antiemetics are also discussed. Old data especially from the experiments employing area postrema ablation must be re-evaluated because it is likely that the operation has damaged other important nucleus in the brain stem. Therefore, the concept of the chemoreceptor trigger zone and "vomiting center" proposed by Borison et al. in 1950s is questionable. Nausea and vomiting caused by cytotoxic drugs have been a serious problem in anti-cancer therapy and prompted lots of scientists to find the mechanism and to develop antiemetics. Effectiveness of 5-HT3 antagonists were shown in late 1980s, and now they are clinically available. I have investigated their mechanisms using Suncus murinus and proposed that the pathways by which cisplatin, one of most emetogenic drugs, induces emesis are as follows: 1) cisplatin is converted to an active metabolite(s), 2) the metabolite(s) somehow produces oxygen free radicals in the enterochromaffin cells, 3) the free radicals release serotonin, 4) the released serotonin stimulates 5-HT3 receptors located on the vagus afferents, 5) impulses are transmitted to the brain stem, or emetic pattern generator and initiate emetic reflex. Therefore, scavengers of free radicals and antioxidants can be a new type of antiemetic drug.
13 citations
TL;DR: In clinical studies, zonisamide exerted the efficacy against partial seizures and some generalized seizures that were comparable to that of carbamazepine and sodium valproate, respectively and was also effective in monotherapy.
Abstract: Zonisamide (1,2-benzisoxazole-3-methanesulfonamide, AD-810) is a broad spectrum antiepileptic drug which has been launched in Japan and South Korea. It lacks the ureide structure included in most of the existing antiepileptic drugs. Zonisamide was synthesized by the sulfonation and the successive amination of 1,2-benzisoxazole-3-acetic acid in a very poor yield. After several efforts to optimize the compound, zonisamide was selected based on the balance of the efficacy and safety. The yield was greatly improved by the development of new synthetic routes. Zonisamide suppressed maximal electroshock seizures in mice, rats, rabbits and dogs. Its therapeutic plasma concentration range between anticonvulsant and neurotoxic effects was much wider than that of the existing antiepileptic drugs. In electroencephalographic studies on animal models of epilepsy, zonisamide, like phenytoin and carbamazepine, restricted the spread or propagation of seizures and, like sodium valproate, it suppressed the epileptogenic focus activity. Zonisamide was effective in several kindling models. In clinical studies, zonisamide exerted the efficacy against partial seizures (simple, complex, secondarily generalized seizures) and some generalized seizures (tonic-clonic, tonic, atypical absence seizures) that were comparable to that of carbamazepine and sodium valproate, respectively. Zonisamide was also effective in monotherapy. The adverse effects related with zonisamide were mainly drowsiness, ataxia, loss of appetite and gastrointestinal symptoms. Serious adverse effects which may be life-threatening have not been reported.
12 citations
TL;DR: This article reviews pharmacochemical investigations of nine Indonesian medicinal plants, i.e. Pongamia pinnata (Papilionaceae), Fagara rhetza (Rutaceae), Calotropis gigantea (Asclepiadaceae), Beilschmiedia madang (Lauraceae), and Merremia mammosa (Convolvulaceae, which were selected among plant materials collected in those surveys.
Abstract: A series of scientific expeditions in Indonesia for collecting informations and materials concerning locally used medicinal plants and Javanese traditional medicine "jamu" have been carried out by us since 1985. This article reviews pharmacochemical investigations of nine Indonesian medicinal plants: i.e. Pongamia pinnata (Papilionaceae), Fagara rhetza (Rutaceae), Calotropis gigantea (Asclepiadaceae), Beilschmiedia madang (Lauraceae), Caesalpinia major (Fabaceae), Peronema canescens (Verbenaceae), Taxus sumatrana (Taxaceae), Alyxia reinwardtii (Apocynaceae), and Merremia mammosa (Convolvulaceae), which were selected among plant materials collected in those surveys.
12 citations
TL;DR: The results suggest that the inhibitory effects of the hybrid liposomes on the growth of HF cells should be related to the membrane fluidity.
Abstract: Remarkably high inhibitory effects of the hybrid liposomes composed of L-alpha-dimyristoyl-phosphatidylcholine (DMPC) and polyoxyethylenealkyl ether (C14(EO)n, n = 6-8 and C12(EO)n, n = 8-12)) on the growth of human lymphoma-human B-lymphocyte hybridoma (HF) cells in vitro were obtained. The hybrid liposomes composed of 90 mol% DMPC/10 mol% C14(EO)n (n = 6-8) or C12(EO)n (n = 8-12) were more fluid as compared with 90 mol% DMPC/10 mol% C14(EO)4 or C12(EO)n (n = 4, 23) hybrid liposomes on the basis of fluorescence polarization measurements. These results suggest that the inhibitory effects of the hybrid liposomes on the growth of HF cells should be related to the membrane fluidity. No toxicity to normal rats in vivo was observed in the experiment using 90 mol% DMPC/10 mol% C14(EO)7 or 90 mol% DMPC/10 mol% C12(EO)12 hybrid liposomes.
10 citations
TL;DR: As the results of antibacterial screening tests in vitro, quinoxaline 1,4-dioxides revealed strong activities against Bacteroides fragilis.
Abstract: Novel quinoxaline 1,4-dioxide derivatives were synthesized from benzofuroxans and the enolic form of 1,3-diketones or 3-oxoalkanoic esters or 3-oxoalkanamides or butanedioic esters catalyzed by silica gel or molecular sieves and their antibacterial activities were evaluated. As the results of antibacterial screening tests in vitro, quinoxaline 1,4-dioxides revealed strong activities against Bacteroides fragilis.
TL;DR: The novel research works in both low temperature plasma chemistry and solid state plasma chemistry were described, and various polymeric prodrugs by mechanochemical polymerization were synthesized and the nature of hydrolyses (drug release) was studied.
Abstract: In this review, our novel research works in both low temperature plasma chemistry and solid state plasma chemistry were described. As for low temperature plasma, the ESR study on plasma-induced radicals of several selected conventional polymers was shown including the detailed analyses of the radical structure and the mechanism by which the radicals were formed on typical degradable methacrylic polymers and cross-linkable polystyrene. One of the pharmaceutical applications of the plasma processing for drug delivery system (DDS) was also described, which includes the preparations of double-compressed tablet consisting of drugs as a core material and various types of polymers as a wall material followed by plasma-irradiation on such a tablet. As for solid state plasma, the detailed reaction mechanism of solid state mechanochemical polymerization was shown including the solid state single electron transfer and the special feature of the resulting polymers. The structural criteria for polymerizable monomer derived from the quantum chemical considerations were also established. Based on the above findings, we synthesized various polymeric prodrugs by mechanochemical polymerization and studied the nature of hydrolyses (drug release).
TL;DR: A simple and precise method was established for the simultaneous determination of evodiamine and rutaecarpine in oriental pharmaceutical decoctions containing Evodia Fruit using high-performance liquid chromatography with sodium dodecyl sulfate (SDS) as an ion-pair reagent.
Abstract: A simple and precise method was established for the simultaneous determination of evodiamine and rutaecarpine in oriental pharmaceutical decoctions containing Evodia Fruit using high-performance liquid chromatography with sodium dodecyl sulfate (SDS) as an ion-pair reagent. Evodiamine and rutaecarpine were eluted within 60 min without interference from co-existing components using an ODS column and a mixture of water-methanol-acetonitrile-SDS-phosphoric acid (600:330:70:5:0.01, v/v/v/w/v, pH 5.0) as a mobile phase.
TL;DR: Application of the developed methods was performed for the studies on the dynamic profile of fetal bile acids in developing fetus and neonates, and the clinical diagnosis of the hepatobiliary diseases of infants and congenital bile acid biosynthetic disorders, Zellweger syndrome, celebrotendinus xanthomatosis, 3-oxo-delta 4-steroid 5 beta-reductase deficiency and congenitals biliary atresia.
Abstract: The unusual bile acids hydroxylated at 1 beta-, 2 beta-, 4 beta-, 6 alpha- and 19-positions of cholic and chenodeoxycholic acids have been found from the meconium, neonatal bile, blood and urine, and amniotic fluid and pregnant urine by GC-MS analysis. These hydroxylated bile acids and their conjugates were synthesized as their references from the corresponding usual bile acids as starting materials, and the simultaneous and high performance analytical methods were developed by GC-MS, HPLC and enzyme immunoassay. The above mentioned unusual bile acids were identified and determined in significant amounts of the total bile acids in the biological fluids from neonates and pregnant women, but not from normal adults. We, therefore, proposed that they should be called as "fetal bile acids". Application of the developed methods was performed for the studies on the dynamic profile of fetal bile acids in developing fetus and neonates, and the clinical diagnosis of the hepatobiliary diseases of infants and congenital bile acid biosynthetic disorders, Zellweger syndrome, celebrotendinus xanthomatosis, 3-oxo-delta 4-steroid 5 beta-reductase deficiency and congenital biliary atresia. Analyses of steroidal hormones, equine estrogens and 18-hydroxycortisol were also described.
TL;DR: The strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations can be a formidable tool for the development of clinically applicable macromolescular drugs.
Abstract: With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.
TL;DR: Four flavonoid compounds, avicularin, hyperin, quercitrin, taxillusin, and three catechin compounds, showing a reddish purple color on the reaction with Ehrlich reagent, were isolated from leaves of Taxillus kaempferi and substantiate the stereochemical configurations of conformer, a and b in the detailed 1H-nuclear magnetic resonance (1H-NMR) spectrum.
Abstract: Four flavonoid compounds, avicularin (1), hyperin (2), quercitrin (3), taxillusin (4), were isolated from leaves of Taxillus kaempferi, and three catechin compounds, (+)-catechin (6), procyanidin B-1 (7), procyanidin B-3 (8), showing a reddish purple color on the reaction with Ehrlich reagent, were also isolated from the stems. Each of these seven isolated compounds were identified by comparing the spectral data with those of the references. Compound 8 was examined to substantiate the stereochemical configurations of conformer, a and b in the detailed 1H-nuclear magnetic resonance (1H-NMR) spectrum using the nuclear Overhauser effect (NOE) difference spectroscopy and spin decoupling experiment in the acetone-d6 solution.
TL;DR: The proposed method was successfully applied to the simultaneous determination of CP and MA, i.e., CPM analysis, in commercial cough and cold drugs which pharmaceutical forms were tablet, granule and syrups.
Abstract: A simple, rapid and convenient chromatographic method, which permits the simultaneous determination of chlorpheniramine (CP) and maleate (MA), recently developed by the authors was applied to the analysis of chlorpheniramine maleate (CPM) in cough and cold drugs. In this method, a Capcell Pak C8 column and an isocratic mobile phase containing 15% methanol, 50 mM KH2PO4 and 5mM tetra-n-butylammonium phosphate as an ion-pair reagent were used. By using the mobile phase adjusted to pH 3.0 with orthophosphoric acid, fumaric acid, MA, CP, acetaminophen (paracetamol), caffeine, and m- and p-hydroxybenzoic acid as candidates for an internal standard were eluted separately within 17 min. Detection was carried out with UV detector at 215 nm. Under the same conditions, five other antihistamines analogous to CPM were also separated. The calibration graphs for CP and MA showed good linearity in the range of 0.5-10 nmol (0.195-3.9 micrograms) per 20 microliters injection, respectively. The proposed method was successfully applied to the simultaneous determination of CP and MA, i.e., CPM analysis, in commercial cough and cold drugs which pharmaceutical forms were tablet, granule and syrups.
TL;DR: A simple and precise method was established for the simultaneous determination of five selected marker components in oriental pharmaceutical decoction "Heii-San" by means of high-performance liquid chromatography using tetra-n-amylammonium bromide (TAA) as an ion-pair reagent.
Abstract: A simple and precise method was established for the simultaneous determination of five selected marker components in oriental pharmaceutical decoction "Heii-San" by means of high-performance liquid chromatography using tetra-n-amylammonium bromide (TAA) as an ion-pair reagent. For the separation of these five components, such as hesperidin (1), 6-gingerol (2), honokiol (3), glycyrrhizin (4) and magnolol (5), an ODS column was used with multi-step gradient elution with 10 mM TAA (H3PO4, pH 4.0)-acetonitrile. The acetonitrile content linearly increased from 25 to 90%. This method was compared with other three methods, i.e. a water-acetonitrile method, a phosphate buffer method and an ion-suppression method. Five main components were eluted within 50 min without interference from co-existing components.
TL;DR: Enantioselective alkylations of the carbanion at the 2-position of the cyclic tautomer established a new route to optically pure alpha-substituted tryptophan derivatives such as 5-bromo-, 5-hydroxy, and 6-methoxy-tryptophans.
Abstract: A historical development of the chemistry of cyclic tautomer of tryptophan is reviewed. The cyclic tautomer of tryptophan, pyrrolo [2,3-b]indole-2-carboxylic acid, was prepared by dissolving N-methoxycarbonyltryptophan ester derivatives in 85% phosphoric acid or trifluoroacetic acid. The cyclic tautomer can be reverted to the indolic form with a dilute acid. The cyclic tautomer is an aniline derivative and the enamine reactivity of the indole ring in tryptophan is protected. The electrophilic substitution and oxidation of these cyclic tautomers opened a new method to prepare 5-substituted and/or 6-substituted tryptophan derivatives such as 5-bromo-, 5-hydroxy, and 6-methoxy-tryptophans. The formation and reactions of cyclic tautomers of diketopiperazines containing tryptophan and 3-indoleacetamide are also discussed. Some indole alkaloids having substituents at the benzene ring such as fumitremorgins, flustramine B, and eudistomines were synthesized by the use of these reactions. Furthermore, enantioselective alkylations of the carbanion at the 2-position of the cyclic tautomer established a new route to optically pure alpha-substituted tryptophans. The 2,3-dehydro derivative of the cyclic tautomer is an alpha, beta-unsaturated ester and was found to be a good precursor of optically pure beta-substituted tryptophans. The 3a-position of the cyclic tautomer is a benzylic position and subjected to radical reactions to give 3a-substituted-pyrroloindoles.
TL;DR: Novel 5-[3-[2-(3,4-dimethoxyphenyl)ethyl]aminopropionyl]-2,3, 4,5- tetrahydro-1, 5-benzothiazepine fumarate showed the most potent inhibitory action on the intracellular Ca2+ release.
Abstract: A series of 2,3,4,5-tetrahydro-1,5-benzothiazepine and related compounds were prepared, and the intracellular Ca2+ inhibitory effects were examined using methoxamine- or caffeine-induced contraction of isolated rabbit arteries. Structure-activity relationship studies of these compounds are discussed and the results suggest that novel 5-[3-[2-(3,4-dimethoxyphenyl)ethyl]aminopropionyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate (20d) showed the most potent inhibitory action on the intracellular Ca2+ release.
TL;DR: In vivo the pharmacokinetics of GA after oral administration of Kampo extracts in healthy volunteers are determined, and the conversion from GL to glycyrrhetic acid (GA) by beta-glucuronidase originated from E. coli occurred slowly.
Abstract: We investigated in vitro the properties of glycyrrhizin (GL), such as dissolution, absorption and resolution, using a Sho-Seiryu-To extract, a Sho-Saiko-To extract, both including a licorice root, and licorice extract. The dissolution of GL differed with the pH of the solvent. The absorption (partition coefficient) of GL decreased with an increase in pH, and increased in the presence of other active constituents, such as baicalin, baicalein, and ephedrine. In the case of the Sho-Saiko-To extract, the conversion from GL to glycyrrhetic acid (GA) by beta-glucuronidase originated from E. coli occurred slowly. It was also suppressed by adding baicalin. We determined in vivo the pharmacokinetics of GA after oral administration of Kampo extracts in healthy volunteers. In each Kampo extract, the time of administration had no influence on the mean maximum blood concentration (Cmax) and the area under the blood concentration-time curve (AUC). Tmax was delayed in the case of the administration after meal (p < 0.05).
TL;DR: Findings suggest the regulatory roles of cell surface receptors-coupled G proteins in signal transductions and cell functions.
Abstract: The elucidation for the mechanism of receptor-mediated signal transduction has been the aim of our extensive studies. Cyclic AMP, which was controlled by membrane adenylyl cyclase, was an intracellular signal (the first second messenger in cells proposed by Sutherland) given by hormones and neurotransmitters. The GTP-binding (G) proteins play an important role in communication between membrane receptors and the adenylyl cyclase catalytic unit. One (Gs) of the G proteins is involved in the activation, while the other (Gi) is involved in the inhibition of adenylyl cyclase. Islet-activating protein (IAP, pertussis toxin, PTX) catalyses the transfer of the ADP-ribose moiety of NAD to the alpha subunit of Gi, resulting in a complete loss of the Gi functions. In some cases, arachidonic acid (AA) regulates cell functions as a second messenger. AA serves as a precursor to a number of biologically active lipids including prostaglandins and leukotrienes. Activation of cell surface receptors of many cell types results in the release of AA from membrane phospholipids by phospholipase A2 (PLA2). A new family of PLA2 has been discovered in the cytosol of various cells. The activation of receptor-mediated AA release by cytosolic PLA2 was also regulated by PTX-sensitive G proteins. PTX treatment inhibited cell growth of fibroblasts by serum and growth factors. G proteins have been involved in receptor-receptor interactions in neuronal cells. These findings suggest the regulatory roles of cell surface receptors-coupled G proteins in signal transductions and cell functions.
TL;DR: The results suggest that SK-204 have an anti-thrombotic action, which is due to neither the inhibition of platelet aggregation nor coagulation, but probably due to the promotion of fibrinolysis and thrombolysis.
Abstract: Effects of the mixture (SK-204) consisting of dried shiitake mushroom (Lentinus edodes) treated with wet-heating and fructo-oligosaccharides (7:3) on the experimental models of pulmonary thrombosis induced by lactic acidosis in rats were evaluated. Chronic oral administration (10 weeks) of SK-204 significantly prevented the thrombus formation on this thrombosis model. However, decreases in the numbers of platelet and fibrinogen level by lactate were not changed by SK-204. These results suggest that SK-204 have an anti-thrombotic action, which is due to neither the inhibition of platelet aggregation nor coagulation, but probably due to the promotion of fibrinolysis and thrombolysis.
TL;DR: 2-Substituted malonamide derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity and 4-(3,4-dichlorophenylcarbamoyl)-N,N-dipentylglutaramic acid was selected as the most preferred compound.
Abstract: 2-Substituted malonamide derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity. Significant CCK-A receptor inhibitory activities were found in only three compounds (4g-i) which have carboxyl group. In order to study structure-activity relationships, carboxyethyl group was selected for 2-substituent and a number of N-substituted malonamides were prepared. After these compounds were tested for CCK-A receptor inhibitory activity, 4-(3,4-dichlorophenylcarbamoyl)-N,N-dipentylglutaramic acid (4h) was selected as the most preferred compound.
TL;DR: The studies on the syntheses and reactions of purines and their nucleosides, carried out by the present author's group for these 34 years, are reviewed with particular emphasis on the employed synthetic strategies and tactics.
Abstract: The studies on the syntheses and reactions of purines and their nucleosides, carried out by the present author's group for these 34 years, are reviewed with particular emphasis on the employed synthetic strategies and tactics. Among the studies included in this review are as follows: ring-opening and recyclization of the adenine ring utilizing an N(1)-alkoxy group; kinetic studies of the Dimroth rearrangement and related reactions in the adenine series; syntheses and reactions of new Nx,Ny-disubstituted adenines and of new Nx-substituted adenosines; syntheses, structure determinations, and structure-activity relationships of new natural cytokinins; syntheses and reactions of new marine 8-oxopurines; syntheses, reactions, and biological activities of the N(7)-oxides of guanine, hypoxanthine, adenine, 6-mercaptopurine, and 6-methylthiopurine.
TL;DR: In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole and a significant reversal of the in vivo antitumor activity of epirUBicin in mice bearing P388/DOX cells was produced.
Abstract: We have previously reported that dipyridamole increases the cytotoxicity of epirubicin and alters the cell cycle in doxorubicin-resistant (P388/DOX) cells, increasing the accumulation of G2/M phase by blocking the cell cycle. In cultured cells, dipyridamole increased dose-dependently the intracellular accumulation of epirubicin in the resistant cells. Simultaneous exposure of the resistant cells to epirubicin and 100 microM dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. Dipyridamole inhibited the enhanced efflux of epirubicin in doxorubicin-resistant cells. However, dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells. In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole. In addition, in vivo results also demonstrated that dipyridamole in combination with epirubicin produced a significant reversal of the in vivo antitumor activity of epirubicin in mice bearing P388/DOX cells. These data imply the enhancement effects of dipyridamole on the efficacy and toxicity of epirubicin.
TL;DR: The results indicate that these compounds are evolutional precursors of the C24 bile acids found in mammalian species and the mechanism of the conversion of cholesterol to the Bile acids in mammals is a recapitulation of the evolution of cholanoid molecules.
Abstract: Bile acids and bile alcohols are termed cholanoids. Biles of evolutionarily primtive vertebrates such as fishes, amphibians, and reptiles contain bile alcohols and higher bile acids in place of C24 bile acids in mammals. These higher cholanoids have the C24 bile acid type of nuclear structure and all or part of the side chain of cholesterol. The chemical structure, the natural distribution, and the biosynthetic pathways of bile alcohols and higher bile acids were studied. The results indicate that these compounds are evolutional precursors of the C24 bile acids found in mammalian species and the mechanism of the conversion of cholesterol to the C24 bile acids in mammals is a recapitulation of the evolution of cholanoid molecules.
TL;DR: Extensions of the "chiral lactim ether route" to the syntheses of the Ochrosia alkaloid (-)-ochropposinine, the Neisosperma alkaloids, and the Ophiorrhizine have unequivocally established the absolute stereochemistries of these three indolo[2,3-a]-quinolizidine alkaloidal types.
Abstract: Nineteen benzo[a]quinolizidine alkaloids (1-19) isolated so far from Alangium plants can be classified into four types (I-IV) according to their chemical structures. Studies on racemic and chiral syntheses of these I-IV-type alkaloids are reviewed with particular emphasis on the strategies and tactics for the syntheses employed by the author. It has been found that racemic syntheses of all of these types of alkaloids are possible through the "lactim ether route" or the "3-acetylpyridine route"; and chiral syntheses, through the "cincholoipon-incorporating route" or the "chiral lactim ether route". As a result of such total syntheses, the structures and absolute configurations of four II-type, two III-type, and two IV-type Alangium alkaloids have been established. Extensions of the "chiral lactim ether route" to the syntheses of the Ochrosia alkaloid (-)-ochropposinine [(-)-93g], the Neisosperma alkaloid (-)-ochromianine [(-)-97], and the Ophiorrhiza alkaloid (-)-ophiorrhizine [(-)-98] have unequivocally established the absolute stereochemistries of these three indolo[2,3-a]-quinolizidine alkaloids.
TL;DR: The physicochemical properties of the enantiomer and racemates of suplatast tosilate (ST) were investigated and it was suggested that ST was classified into a racemic compound crystal.
Abstract: The physicochemical properties of the enantiomer and racemates of suplatast tosilate (ST) were investigated by means of infrared spectroscopy, solid-state 13C CP/MAS NMR spectroscopy, thermal analysis, and X-ray diffraction analysis, and by measuring the solubility and hygroscopy. The infrared and NMR spectra and X-ray diffraction pattern of the enantiomer were distinctly different from those of the racemate. The melting point of the enantiomer was lower than that of the racemate by 5 degrees C, while the solubility of the enantiomer was 1.3 times higher than that of the racemate. The hygroscopic rate of the enantiomer was greater than that of the racemate. These results suggested that ST was classified into a racemic compound crystal. Furthermore, by comparing the relative peak intensity ratios on X-ray diffraction patterns of the crystals with various optical purities prepared by recrystallization, it was found that a mixture of racemic compound crystals and either of racemic mixture crystals or racemic solid solutions was obtained by recrystallization of ST in the content of 0 to 64%ee, while the recrystallization of ST in the content of more than 64%ee led to the formation of racemic mixture crystals or racemic solid solutions.