Biomedical subjects
Publications and source records attributed to K Takagi.
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The bioavailability and pharmacokinetics of theophylline after a single intravenous administration of theophylline and multiple oral administration of a sustained-release theophylline tablet formation were studied in dogs. In addition, the pharmacokinetics of theophylline after multiple oral doses of the drug was also studied in asthmatic patients. In the intravenous administration of theophylline (5 mg/kg) to dogs, the theophylline half-life was 4.0 +/- 0.2 h. The apparent volume of distribution (Vd) and plasma theophylline clearance (CL) were 0.734 +/- 0.019 l/kg and 126.7 +/- 3.4 ml/kg/h, respectively. In the multiple oral doses of the drug in amounts ranging from 7.52 to 9.09 mg/kg, the Vd and CL were 0.765 +/- 0.021 l/kg and 111.0 +/- 2.4 ml/kg/h, respectively. The mean oral absorption rate constant (ka) was calculated to be 0.355 +/- 0.035 h-1 and the mean elimination rate constant (kel) was 0.146 +/- 0.007 h-1. The absolute bioavailability of the drug calculated by a computer fitting method was 1.08 +/- 0.07. The result suggests that the drug has complete absorption. On the other hand, the pharmacokinetic parameters in the asthmatic patients were 0.337 +/- 0.055 l/kg for the Vd, 32.55 +/- 3.48 ml/kg/h for the CL, 0.222 +/- 0.058 h-1 for the ka and 0.105 +/- 0.016 h-1 for the kel, respectively. This study indicated that the dog may be useful to predict bioavailability of a sustained-release theophylline tablet formulation in humans. However, it showed that there are differences between dogs and humans in the pharmacokinetic parameters.
The indication for EDSP was studied in 75 patients with early gastric cancer diagnosed endoscopically which had been obtained over a period of 11 years (1979 to 1985) at the Cancer Institute Hospital, Tokyo and the following results were obtained. EDSP consists of two procedures using double channel fiberscope; a sessile or depressed lesion pulled upward by one snare cautery (standard EDSP) is transformed into a subpedunculated one, which allows another snare cautery of pseudostalk, and it is excised by using coagulation current. EDSP was performed in 53 cases of IIa type and 22 cases of IIc type. Excision by one snare cautery was possible in 90.9% (40/44) of IIa lesion measuring less than 2 cm and in 100% (14/14) of IIc lesion measuring less than 1 cm, the total being 85.3% (64/75). There was no residual cancer in 41 cases of IIa lesion (93.2%) and 17 cases (85.0%) of IIc lesion with two recurrent cancers confirmed by follow-up endoscopy. Residual cancer was found in 6 cases (9.1%) which were operated on. The results mentioned above show the usefulness of EDSP and selection of case without lymph node metastasis permitting complete excision by one snare cautery is of much importance. EDSP is indicated for IIa lesion of differentiated type measuring less than 2 cm, IIc lesion of differentiated type without ulceration measuring less than 1 cm and IIc lesion of undifferentiated type without ulceration measuring less than 0.5 cm that is not located in the fundic gland area.
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The effects of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), a new hypolipidemic agent, on serum cholesterol level and cholesterol biosynthesis were studied in normolipidemic rats. KCD-232 dose-dependently reduced the serum cholesterol level. The in vivo incorporation of [14C]-acetate and 3H from [3H]water into liver digitonin-precipitable sterols was inhibited by oral administration of KCD-232, while that of [14C]mevalonic acid into the sterols was not inhibited. Hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity was suppressed significantly by the oral administration of the drug. A KCD-232 metabolite, 4-(4'-chlorobenzyloxy)benzoic acid (MII), strongly inhibited [14C]acetate incorporation and weakly inhibited [14C]mevalonic acid incorporation into the sterols in liver slices. MII also significantly inhibited the sterol synthetic rate measured with [3H]water and the HMG-CoA reductase activity in dispersed hepatocytes. MII and its CoA thioester (MII-CoA) inhibited the incorporation of [14C]acetate, [14C]acetyl-CoA and [14C]HMG-CoA into nonsaponifiable lipids in a cell-free enzyme system from rat liver. MII-CoA further showed a weak inhibition of [14C]-mevalonic acid incorporation into nonsaponifiable lipids in the system, while MII showed no effect on mevalonic acid incorporation. These results indicate that KCD-232 possesses a major inhibitory site for sterol synthesis on HMG-CoA reductase due to both MII and MII-CoA, and a possible second site of action beyond mevalonic acid due to MII-CoA. The latter inhibitory site, however, is considered to play a minor role in the inhibition of sterol synthesis in vivo.
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Changes in serum lipoprotein profiles were characterized in Donryu rats subcutaneously implanted with an ascites hepatoma line of AH109A cells and the effect of a new hypolipidemic agent with a structure of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) was estimated. With the growth of hepatoma for periods of up to three weeks, a striking decrease in the high density lipoprotein (HDL) fraction and an enormous increase in the VLDL + LDL (very low density lipoprotein + low density lipoprotein) fraction were found in hepatoma-bearing rats when either precipitation method or electrophoresis was used. These lipoprotein profiles were not influenced by sex. Judging from the electrophoretogram, the increase in VLDL + LDL fraction was due mainly to an increase in VLDL fraction. The oral administration of KCD-232 significantly suppressed the hepatoma-induced increase in VLDL + LDL with little or no influence on the hepatoma-induced decrease in HDL. There existed a positive correlation between the hepatoma weight and (VLDL + LDL)-cholesterol concentration and a negative one between hepatoma and HDL-cholesterol.
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We studied the effects of the cyclooxygenase inhibitors, indomethacin and aspirin, the leukotriene antagonist, FPL 55712 and the Ca antagonist, verapamil on basal tone and Ca-induced contractions in the human and guinea-pig tracheal muscle. Indomethacin and aspirin usually increased spontaneous tone or Ca-induced contractions in human strips, while consistently decreased tension development in the guinea-pig muscle. FPL 55712 strongly reduced contractions in the human, whereas it had a very weak effect on the guinea-pig muscle. Verapamil had a small inhibitory effect in the human trachea, either at 5.9 or 40 mM K, but markedly suppressed Ca-induced contractions of guinea-pig trachea in 40 mM K and had little effect on contractions in 5.9 mM K in this tissue. It is concluded that active tone in the two different tracheal muscles were controlled by different processes; that different arachidonate by-products may exert an effect on basal tone in the two different muscles; and that different plasma membrane Ca channels may be operative under basal conditions in the different muscles.
In the guinea-pig tracheal smooth muscle, effects of various relaxants were compared in normal (5.9 mM) and excess (40 mM) K media. The relaxing effect of calcium-channel blockers, nifedipine and verapamil (group I) was potentiated by increasing the external K concentration. The effect of the drugs which are supposed to increase intracellular cyclic AMP, such as isoprenaline, forskolin, isobutylmethylxanthine, theophylline, dibutyryl cyclic AMP (group II) was moderately reduced by excess K. Nitroprusside, 8-bromo-cyclic GMP and sodium nitrite (group III) are generally considered to increase intracellular cyclic GMP and their effect was markedly reduced by excess K. When the tension development was made the same at 5.9 mM K and 40 mM K by adjusting the Ca concentration, the relaxing effect was similar and independent of the K concentration both for group II and group III drugs. It seems that the group II drugs can better overcome a large influx of Ca than group III drugs.
A homodimer protein consisting of two 38,000 dalton peptides was isolated from a murine leukemia cell line (M1). The binding molar ratio of the 38K-dimer protein to purified skeletal muscle actin was saturated at 1:3, and when the 38K-dimer/actin ratio exceeded 1:12, gelation occurred. This gelation was completely inhibited by the presence of either 10 mM KCl or 20 mM NaCl. The protein induced actin filament bundling, which required a higher 38K-dimer/actin ratio and was not affected by the presence of monovalent cations. During the differentiation of Ml cells, the sensitivity of the 38K protein to monovalent cations was decreased; that is 20 mM KCl or 50 mM NaCl was required to inhibit the gelation by the 38K protein isolated from differentiated cells. On the other hand, the intracellular K+ content of Ml cells decreased from 70 +/- 5 mM to 18 +/- 3 mM, and Na+ increased from 10 +/- 5 mM to 40 +/- 10 mM during the differentiation. These findings suggest that the differentiation brought about conditions favourable for the 38K protein to induce actin gelation, and in turn, the locomotive and phagocytic activities which were induced only after differentiation in this cell line.
Two hundred and sixty-eight Japanese aged 19 or below were studied retrospectively from their medical records to determine the relationship between the sibship size (number of siblings in the family) and the appearance of symptoms of anxiety, hypochondriasis and depression during the time period I (1955 + 1960 + 1965) and the time period II (1970 + 1975 + 1978). The results showed that only sons and either sex of a large sibship size (4 or more) possessed these three symptoms to a larger extent than only daughters and either sex of a medium sibship size (2 or 3) during both time periods. These three adult-type neurotic symptoms were thought to be manifested among the children and adolescents who communicated primarily with adults and/or those who were required by their parents to exhibit adult-type behavior whether in traditional or in modern Japanese families.
To evaluate the clinical usefulness in terms of estimation for glomerular filtration rate (GFR), we determined the levels of alpha 1-microglobulin (alpha 1m) in the serum and urine of patients with various renal diseases and compared with those of beta 2-microglobulin (beta 2m) and creatinine. Serum and urinary alpha 1m levels were measured by using single-radial immunodiffusion method. 24-hour creatinine clearance (Ccr) was used as a indicator of GFR. There was a significant positive correlation between serum alpha 1m and creatinine levels (r = 0.75, p less than 0.001). Serum alpha 1m, beta 2m and creatinine inversely correlated and logarithmically correlated to Ccr as shown in the following equations: log alpha 1m = 2.30 - 0.42 X log Ccr (r = -0.74); log beta 2m = 2.06 - 0.91 X log Ccr (r = -0.92); log creatinine = 1.57 - 0.78 X log Ccr (r = -0.94). Both correlation coefficient and regression coefficient for alpha 1m were rather poor compared to those for beta 2m and creatinine. However, alpha 1m levels started to increase over normal range when Ccr fell below 80 liters/day, while beta 2m and creatinine remained within normal ranges. The daily urinary excretion of alpha 1m was increased in the patients whose Ccr was within normal limits compared to that of healthy control subjects (15.2 +/- 3.2 mg/day, n = 19, vs. 5.7 +/- 0.7, n = 7, p less than 0.001). Fractional clearance of alpha 1m increased proportionally to the decrease of Ccr. These data suggest that combined measurements of alpha 1m in the serum and urine seem to be useful to estimate GFR, especially to detect the mild reduction of CFR.
Cell extracts of a murine leukemia cell line, M1, apparently contain three kinds of actin-gelation factors; a filamin-like protein, and 38K-dimer and 105K-dimer proteins. Unlike gelation by the filamin-like protein, gelation by the latter two proteins is inhibited by low concentrations of KCl. Our study of the 38K protein has been reported elsewhere (Takagi, K. et al., J. Biochem. Tokyo 97, 605-616, 1985). We here describe the purification and characterization of the 105K protein. The 105K protein differs from the alpha-actinin group of proteins in its antigenicity, peptide components and Ca2+-insensitivity. The saturated binding ratio of the protein to purified skeletal muscle actin is 1:8; when this ratio exceeds 1:20, gelation takes place. This gelation is inhibited completely by the presence of 25 mM KCl. Electron microscopy revealed that, in the absence of KCl, the 105K protein/actin mixture forms short actin bundles that are accompanied by a meshwork of short single filaments. The presence of 25 mM KCl did not prevent actin-bundling, but the bundles became longer and the meshwork of short filaments was no longer present.
The effect of 4-(4'-chlorobenzyloxy)benzoic acid (MII), a metabolite of a new hypolipidemic agent 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), on lipid synthesis and cell growth was studied in human skin fibroblasts (HSF), mouse skin fibroblasts (MSF) and other rodent-derived cell. MII inhibited sterol synthesis in both HSF and MSF in a dose dependent manner. The drug also suppressed fatty acid synthesis, weakly in HSF and markedly in MSF. The growth of MSF was inhibited by MII in a dose dependent manner, whereas that of HSF was not inhibited at all by MII up to 1 mM. The MII-mediated inhibition of MSF growth was not prevented by the addition to the medium of intermediates of the cholesterol synthetic pathway, i.e., mevalonate, squalene or lanosterol. Furthermore, the growth of several cell lines derived from rodents (L, CHL and AH109A cells) was suppressed by MII. These results suggested a possibility that the different effects of MII on the growth of HSF and MSF might be due partly to differences in the effect of MII on fatty acid synthesis between human and rodent cells.
Mechanisms for hypercholesterolemia and hypertriglyceridemia and the effects of KCD-232, a new hypolipidemic agent, on them were studied in male Wistar rats with daunorubicin (DR)-induced nephrosis. Single intravenous injection of DR dose-dependently increased urinary protein loss and serum lipid levels (0,3,6 and 12 mg/kg). Twenty-four days after the injection of DR (6 mg/kg), serum cholesterol (Ch) and triglyceride (TG) levels markedly increased and free fatty acid level tended to decrease with no effects on liver lipid levels. Hepatic Ch synthesis from [14C]acetate in vitro increased by 2.1-fold, while exogenous Ch absorption slightly decreased. The clearance of intravenously injected [3H]Ch from the circulation was delayed. Hepatic fatty acid (FA) synthesis also increased by 2.7-fold, and hepatic TG lipase activity tended to decrease. KCD-232 improved the hypercholesterolemia and hypertriglyceridemia of DR-treated rats. The drug inhibited the elevated hepatic Ch synthesis and exogenous Ch absorption and thus improved the delayed Ch clearance from the circulation. KCD-232 markedly inhibited the elevated hepatic FA synthesis and stimulated both hepatic FA oxidation and lipoprotein lipase activity from the epididymal adipose tissue of the nephrotic rats. These results suggest that 1. DR-induced hypercholesterolemia is due to both an increased Ch synthesis in the liver and delayed clearance of Ch from the circulation; 2. DR-induced hypertriglyceridemia is caused by both an increased hepatic FA synthesis and depressed TG hydrolysis in the circulation; 3. KCD-232 improves the hypercholesterolemia by inhibiting the elevated Ch synthesis and Ch absorption from the gut; and 4. KCD-232 improves the hypertriglyceridemia by inhibiting the elevated hepatic FA synthesis and by stimulating both hepatic FA oxidation and TG hydrolysis activity in the circulation.
This report deals with temporary threshold shifts (TTSs) induced by intermittent white noise and continuous noise of equal energy. On-times of the six intermittent noises in their same duty cycle, which was fixed at 1 s, were 25, 50, 100, 200, 400 and 800 ms and the corresponding sound pressure levels of the noise were 114, 111, 108, 105, 102 and 99 dB, maintaining the total energy of the noise at an equal level. The sound pressure level of the continuous noise was 98 dB. Seven young students with normal hearing acuity were exposed to these 7 sounds for 40 min. TTSs at 3, 4 and 6 kHz were measured at the time of 10, 20 and 40 min after the onset. The results showed that significant differences were found among the TTSs from the sounds with different on-times and in particular that TTS increased with on-times above 100 ms or 200 ms. This fact suggests that the equal energy assumption may not hold in the prediction of TTS from intermittent noise. It is suggested that both the on-fraction rule and the unit-step-function method might be applicable to the prediction of TTS due to intermittent noise with bursts longer than 200 ms.