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We investigated changes in drug disposition and toxicities with CPT-11 in 15 dialysis patients with gastrointestinal cancers to clarify whether CPT-11 could be administered safely in such patients. For comparison, the same parameters were also investigated in 10 cancer patients not undergoing dialysis. Items investigated included (1) plasma concentrations of SN-38, SN-38G and CPT-11 at 0, 1, 12, 24, 36, 48 and 72h after administration, together with a comparison of mean AUC values for 3 dose levels of CPT-11 (50, 60 and 70mg/m2) in dialysis patients and controls;and (2) occurrence of adverse events. Several findings emerged from this study:(1) No significant difference was observed in the AUC for SN-38 or CPT-11 between the dialysis and control groups;(2) The AUC for SN-38G at each dose was significantly higher in dialysis patients;and (3) Grade 1-4 leucopenia was observed in 11 of the dialysis patients. One patient developed grade 4 leucopenia and died due to sepsis. Anorexia, diarrhea, nausea, alopecia and interstitial pneumonia occurred in 6 dialysis patients. We found changes in drug dispositions of CPT-11, SN-38 and SN-38G in dialysis patients, suggesting that hepatic excretion, especially that of SN-38G, was increased. No significant difference in occurrence of adverse events was observed between the 2 groups. This indicates that CPT-11 can be administered safely in patients on dialysis.

In Liaoning Province in northeastern China, we found a G6PD-deficient patient at the age of 3. By the classification of the World Health Organization, this patient was categorized as class I (very severe G6PD deficiency). When we investigated the G6PD gene of the patient, we found that he had a replacement of G to A at nucleotide 1339. As a result, the amino acid at position 447 should change from Gly to Arg. This replacement is known as G6PD Santiago de Cuba, because it was first discovered in a Cuban boy who showed heavy chronic anemia. Today, 28 G6PD variants have been reported in the Chinese population, and all are categorized as class II (severe deficiency) or class III (mild deficiency);in class II or III deficiency, anemia is not present in daily life, but hemolytic attack can occur when the carrier ingests certain oxidative medicines or foods. This is the first report of a G6PD-deficient Chinese patient in the category of class I. We intended to find other G6PD-deficient cases in northeastern China and tested several hundred blood samples, but no cases of G6PD deficiency were found (0/414). In central China, where falciparum malaria was endemic from the 1950s to 1970s, we found two G6PD-deficient cases (2/27) and the other members from their families whose variant type was G6PD Kaiping (1388GT), which is a common variant in the Chinese population.

Differential, histochemical and immunohistochemical changes were observed in hepatocytes from immediately to 7 days after isoflurane or sevoflurane exposure (at H 0 to on Day 7) to study the process of development and recovery in anesthetic-induced hepatic injury. A total of 570 7-week-old male Sprague-Dawley rats with or without phenobarbital treatment were exposed to isoflurane or sevoflurane in 100%, 21%, or 10% oxygen, or to 10% oxygen alone for 2h. In phenobarbital-treated rats, hepatocytes both with and without anesthetic exposure markedly changed in 10% oxygen at H 0. Glycogen and ribosomal ribonucleic acid (rRNA) disappeared at H 0 and at H 6, respectively, and at H 6, AST levels in the blood rose. From H 6 to Day 1, necrosis developed more markedly and widely in zone 3 hepatocytes exposed to anesthetics in 10% oxygen than in those exposed to oxygen alone. All degenerated tissues had returned to normal levels by day 7. Recovery of the hepatolobular structure may be attributed to rearrangement of remaining hepatocytes in the portal vein area. Both the disappearance of glycogen and rRNA and the increase in blood AST levels after exposure to isoflurane or sevoflurane are considered to be factors contributing to the induction of necrosis around the central vein. The grade of isoflurane-induced hepatic injury was found to be significantly higher than that of sevoflurane.

Effect of ornithine which is known to inhibit L-arginine uptake via cationic amino acid transport system has been tested, and compared to aminoguanidine, an iNOS inhibitor in lypopolysaccharide (LPS)-induced endotoxemia in rats. Serum nitrite/nitrate and malondialdehyde (MDA) level have been measured, and ileal histology has also been examined. Endotoxin increased serum nitrite/nitrate and MDA levels from 15.7+/- 2.4 micromol/ml and 2.1 +/-0.2 nmol/ml to 23.1 +/- 1.0 micromol/ml and 5.2+/- 0.3 nmol/ml (both P<0.05), respectively. In addition, LPS caused ileal degeneration. L-ornithine (500 mg/kg) did not improve septic manifestations, i.e., serum nitrite/nitrate and MDA levels did not differ from those in endotoxemia. Neither does it have an improving action on ileal histology. However, higher dose of L-ornithine (2,500 mg/kg) lowered the increased level of nitrite/nitrate and MDA by LPS. Moreover, it restored ileal histology from grade 3 (median) to 0 (median) (P<0.05). On the other hand, aminoguanidine (100 mg/kg) normalized serum nitrite/nitrate and MDA levels but not ileal histology in endotoxemic rats. In conclusion, high dose of L-ornithine could improve endotoxemic parameters in LPS-treated rats.

This study was designed to explore whether it was possible to evaluate the severity of VSD, PDA, and ASD by measuring brain natriuretic peptide (BNP) levels. We also investigated normal BNP levels in children to provide a baseline for our study. We measured BNP levels in 253 normal children, including 11 normal neonates, and in 91 VSD patients, 29 PDA patients, and 34 ASD patients. BNP levels showed no age-related differences in normal children (the mean value: 5.3 +/- 3.8 pg/ml). In the healthy neonates, BNP levels rose from 10.4 +/- 11.9 pg/ml in cord blood to 118.8 +/- 83.2 pg/ml on day 0, then fell to 15.3 +/- 7.8 pg/ml by day 7. In VSD and PDA patients, BNP levels correlated significantly with Qp/Qs, LVEDV, and peak RVP/LVP. In ASD patients, BNP levels correlated with Qp/Qs and RVEDV. Especially, in VSD patients, as an index corresponding to 1.5-2.0 of the Qp/Qs ratio, BNP levels of 20-35 pg/ml were found to be best with regard to both sensitivity and specificity. In the healthy neonates, BNP levels changed rapidly after birth. In VSD, PDA, and ASD patients, BNP levels were well-correlated with the severity of the disease. Especially, in VSD patients, it that appears BNP levels may be useful in evaluating surgical indications, with 20-35 pg/ml levels being the appropriate cut-off value.

Chemical shift MRI is widely used for identifying adenomas, but it is not a perfect method. We determined whether combined dynamic MRI methods can lead to improved diagnostic accuracy. Fifty-seven adrenal masses were examined by chemical shift and dynamic MR imaging using 2 MR systems. The masses included 38 adenomas and 19 non-adenomas. In chemical shift MRI studies, the signal intensity index (SI) was calculated, and the lesions classified into 5 types in the dynamic MRI studies. Of the 38 adenomas studied, 37 had an SI greater than 0. In the dynamic MRI, 34 of 38 adenomas showed a benign pattern (type 1). If the SI for the adenomas in the chemical shift MRI was considered to be greater than 0, the positive predictive value was 0.9, and the negative predictive value was 0.94 and kappa = 0.79. If type 1 was considered to indicate adenomas in the dynamic MRI, the corresponding values were 0.94, 0.81 and kappa = 0.77 respectively. The results obtained when the 2 methods were combined were 1, 0.95 and kappa = 0.96 respectively. The chemical shift MRI was found to be useful for identifying adenomas in most cases. If the adrenal mass had a low SI (0 < SI < 5), dynamic MRI was also found to be helpful for making a differential diagnosis.

For the purpose of forecasting the prevalence ofJapanese encephalitis in Japan, we tried to find out the correlation of factors between median and mode dates of epidemic time curve of prevalence on one hand, and average atmospheric temperatures of prefectures in June and July (T6,7 in short) (X¹), the time when HI reaction of swine became positive to the degree of 50 per cent (D. pos. swine in short) (X²), the latitude (x³) and longitude (x4) in respective prefectures (in 1965 and 1967). On the other we also estimated the median and mode dates of this epidemic curve of the prevalence in 1968 and 1969, from the regression equation of one variable and multiple regression equation from the above factors using an electronic computer. The usefulness of adding factors concerned with mosquitoes to the above four factors is proven by the accuracy of estimation. And the following results were obtained. 1) Phenomenally speaking, the prevalence of Japanese encephalitis follows the principle of "advancing of prevalence towards the north and east" and essentially speaking, it depends upon high atmospheric temperature and the outbreak of many hazardous mosquitoes by the high atmospheric temperature. 2) To estimate median date (y) and mode rate (z) of the epidemic time curve of the prevalence, we can use the next equations; The regression equations to estimate y and z from T 6,7(X) are as follows. y = - 3. 75X¹ + 144.47 σ = 12.4.·. [1] z = - 3. 80X¹ + 157 .26 σ = 14.9.. · [1]' The regression equation from D. pos. swine (X²) are as follows. y = 0. 68X² + 31. 82 σ = 9.2· .. [2] z=0. 76X² +40. 71 σ= 12.0 .. · [2]' The multiple regression equation from T6 ,7 and D. pos. swme are as follows. y = -1. 07X¹ +0 .62x² +59. 37 σ= 9.7 ... [3] z= -0. 79x¹ +0. 71x² +61.02 σ= 12.0· .. [3]' The multiple regression equations from T 6•7, D. pos. swine, latitude and longitude are as follows Y= -1.01x¹ +0.58x² -0.26x³+0 .37x4 + 18.50 σ= 9.8･･･ [4] z = -0. 32x¹ +0. 52x² +2 .05x³ +0 .54x4 -87. 81 σ= 11.8 [4]' 3) We Obtained the estimated value of median date in 17 prefectures in Kyushu, Chugoku, Shikoku, Kinki and Kanto provinces in 1968 and in 13 prefectures in 1969 from [l] or [2] or [3] or [4] equation. Nine prefectures out of 17 by [l], 12 prefectures by [2], 13 by [3J and [4] in 1968. [4] could be estimated with about 10 days error or less. And in 1969, 9 out of 13 by [3] and 7 out of 13 by [4] could be accurately esti· mated. The estimation by the multiple regression equation using many factors is most useful for the calculation. 4) The time when the number of patients increases at maximum can be pointed out by the lower limit of prediction region obtained from data in each prefecture. And the lower limit was the estimated median value minus about 20 days by [1] and about 16 days by [2] or [3] or [4] under the next condition; α = 0. 1, N= 75. 5) The mode dates in 17 prefectures out of 19 were estimated by [1]', [2]', [3]' and [4]'. 12 prefectures out of 17 by [1]', 7 by [2]', 10 by [3]' and 13 by [4]' could be estimated with about 12 days error or less in 1968 and 9 out of 13 was correctly estimated by [3]' and [4]' in 1969. The estimation by the regression line of one factor was s~mewhat different from each other, but when multiple regression line of four factors was used the estimation became more correct. Judging from these results, it is adequate to use the multiple regression equation of [4] and [4]' when we want to forecast the median date or mode date ofJapanese encephalitis time cure. 6) In the case of adding two factors concerned with mosquitoes to T6,7 (X¹), D. pos. swine (x²), latitude (x³), longitude (x4), multiple regression equations become as follows. y= -1.46x¹+0.14X²+0.068x5+89.03 σ= 6.9.. ·[5] z= -3. 29x¹+0 .13x²-0. 010x5+ 143.63 σ= 18.6··· [5]' y=-4.20x¹+0.35x²+0.29x6 + 53.70 σ= 4.2 .. ·[6] z=-2.56x¹-0.0lx²-0.02x6 +128.96 σ=11.4 [6]' y= 4.76x¹+0.41x²+0.13x5+0.22x6-72.78 σ= 4.5 [7] z = - 2. l0x¹ + 0. 05x²+ 0. 11 x5 - 0. 08x6+ 113.4 σ= 10. 7.. · [7]' where x5 is the time when the number of mosquitoes (C. T. collected by light trap reached the maximum and X6 is the time when hazardous mosq uitoes were dected. In the case of median date, 5 prefectures out of 6 prefectures by [5], 2 out of 6 by [6] and 2 out of 5 by [7], and in the case of mode date, 5 out of 6 by [5]', 4 out of 5 by [6]' and 4 out of 5 by [7]' could be accurately estimated in 1969.

Clinical features were studied in 125 patients with sarcoidosis (72 females and 53 males) diagnosed at Okayama University Hospital during a recent 10-year period. The age distribution had two peaks in patients in their 20s and the 50s. Over half of the patients were detected at health screening check and were asymptomatic, while the remaining were symptomatic. Twelve patients were in stage 0, 41 were in stage I, 54 were in stage II, 16 were in stage III, and 2 were in stage IV according to the chest x-ray findings. Serum angiotensin converting enzyme levels and serum lysozyme levels were elevated in 60% and 76% of the patients, respectively. The bronchoalveolar lavage fluid showed lymphocytosis, especially of helper T-cells. The clinical features of sarcoidosis appear to depend on the duration of the disease.

The effects of cepharanthin (Ce), glycyrrhizin (G), verapamil (V), and G plus V on induced thermotolerance in NIH3T3 cells were studied. Cells were heated with or without the drug at 45 degrees C for 20 min (the first heating), incubated at 37 degrees C for 12h (the incubation period), and heated again at 45 degrees C for 0-210 min (the second heating). G and V were added throughout the experiment, while Ce was added throughout the experiment or during only the first or second heating, or the incubation period. The cells were harvested after the second heating to evaluate cell survival. In control experiments without any drug, thermotolerance developed and reached the highest peak in the cells incubated for 12h at 37 degrees C. However, thermotolerance in the control cells was suppressed by incubating them at 0 degree C, but developed by subsequent incubation at 37 degrees C. This suggests that the acquisition of thermotolerance by the cells required metabolic processes during the incubation at 37 degrees C. When each drug was present throughout the experiment, only Ce or the combined use of G and V was effective in reducing thermotolerance. Thermotolerance was also suppressed in the presence of Ce during the second heating. These results indicate that Ce reduces thermotolerance by enhancing thermosensitivity rather than by inhibiting the development of thermotolerance.

In order to elucidate the role of erythrocyte catalase in the accumulation of mercury in erythrocytes, labeled erythrocytes and plasma were prepared by exposing normal and acatalasemic mice to radioactive mercury vapor (203Hg0: 6.8mg/m3) for 30 min. Labeled erythrocytes (or plasma) were mixed with unlabeled plasma (or erythrocytes) of normal or acatalasemic mice and incubated at 0 degrees C for 1 h. After incubation, the radioactivity of mercury in the erythrocytes and the plasma was measured by a gammascintillation counter. When labeled erythrocytes were incubated with unlabeled plasma, the ratio of mercury transferred from acatalasemic erythrocytes to normal plasma (11.6%) or to acatalasemic plasma (13.3%) were significantly higher than that from normal erythrocytes to normal plasma (1.8%) or to acatalasemic plasma (2.2%). When labeled normal (or acatalasemic) plasma was incubated with unlabeled normal or acatalasemic erythrocytes, the uptake of mercury by acatalasemic erythrocytes from normal plasma was 2.0%, and 1.2% from acatalasemic plasma, which tended to be lower than that by normal erythrocytes from normal plasma (3.4%) or from acatalasemic plasma (2.2%). The results indicated impaired accumulation of mercury in acatalasemic erythrocytes, suggesting the importance of catalase in taking up mercury in erythrocytes and protecting other organs from toxic effects of metallic mercury.

Man bestimmte die Gerinnungszeit einer Mischung von 0.1 ml des frischen Zitratplasmas, 0.1 ml einer Epsilon-Aminokapronsäure-Lösung in Konzentrationen von 0, 02, 0.5, 2.5, 10, 20, 50 und 100 gamma, 0.1 ml CaCl² Lösung und 0.1 ml Michaelis' Puffer. Die erwähnten EACA-Konzentrationen hatten keinen charakteristischen Einfluss auf die Rekalzifikationszeit des frischen und des gelösten lyophilisierten Plasmas.

By means of the thin layer chromatography (TLC) a study was carried out on the decomposition of methyl parathion, ethyl parathion and sumithion when exposed to heat or ultra-violet irradiation. The results are briefly summarized as follows. 1. Parathions, when exposed to heat, form hydrolysates and such 0-analog as paraoxon as well as S-alky1 isomers. 2. When parathions are exposed to ultra-violet rays at 365 mμ and 254 mμ, the rate of decomposition is extremely slow. For example, when exposed to such rays in Petri dish for 5 hours, only a small amount of S-alkyl isomer is formed. 3. After heating parathions in a small test tube and conducting TLC, when each 0-analog and S-alkyl isomer above mentioned is confirmed, it is possible to identify a minute amount of each parathion by this method, and thus this method is feasible to apply to practical poison examination as a rapid and simple qualitative examination method.

Cb strain female mice were exposed to 800 p.p.m. of carbon tetrachloride for 3 hours by the use of newly devised gas chamber via constant current of gas. Contents of ATP, triglyceride and total lipid in the liver were measured at appropriate intervals after inhalation of carbon tetrachloride and compared to non-treated controls. And P : 0 ratio of the liver mitochondria was measured by oxymeter and morphological changes of liver mitochondria were observed by electron microscopy. The following results were obtained. 1. ATP conten t in the liver decreased slightly immediately after inhalation, rapidly decreased until 4 hours after inhalation and gradually decreased until 20 hours after inhalation. 2. Contents of total lipids increased slightly immediately after the exposure and increased gradually until 20 hours later. Contents of triglyceride in the liver increased at almost constant rate during and after the exposure. 3. P : 0 ratio of liver mitochondria did not change immediately after the exposure and gradually increased after the exposure, keeping parallel relation to decrease in ATP content in the liver. Decrease in ATP content in the liver after inhalation of carbon tetrachloride seems to be mainly due to uncoupling of oxidative phosphorylation of liver mitochondria. 4. Morphological changes of liver mitochondria were observed at 4 hours after the exposure by electron microscopy. 5. Decrease in ATP levels of the liver suggested to have a close relation to accumulation of lipid in the liver after the inhalation of carbon tetrachloride.

1. After the centrifugation of sonicated heavy beef heart mitochondria at 75, 000 × g for 10 minutes, the supernatant was centrifuged at 144, 000 × g for 30 minutes. The residue was revealed being composed of vesicular inner membrane fragments (ETPH), about 600 to 1000 Å. in diameter, showing a morphological homogeneity and a high capacity of oxidative phosphorylation. 2. The Pia ratio of the ETPH in the presence of succinate and of NADH2 was 1.68 and 2.54, respectively, and the corrected Pia value for O2 gas equilibrium was 1. 01 and 1.40, respectively. 3. The capacity of oxidative phosphorylation in ETPH fraction was parallel to the activity of the oligomycin. sensitive ATPase in these fractions. 4. The P/0 ratio of ETPH was decreased to about 50 % by hypotonic treatment. The decrease of P/0 ratio was restored to the level of about 90 % by incubating the ETPH with ATP and BSA. In the instance where the P/0 ratio was low level in the hypotonic medium, the surface structure of ETPH was observed as a swollen form and the head pieces of the elementary particles were clearly observed in contrast to the solid surface structure of ETPH in the isotonic medium. 5. The P/0 ratio of ETPH was decreased to about 60 % by relatively severe sonication, and after separating the residue from the supernatant, that of the residue decreased further to about 40 %. The P/0 ratio of the residue was restored to the level before the separation on the addition of the supernatant containing oligomycin-insensitive ATPase. 6. A discussion was made on the correlation between the surface structure and the activities at terminal phosphorylation step of ETPH after the simple physico-chemical treatment.

In order to know the precise quantity of catalase protein in acatalasemic and hypocatalasemic blood, immunological studies were conducted using hemolysates or acetone extracts of those blood as antigen. 1) The ratio of catalase contained in normal, hypocatalasemic and acatalasemic blood, calculated from precipitates produced in the reaction between catalase antibody and hemolysates was 1.0 : 0.5 : 0.07. 2) The ratio of catalase in normal, hypocatalasemic and acatalasemic blood, calculated from precipitates from the catalase antibody and the acetone extracts was 1.0: 0.49 : 0.11. In the precipitin ring tests using acetone extract, the antigen titer in normal, hypocatalasemic and acatalasemic extracts was 40, 20, and 0 respectively. 3) From our experiments it can be said that hypocatalasemic blood shows one half the catalase activity of normal blood, due to one half the quantity of catalase protein, and that acatalasemic blood lacks catalase activity due to the absence of the catalase protein. These findings strongly suggest that no substances exist which suppress or inhibit the catalase activity in hypocatalasemic and acatalasemic blood.