A curve fitting program, MULTI (FILT), in which an algorithm of fast inverse Laplace transform is incorporated, was introduced into the area of drug disposition. The reliance of MULTI (FILT) was verified by the Monte Carlo simulation based on compartment models. MULTI (FILT) was applied to the analysis of the local dispositions of drugs through the liver, including the construction of new dispersion model, the effect of albumin in perfusate, and the effect of perfusion rate. The elimination in the lung and the enterohepatic circulation were also evaluated using MULTI (FILT) in a simple manner.
Ring formation and syntheses of natural products were carried out utilizing latent powers of polyfunctional groups. Thus two novel methodologies, an intramolecular double Michael reaction and a tandem intramolecular Michael-aldol reaction, have been developed. Atisirene (7), atisine (18), pentalenic acid (28), pentalenene (29), epilupinine (32), and tylophorine (36) were synthesized using the intramolecular double Michael reaction. Several frameworks of natural products, possessing polycyclic systems fused to cyclobutane, were constructed by the tandem intramolecular Michaelaldol reaction. Furthermore, various natural products, testosterone (67), androsterone (68), 3-oxosilphinene (72), Δ9(12)-capnellene (78), as well as 1β-methylcarbapenem antibiotic (96) were stereoselectively synthesized by means of the intramolecular Diels-Alder reaction or the intramolecular 1, 3-dipolar cycloaddition.
A Chinese herbal medicinal prescription, Inchinko-to, was studied for the inhibitory activity on adenosine 3', 5'-cyclic monophosphate (cAMP) phosphodiesterase (PDE). The inhibitory activity on cAMP PDE of the extract of each constituent from the crude drug and of several compounds isolated from the drug was studied. By changing the combination ratio of two kinds of the crude drugs from 1 : 1 to 1 : 5, the inhibitory activity on cAMP PDE was estimated and it was found to be highest at the ratio of 1 : 3 in Rhubarb and Gardenia fruit, and at 1 : 4 in Rhubarb and Capillaris buds. These were the same ratio which is now commonly used for Chinese herbal medicinal prescription in Japan. Similar results were obtained in the combination test of the components of the crude drug such as emodin, geniposide, capillarisin and dimethylesculetin. The effects of Inchinko-to and its prescription which lacks one of the constituents of the crude drugs on carbon tetrachloride inducing liver injury in mice were also studied. Among the four prescriptions the antihepatotoxic activities were observed in the prescriptions containing Capillaris buds. Correlation between the administrated content of dimethylesculetin and antihepatotoxic activity was not recognized.
FUT-187 (I), 6-amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, is a new synthesized proteinase inhibitor. Decomposition kinetics and photoreactivity of I in aqueous solution were studied. In aqueous solution, I was hydrolyzed to its moieties, [4-(4, 5-dihydro-1H-imidazol-2-yl)amino] benzoic acid (IABA) and 6-amidino-2-naphthol (AN). The hydrolysis followed a pseudo-first order reaction. I was stable under acidic condition between pH 2 and pH 3 and decomposed by irradiation from xenon light to form IABA, AN and compound II. The structure of II was studied by nuclear magnetic resonance, infrared, mass and ultraviolet spectra and identification tests. It was shown that II was 6-amidino-2-hydroxy-1-naphthyl[4-(4, 5-dihydro-1H-imidazol-2-yl)amino]-phenyl ketone, benzophenone derivative, produced by photorearrangement reaction of I.
We applied the limulus amebocyte lysate (LAL) test to the detection of bacterial endotoxins in therapeutic human plasma protein fraction (PPF) and compared the LAL-test with the rabbit pyrogen test. Two endotoxin-specific LAL-reagents were used for the colorimetric method and turbidimetric kinetic method. The amounts of added endotoxin to the PPF were correctly estimated by either method. The results of four independent assays for the 53 samples of PPF corresponded well with each other (correlation coefficient : 0.851-0.959, regression coefficient : 0.898-1.151). The amounts of endotoxin in the PPF estimated by the LAL-test significantly correlated with the rise of body temperature in rabbits (correlation coefficient : 0.547-0.642, and 0.911-0.934 for the endotoxin added samples). These results suggest that the LAL-test could be used as an alternative method for the rabbit pyrogen test to PPF.
The amount of peroxide lipid in vivo in the early stage of the experimental model of myocardial infarction in a rat induced by the administration of isoproterenol (Isp) was measured as the value of malonic dialdehyde (MDA). The model of myocardial infarction was made by giving 75 mg/kg of Isp to the rat weighing 270±10 g. After the administration of Isp, the amounts of lipid in the serum and in the myocardial tissue were measured, and a blood chemistry test (glutamic oxaloacetic dehydrogenase, glutamic pyruvic transaminase, lactate dehydrogenase, free fatty acid, creatine kinase) was simultaneously carried out on the serum. The value of the amount of peroxide lipid in the serum began to elevate 3 h after the administration of Isp and reached a mximum value at 6 h. The value of the amount of peroxide lipid in the tissue began to elevate 30 min after the administration and reached a maximum at 3 h. Each blood chemistry disclosed the elevation 30 min after the administration. As mentioned above, the production of peroxide lipid in vivo on the myocardial disorder in the early stage after the administration of Isp and the biochemical changes showed a significant correlation. From these results it is suggested that the myocardial disorder induced by the administration of Isp has already developed at 30 min after the administration.
Isomers of ursodeoxycholic acid, 3β, 7α- and 3β, 7β-dihydroxy-5β-cholan-24-oic acids (3β7αU and 3β7βU) crystallize in the orthorhombic space group P212121 containing one molecule and in the monoclinic group P21 containing two independent molecules in an asymmetric unit. The cell dimensions are a=28.032(17), b=9.973(5), c=8.049(6)Å for 3β7αU, and a=11.771(8), b=27.999(12), c=6.637(2)Å, β=90.78(6)° for 3β7βU, respectively. Both structures were solved by the direct method and refined to the residual values of 0.065 (3β7αU) and 0.059 (3β7βU). The conformations of the D rings of each molecule are different from each other : 3β7αU intermediate, 3β7βU (A and B) half-chair form. In the crystal, 3β7αU molecules are connected by a hydrogen bond extended nearly parallel to the bc plane and 3β7βU molecules are connected by the helical hydrogen bond system or by the zigzag one parallel to the ac plane.
Antimutagenic activities of hexane extracts obtained from the fruit extract (UE) and the Kernels (KE) of P. mume were examined. These extracts showed inhibitory activities to known mutagens, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, benzo[α]pyrene and aflatoxin B1 in the Ames assay using Salmonella typhimurium TA100 and TA98 strains. The UE and KE fractions were then separated by silicic acid column chromatography with a stepwise elution method using ether-hexane. The location of the active substances in the fractions was also determined by thin-layer chromatography. Consequently, it was found that the effective substances for the desmutagenicity were fatty acids, and identified by gas liquid chromatography, mainly as oleic acid, linoleic acid and linolenic acid in UE, and mainly as oleic acid and linoleic acid in KE, respectively.
Several 1-alkoxy-2, 3-dichloro-4-hydroxynaphthalene derivatives were prepared. These compounds were oxidized by hydrogen peroxide in the presence of a peroxidase to give 2, 3-dichloro-1, 4-naphthoquinone, which then reacted with various alkyl benzoylacetates to develop blue coloration with absorption maximum at >600 nm. The color development reaction can be applied to the determination of appropriate serum constituents such as cholesterol.