Estimation of blood concentration of drugs after topical application from in vitro skin permeation data. II. Approach by using diffusion model and compartment model.
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Biomedical subjects
Publications and source records attributed to Y Morimoto.
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The ultrasonographic characteristics of hepatocellular carcinomas (HCC) were investigated. Four typical features of HCCs, "mosaic internal echo pattern", "halo", "lateral shadow" and "posterior echo enhancement", were not recognized in minute HCCs smaller than 2 cm in diameter. These characteristics developed as the tumors grew. Only hypoechoic space-occupying lesions can be considered as small HCCs. In differentiating small HCCs from hypoechoic non-malignant space-occupying lesions in the cirrhotic liver, the ratios of short to long dimensions of the lesions seemed to be important since the ratios of HCCs were significantly larger than those of non-malignant lesions. The fact that 3 hyperechoic small HCCs could not be diagnosed even by celiac arteriography has suggested to us that ultrasonically guided biopsies should be performed in order to differentiate from small hemangiomas. Serum alpha-fetoprotein (AFP) levels of 1/3 of the patients with HCCs were below 100 ng/ml, indicating that it is impossible to detect small HCCs only by measuring serum AFP.
Intracellular pH was measured with single- or double-barreled liquid ion-exchanger microelectrodes in the bullfrog sartorius muscle perfused in vitro. A neutral carrier ligand was used for pH sensor of microelectrodes. Average slopes of the single-barreled microelectrodes were -56.4 +/- 1.34 mV/pH (n = 30) and the double-barreled -52.6 +/- 1.34 mV/pH (n = 65). While changing acid-base parameters of bathing media (pHe from 6.7 to 8.4, PCO2 from 3.7 to 37 mmHg, and HCO3- concentrations from 5 to 75 mM), paired muscle cell pH (pHi) and membrane potential (EM) values were determined at 23 degrees C. In control conditions (pHe = 7.6, HCO3- = 15 mM, PCO2 = 11 mmHg), pHi and EM (n = 20) averaged 6.99 +/- 0.04 (S.E.) and -69.2 +/- 2.2 mV, respectively. A negative correlation was observed between pHi and EM (correlation coefficient r = -0.564, p less than 0.002). The change in EM per unit pH change was approximately -30mV, indicating that the H+ distribution across the cell membrane only incompletely obeys the Donnan rule. The pHi varied more or less with pHe. Namely, changes in pHe and PCO2 at constant HCO3- produced relatively large changes in pHi, but elevation of pHe and HCO3- at constant PCO2 produced relatively minor rise in pHi. The stability of pHi or the size of buffer capacity were proportional to external HCO3- concentrations. These data suggested that a transmembrane distribution of buffer pairs depends largely on non-ionic diffusion of CO2-HCO3- buffer system and partly on ion fluxes of HCO3- or H+.
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Goodpasture (GP) antigens, protein components reactive with human autoantibodies against glomerular basement membrane (GBM), were identified in human alveolar basement membrane (ABM) using an enzyme-linked immunoassay (ELISA), Western blotting and immunoprecipitation. All six anti-GBM antisera studied, three obtained from patients with glomerulonephritis and pulmonary haemorrhages (i.e. GP syndrome), and three from patients with glomerulonephritis alone, distinctively reacted with collagenase-digested (CD) ABM. Very cationic 22-28 kD and 40-48 kD components were detected by blot analysis combined with two-dimensional gel electrophoresis. These proteins showed some similarities to GP antigens in human GBM with respect to the monomer-dimer composition and charge distribution. Inhibition ELISA revealed that the binding of anti-GBM antisera to CDGBM decreased when they were pre-incubated with CDABM, suggesting that the anti-GBM antisera recognized the same epitope(s) on the GBM and ABM. Heterogeneity of the GP antigens in human ABM was demonstrated by blotting; monomeric antigens were absent or at low levels in the CDABM of three out of 10 normal individuals. In immunoprecipitation, anti-GBM antisera from patients with and without pulmonary haemorrhage showed different reactivities with CDABM. The former antisera precipitated both monomeric and dimeric components, but the latter did not. The observations of variation in monomer-dimer composition of ABM, and the different binding of anti-GBM antisera to it may explain why only some patients with anti-GBM nephritis have lung involvement.
Effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413) on the central nervous system were compared with those of ketotifen and chlorpheniramine. Among the various activities related to the central nervous system, KB-2413 showed inhibitory effects on locomotor activity, acetic acid-induced writhing in mice and reserpine-induced hypothermia in rats at a high dose such as 100 mg/kg p.o. However, in mice, it (10-100 mg/kg p.o.) exerted no significant influence on muscle tone, various experimental convulsions, oxotremorine-induced tremor, physostigmine-induced mortality or hexobarbital-induced sleep, and in rats, it had no effect on rectal temperature or conditioned avoidance. It also did not affect spontaneous electroencephalogram (EEG), EEG arousal responses or photic driving response in rabbits at 5 mg/kg i.v. On the other hand, ketotifen and chlorpheniramine affected more widely and strongly the central nervous system than KB-2413. In conclusion, KB-2413 showed a less potent effect on the central nervous system than ketotifen and chlorpheniramine, and no results suggested serious side effects of KB-2413.
Effects of 1-(2-ethoxyethyl)-2(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413) on the circulation and the other systems were compared with those of ketotifen and chlorpheniramine. 1. Among the effects on the circulation and the respiratory system, KB-2413 as well as ketotifen and chlorpheniramine transiently inhibited respiration at 3 mg/kg i.v. and slightly decreased blood pressure in dogs. KB-2413 slightly decreased heart rate in dogs, but ketotifen slightly increased it. 2. KB-2413 at 100 mg/kg p.o. slightly decreased the volume of gastric juice in rats and dose-dependently increased biliary secretion in rats in the dose range of 10-100 mg/kg i.d. On the other hand, ketotifen and chlorpheniramine decreased biliary secretion. 3. KB-2413 inhibited the spontaneous movements of various isolated smooth muscles at a high concentration of 10(-4) g/ml. 4. The autonomic system in cats and the motor nervous system in rats were not influenced by KB-2413 at 3 mg/kg i.v. 5. The blood clotting system, blood sugar level, urine volume and urinary electrolytes in rats were not affected by KB-2413 in the dose range of 10-100 mg/kg p.o. 6. KB-2413 inhibited carrageenin-induced rat paw edema at 100 mg/kg p.o. In conclusion, KB-2413 showed a less potent effect on the circulation and the other systems than ketotifen and chlorpheniramine, and no results suggested serious side effects of KB-2413.
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Explants of human endometrium and decidua were cultured for 96 hours using the organ culture method. The tissues were observed under light and electron microscopes. The prolactin concentrations of the mediums and of the tissues were assayed with I131-prolactin kits. The prolactin concentrations in the mediums continued to increase during the 96-hour organ culture to 16ng/100mg w.w. for the proliferative endometrium, 200ng/100mg w.w. for the late secretory endometrium and 5.5 micrograms/100mg w.w. for the early gestational decidua. Ultrastructurally, each endometrial stromal cell and decidual stromal cell revealed its secretory appearance. For instance, after the culture there was an increase in ribosomes and Golgi apparatus, and the cisternae of the rough endoplasmic reticulum (r-ER) expanded. The differentiation of the stromal cells into fully developed decidual cells in ultrastructure was proportional to the increase in prolactin concentrations in the medium during the culture.
Decidua parietalis in the early stage of gestation were cultured for 96 hours using the organ culture method. The cultured explants were observed under electron microscopes and the prolactin concentrations of the mediums and of the tissues were measured by radioimmunoassay to study their endocrinological activity. The following five characteristic components of decidual cells were ultrastructurally selected to type the cells: 1) thickness of external lamina, 2) chromatin patterns of nuclei, 3) amounts of cytoplasmic organelles, 4) existence of dilatation of cisternae of rough endoplasmic reticulum and 5) existence of peduncular cytoplasmic processes and reflexive gap junctions. Using these five characteristics, the decidual stromal cells were classified into 3 types. After the organ culture had set for 96 hours, Type III cells increased and massive amounts of prolactin were detectable in the mediums.
For local treatment of inflammatory breast cancer and recurrent breast cancers with liver metastasis, we applied intraarterial infusion chemoembolization therapy utilizing albumin microspheres containing adriamycin (ADM-ms), which was developed by Morimoto. In this study, there were 2 cases of inflammatory breast cancer and 3 cases of recurrent breast cancers with liver metastasis. Arterial canulation of primary breast cancer were made through both arteries, the internal mammary artery and lateral thoracic artery, which were feeding arteries of the breast. ADM-ms was injected into both arteries and its tumor effect was evaluated clinically and histologically. Remarkable reduction in tumor size was recognized. Histologic examination of resected specimens revealed extensive fibrosis in the center of the primary tumors. A few cancer cells, degenerated in various degrees, were found remaining in the periphery of the necrotic mass. Local side effects of the microspheres were skin disturbances such as pain, redness and blistering. ADM-ms was injected into the hepatic artery for the liver metastatic cases, and its antitumor effect was evaluated by CT scan or echography. Effective reduction in tumor size was only recognized in one case. No serious systemic side effects, not recognized in any case. Our report reviews the effectiveness of this therapy as a preliminary procedure for surgical treatment of inoperable inflammatory breast cancer.
Hydrolysis of cefixime in buffer solutions (pH 1-9) at 25 degrees C and a constant ionic strength of 0.3 was investigated using ion-pair reversed-phase HPLC. Hydrolysis rates followed pseudo first-order kinetics; the rate of hydrolysis of cefixime was very slow at pH 4-7, slightly faster at lower pH, and quite rapid at higher pH. In the early stages of hydrolysis, six major degradation products were isolated and identified: a beta-lactam ring-opened product and a 7-epimer (basic conditions), three lactones derived from intramolecular cyclization between the 2-carboxyl and 3-vinyl groups (acidic conditions), and an aldehyde derivative involving a 7-acyl moiety (neutral conditions). Principal degradation pathways for cefixime were found to involve initial cleavage of the beta-lactam ring.