Bicarbonate secretion from the surface epithelial cells in the duodenum is an active process depending on tissue metabolism and blood flow, and regulated by humoral and neuronal factors as well as endogenous prostaglandins (PGs). The duodenal mucosa has been also able to respond luminal acid by a significant rise in alkaline secretion, mediated mainly by PGs, and the impairment of this process is involved in the pathogenic mechanism of various duodenal ulcer models. The mechanism of mucosal protection by HCO3- secretion is two ways : one is neutralization of luminal acid, and the other the establishment of pH gradient in the mucus gel with the aid of the physicochemical property of mucus. Although the majority of H+ is neutralized by secreted HCO3- in the lumen and mucus gel, the ultimate mucosal protection is ensured by removal of back-diffused H+ through intramucosal neutralization with HCO3- and translocation by blood flow. Thus, HCO3- secretion in collaboration with mucus plays an important role as the first line of defense (pre-epithelial barrier) in the duodenal mucosal protection.
A number of 2-substituted 4, 5-diphenylthiazoles were synthesized by the nucleophilic substitution of 2-methylsulfonyl-4, 5-diphenylthiazole with various sodium alkoxides, amines, and carbanions of active methylene compounds. 2-Methylsulfonyl-4, 5-diphenylthiazole was obtained by the potassium permanganate oxidation of 2-methylthio-4, 5-diphenylthiazole in the presence of a phase-transfer catalyst. 2-Ethoxy-4, 5-bis (4-methoxyphenyl) thiazole was prepared in a similar manner. 2-Ethynyl-4, 5-diphenylthiazoles were synthesized by the palladium catalyst cross-coupling reaction of 2-iodo-4, 5-diphenylthiazole with monosubstituted acetylenes. These compounds were tested for inhibitory activity against blood platelet aggregation in vitro. Among them, 2-alkoxy-, and 2-(4-methylpiperazin-1-yl)-4, 5-diphenylthiazole were found to have potent inhibitory activity.
Debenzylating enzyme catalyzes the hydrolysis of cetraxate benzyl ester hydrochloride (2) into cetraxate hydrochloride (1, antiulcer agent). Screening and distribution of the debenzylating microorganisms were undertaken to obtain microorganisms with superior debenzylating activities. Many microorganisms including yeast, bacteria, actinomycetes and fungi were found to have the ability of debenzylating 2. The order of the strength of the debenzylating activity toward 2 is fungi>bacteria>actinomycetes>yeast, and that of the hydrolyzing activity toward phenyl ester portion of 2 is actinomycetes>yeast>bacteria>fungi, on the whole. Fungi have the characteristics of secreting the debenzylating enzyme. It was suggested that Aspergillus sp. was one of the most useful microorganisms for the industrial enzymatic preparation of 1 from 2.
The transporting properties of benzoic acid (BA) and its derivatives such as hippuric acid (HPA), p-aminohippuric acid (AHPA), N-benzoyl-β-alanine (NBA), p-amino-N-benzoyl-β-alanine (ANBA), N-benzoyl-6-aminocaproic acid (NBC), p-amino-N-benzoyl-6-aminocaproic acid (ANBC), o-, m- or p-hydroxybenzoic acid (o-, m- or p-HBA) and α- or γ-resorcylic acid (α- or γ-RA) through erythrocyte membranes were examined in two aspects of the inward direction from a drug-containing medium into the erythrocyte and the outward direction from the drug-containing erythrocyte to the drug-free medium. The significant difference in the rate of transport was observed between both directions. The introduction of a few methylene groups into the amino acid moieties of BA derivatives was slower in the rate of transport than that of more methylene groups. The rate of transport was slowed down by the introduction of amino group at p-position : NBC>NBA>HPA»ANBC>ANBA>AHPA. The rate of transport in these drugs was correlated with the changes in partition coefficients. The same correlation was also observed in the drugs to which hydroxyl groups were introduced except α- or γ-RA. This transport of α- or γ-RA suggested the participation of the band 3 anion transporter protein.
The interaction between bromhexine HCl and polyethylene containers was studied in solutions and in tablet packaging systems. Various bromhexine HCl aqueous solutions of different pHs were stored in polyethylene containers at 25°C. The remaining amount of bromhexine HCl was determined by high performance liquid chromatography. It was observed that the transition of bromhexine HCl to polyethylene was inhibited by the addition of some surfactants into the solution, and by lowering the solution pH. In the solid dosage forms, influences of the additives were also studied. It was observed that the decrease of the content of bromhexine HCl in the solid dosage form was inhibited by the addition of acids (citric acid, tartaric acid) and surfuctant (sodium dodecyl sulfate) and accelerated by the addition of sodium bicarbonate, similarly to those in solutions. The results indicated that the transition to polyethylene films was influenced by the molecular state of bromhexine HCl.
2-Ethyl-11b-methyl-2, 3, 7, 11b-tetrahydrooxazolo [3, 2-d] [1, 4] benzodiazepin-6 (5H)-one (Ie), its 2-phenyl derivative (If), and 1, 3-dihydro-5-methyl-2H-1, 4-benzodiazepin-2-one (III) were synthesized to elucidate the contribution of the iminium structure (II) to the proton exchange reaction of 11b-methylbenzodiazepinooxazoles. The 11b-methyl protons of Ie and If and the 5-methyl protons of III were exchanged with deuterium in methanol-d4 solution at 23°C. The exchange rates were accelerated in the presence of trifluoroacetic acid-d1. Methanol solutions of Ie, If, and III had fluorescence due to such iminium structures as II and III·H+ of these compounds, and the fluorescence was not observed in the original (oxazolidine ring-closed) structures of I and III. Percentages of iminium form in methanol solution were estimated by using fluorescence intensity. There found a relationship between the magnitude of the exchange rates and the fluorescence intensity. These results indicate that benzodiazepinooxazoles (including Ie and If) have the iminium form to some extent in the solution and diastereoisomerization of oxazolam occurs via a similar iminium intermediate.
It was reported that Paeoniae Radix extracts (S) depressed the contraction induced by electrical stimulation on the isolated guinea pig ileum. In the present study, the mechanisms of the inhibitory action of S on the contraction of guinea pig ileum were investigated. Theophylline and phentolamine are respective antagonists of adenosine and norepinephrine, decreased the inhibitory action by S on the contraction of guinea pig ileum about 50%. Thus these data suggest that some unknown substances with adrenergic and adenosine like actions may be contained in S. Furthermore the possibility of other inhibitors in S was suggested.
The selective toxicity was often shown by experiments with in vitro screening test in human cancer cell (JTC-26) and human normal embroyonic cell (HE-1) on the crude extract of crude drugs. The active fractions with selective toxicity were obtained by column chromatography. However, the selective toxicity disappeared in the simple constituent in which the activity remained. The selective toxicity of crude drugs was presumed to appeare with the complex constituents.
This paper describes the preparation of 7-dimethylaminocoumarin-3-isocyanate (MACI) having 7-dimethylaminocoumarin as a high sensitive fluorophore together with an isocyanate group as a reacting moiety and a preliminary investigation as a precolumn flourescence derivatization reagent for alcohols in high performance liquid chromatography (HPLC). Alcohols were derivatized quantitatively into the corresponding fluorescent urethanes by treating with MACI at 80°C for 10 min. The derivatives were subjected to HPLC on an Inertsil ODS (250×4.6 mm i.d., 5 μm) column with acetonitrile-ethanol-water (50 : 49 : 1) as mobile phase and monitored with an excitation wavelength of 382 nm and an emission wavelength of 479 nm. The detection limit of cholestanol was 10 fmol for an injection volume of 10 μl.
The effect of a single or multiple administration of sizofiran (SPG), an anti-tumor polysaccharide, on a hepatic drug-metabolizing enzyme system was studied in rats. When SPG was given intravenously at a single dose of 0.5 or 10 mg/kg, no alteration was observed in activities of aminopyrine (AP) N-demethylase and aniline hydroxylase, and in cytochrome P-450 (P-450) content in the livers of rats 48 h after dosing. However, only AP demethylase activity decreased by 34% after the administration of 200 mg/kg. Similarly, no change in the hepatic enzyme activities and P-450 content was observed for up to 180 d after a single dose of 10 mg/kg. Subcutaneous treatment of animals with either 10 or 40 mg/kg dose for 3 and 6 months resulted in no alteration in the enzyme activities and P-450 content. These results may indicate that the therapeutically effective dose of SPG has no effect on a hepatic drug-metabolizing enzyme system in rats.