The metabolic disposition of thymoxamine hydrochloride (thymoxamine), in paticular its pharmacokinetics and bioavailability, was investigated in rats, beagle dogs and rabbits. After oral or intravenous administration of thymoxamine to animal species, free and conjugated forms of deacetyl-thymoxamine (DAM) and deacetyl-demethyl-thymoxamine (Met-X) were detected in plasma and tissues, without unchanged thymoxamine. From examination of pharmacokinetic parameters, it is suggested that thymoxamine administered orally absorbed rapidly from gastric intestinal tract, and the disappearance rate of thymoxamine was rapid relatively. It was cleared that rats and beagle dogs were readily affected the first-pass effects, compared with human. Gastrointestinal tract absorption in rabbit was show to occur mainly form intestine and to lesser, though significant, from stomach. In tissue distribution, DAM was extremely high concentration in the kidney and liver at 15-30 min after oral administration of 100 mg/kg of thymoxamine to rats. Within 48 hr, total cumulative excretion of two metabolites in urine and feces accounted for about 94 % of dosage. Evalution of ear skin temperature in beagle dogs was caused by oral administration of 120 mg/body (14.4 mg/kg) of thymoxamine-tablets, and then minimum effective concentration of DAM in plasma was 0.5 erg/ml. Comparative studies of thymoxamine and DAM in beagle dogs, bioavailability of thymoxamine was superior to DAM. Consequently, it is concluded that thymoxamine is a prodrug to DAM, which amis at improvement in bioavilability of DAM.

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The pharmacological properties of thymoxamine hydrochloride (thymoxamine) and its two metabolites, deacetyl-thymoxamine (DAM) and deacetyl-demethyl-thymoxamine (Met-X), were investigated using the isolated smooth muscle preparation. The rank order of potency of competitive α-adrenoceptor blocking action was: phentolamine>thymoxamine≅DAM>Met-X in isolated vas deferens and thoracic aorta spiral strip of rats. The antagonistic effects of thymoxamine, DAM and Met-X against two α-adrenoceptor agonists, norepinephrine or phenylephrine, were competitively in the helically-cut strips of isolated rabbit thoracic aorta, too. It was indicated that thymoxamine and DAM have selective α₁-adrenoceptor blocking actions because the antagonistic effects of these drugs were greater to phenylephrine than norepinephrine. Antihistaminic actions of thymoxamine and two metabolites were potencies as well as α-antagonistic effects in isolated guinea-pig ileum. Furthermore, thymoxamine and its metabolites did not have markedly anticholinergic, antiserotonergic and calcium-antagonistic actions. In isolated thoracic aorta strips of rabbit, the K⁺-induced contractile responses were inhibited by thymoxamine (1×10^-4-3×10^-4M) at 30-80 %, when non-specific inhibitory effects of thymoxamine did not influence on the cyclic AMP and cyclic GMP contents in vascular tissues.
Those results suggest that pharmacological properties and potencies of DAM have α₁-adrenoceptor antagonistic and weak antihistaminic actions as same as thymoxamine.
It was seemed to support that these evidence were able to expect sufficiently the pharmacological actions of thymoxaminein vivo.

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The relative selectivity of thymoxamine hydrochloride (thymoxamine) and its metabolites, deacetyl-thymoxamine (DAM) and deacetyl-demethyl-thymoxamine (Met-X) were investigated for α₁- and α₂-adrenoceptors in the isolated main pulmonary arteries of rabbits, compared with prazosin, yohimbine, phentolamine and ifenprodil. Thymoxamine, DAM and Met-X have competitive a-adrenoceptor blocking actions. The rank order of potency of antagonists against norepinephrine was: prazosin>phentolamine>DAM=ifenprodil≅thymoxamine>yohimbine≅Met-X, and that for phenylephrine was: prazosin>phentolamine≅DAM≅thymoxamine>ifenprodil>Met-X>yohimbine. Thymoxamine, DAM, ifenprodil and prazosin inhibited with twitch responses to electrical transmural stimulation dose-dependently, however, yohimbine enhanced the twitch responses. In isotope experiments using of³H-norepinephrine (³H-NE), thymoxamine and its two metabolites, inhibited the contractile responses induced by electrical stimulation without affecting the stimulation-evoked³H-NE efflux. Furthermore, thymoxamine, DAM and Met-X enhanced the clonidine-induced relaxation, but had no affect on the reduction of³H-NE efflux. Therefore, it is suggested that thymoxamine and two meta-bolites, DAM and Met-X, possess selectivity for the α₁-adrenoceptor as well as prazosin, differed from ifenprodil, phentolamine and yohimbine.

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We examined that effects of thymoxamine hydrochloride (thymoxamine) on the peripheral blood vesseles, in particular cerebral circulation and cerebral metabolic function, in vitroandin vivostudies.
1) Thymoxamine was more effective in antagonizing methoxamine than clonidine-induced contractile responses in dog basiler arteries.
2) Vasodilating actions of thymoxamine were greater in basiler artery than in mesentric and femoral arteries of dogs.
3) The blood vesseles of ear were markedly vasodilated by oral administration of 120mg/ kg/day of thymoxamine, with rise of skin temperature of ear in the rabbits.
4) Pial arteries of cerebral in cats, vasodilating effects of thymoxamine (0.03-3.0mg/kg i.v.) were greater in thin blood vesseles than in thick blood vesseles.
5) Thymoxamine (0.1-3.0 mg/kg i.v.) increased dose-dependently not only the basiler artery blood flow but also the internal carotid artery blood flow in an anesthesic cats.
6) The regional blood flow of hippocampal and amygdala in cat brain were significantly increased by treated with thyoxmamine (0.03-3.0 mg/kg i.v.) and cerebral cortical and hypothalamic blood flows showed tend to increase.
7) Lowering of mitochondrial respiratory control due to the ligation of bilateral carotid arteries of spontaneously hypertensive rats showed tend to improve with treatment with thymoxamine.
These results seems to support that the clinical usefulness of thymoxamine in the patients with cerebrovascular disorders.

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Catecholamine (noradrenaline or adrenaline) and saline were administered subcutaneously to 27 male healthy medical students and relationship between plasma catecholamine levels and pharmacodynamics were studied. Plasma noradrenaline level significantly increased from 1.78±0.28 to 11.29±2.98 pmol/ml at 5 min after 0.4mg of noradrenaline injection. Plasma adrenaline level also significantly increased from 0.28±0.06 to 1.37±0.26 pmol/ml at 5 min after 0.3 mg of adrenaline injection. Systolic and diastolic blood pressure increased and heart rate decreased significantly after noradrenaline administration. Significant increase in blood pressure after noradrenaline was due to increase in peripheral resistant depend on a-effect of noradrenaline. Significant decrease in heart rate after noradrenaline was though to be vagal reflex. T wave hight on E. C. G. decreased significantly after adrenaline administration. Significant decrease in T wave hight after adrenaline was thought to be due to direct effect of adrenaline on the membrane of cardiac muscle cell.

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Five male subjects were tested to investigate the effect of arterial occlusion upon contractile as well as electrophysiological responses during controlled muscular contractions induced by tetanic nerve stimulations at various frequencies for a period of one minute. The evoked mass action potentials from the triceps surae muscle group (the gastrocnemius and soleus) were continuosly recorded together with mechanical force output different circulatory conditions, i.e., free circulation, continuous occlusion (CO) and release of occlusion after 30 sec of continuous occlusion (OR) . Results indicated that 1) significant decreases in the evoked potential conduction velocity were found during CO and OR conditions, suggesting some degree of neuromuscular transmission impairment during aterial occlusion, 2) comparisons of CO and OR conditions revealed that significantly greater reduction in the evoked polential amplitude due to a reduced muscle membrane excitability was found shortly after the occlusion release, and 3) this reduction in the evoked potential was accompanied by a parallel decline in the developed force. These results support the notion that the amount of extracellular fluid volume can play an important role in prolonging the onset of intramuscular acidification, thus indirectly affecting muscle membrane excitability and contractile function.

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A new reliable treatment was developed for quantitative bacterial endotoxin microassay in rabbit blood, using limulus amebocyte lysate and chromogenic substrate (Boc-LeuGly-Arg-p-nitroanilide) . Some difficulties have occured in the use of the limulus amebocytelysate test, because of the presence of false negative and false positive substances which interfere with the limulus-endotoxin reaction in plasma. Optimal conditions to remove interferingsubstances in plasma samples prior to assay were determined. Addition of 0.26M perchloricacid to platelet-rich plasma and heated to 60°C for 5 min to remove interfering substances. Therecovery of endotoxins from various sources such as E. coli 0111: B4, E. coli 055: B5, E. coli O127: B8, S. typhimurium, S. minnesota 9700, S. tyhosa, S. abortus equi, S. enteritidis, Sigella flexneri, Pseudomonas aeruginosa was 103.3±4.9, 98.6±5.2, 109.7±5.9, 105.6±4.8, 100.5±4.7, 108.3±5.1, 105.2±4.4, 94.2±4.6, 96.9±3.7, and 102.1±5.2% (mean±SD; n=6), respectively. The result showed that the recoveries of various endotoxins from plasma werealmost 100%. The lower limit of assay sensitivity was 1pg/ml.
The widely used chloroform extraction method was found not to be effective to remove theinterefering substances from plasma, the recovery was 6.9±2.0% (mean±SD ; n=5) . The dilution and heating extraction method was found to be effective to remove false positive substances, but endotoxin recovery from plasma was poor.
The endotoxin concentration in plasma of rabbits after intravenous injection was assayed.As a result, in the group receiving 5μg/kg of endotoxin, approximately 98%of the endotoxin disappeared within 30min. However, blood specimens in the group receiving 500μg/kg reachedequilibrium in vivo within 15 min and two of three rabbits were killed. The high level ofendotoxin remained in the plasma of survived rabbit 24hr after receiving 500μg/kg of endotoxin.
The pyrogenicity of ndotoxin was found not to be the direct action. The pyrogenicity seemed to be the action by the endogenious pyrogen.

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It was found previously in our labolatory that the centromedian nucleus of the thalamus (L-CM) was considered belonging to an analgesia inhibitory system since 1) lesion of the L-CM enhanced acupuncture analgesia (AA) caused by low frequency stimulation of the tibial muscle of rats, which was measured by tail flick test, 2) this stimulatron produced analgesia in the abolished AA after lesion of AA producing afferent pathway, which initiated from the tibial muscle and reached to the hypophysis, and 3) the same stimulation of the abdominal muscle did not produce analgesia in normal condition but produced analgesia after lesion of the L-CM. It was also found that D-phenylalanine (DPA) acts just like as lesion of the L-CM. In present experiments, it was examined by lesion and stimulation experiments of the posterior hypothalamus that the part of the posterior hypothalamus acts as an analgesia inhibitory system like L-CM. The effect of DPA on analgesia inhibition by stimulation of the analgesia inhibitory system was also examined. The restricted lesion of the part of the posterior hypothalamus (PH) by means of electrode insertion produced two kinds of changes in AA and morphine analgesia, which was caused by intraperitoneal 0.5mg/kg morphine and was equivalent to AA. One is enhancement of analgesia, and the other is little change of analgesia. Stimulation of the PH through inserted electrode for lesion inhibited the enhanced part of analgesia and the non-enhanced analgesia during stimulation, which were largely antagonized by dexamethasone applied 0.4mg/kg 24 hours and 0.2mg/kg 2 hours before experiment, and remaining analgesia was antagonized by 1 mg/kg naloxone, while it was found previously that AA was antagonized by naloxone, not by dexamethasone. Since all these results were same as those obtained after L-CM lesion, it was obvious that I-PH acts as the analgsia inhibitory system like L-CM, and that encancement of analgesia was the result of lesion of analgesia inhibitory system and non-enhanced analgesia was the results of both lesions of analgesia inhitory system and AA producing afferent pathway in the posterior hypothalamus. The complete inhibition of analgesia caused by I-PH stimulation was antagonized by pre-treatment of 250mg/kg DPA. Therefore it was concluded that inhibitory action of analgesia inhibitory system was antagonzed by DPA.

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Plasma and urine β-thromboglobulin (β-TG) values were measured in 130 cases, in which 65 cases were hematopoietic disorders, mainly myeloproliferative disorders (MPD), and the other 65 cases were renal disorders, mainly chronic renal failure. The normal values of β-TG were 22.7±13.0ng/ml in the plasma and 0.33±0.13ng/ml in the urine. In MPD, plasma β-TG values were significantly increased to 81±67.6ng/ml (p<0.01), especially in ET and CML. There was significant correlation between plasma β-TG values and platelet counts (r=0.877, p<0.01) in all cases of MPD, especially ET and PV. In the cases of decreased platelet aggregation induced by epinephrine and ristocetin, plasma β-TG values showed increase. Plasma β-TG values were almost within normal range in leukemia, varied in lymphoma and paraproteinemia. Plasma, β-TG values were elevated in most cases of PNH and in some cases of ITP. In hemodialyzed patients, the plasma β-TG values were 113.8±45.6ng/ml, significantly higher than in those with renal disease (p<0.01), and the patients hemodialyzed for longer than one year showed increased β-TG values as compared with those treated for less than a year (p <0.025) . The plasma β-TG values increased gradually during the course of hemodialysis (p<0.01) . Plasma β-TG values of hemodialyzed patients with normal platelet aggregation were low compared with those with decreased platelet aggregation (especially induced by ADP) . Plasma β-TG values also increased in cases in which prolonged bleeding time and decreased retention were indicated. Plasma β-TG values in non-dialyzed patients with renal disease were 83.4±39.3; with CRF cases they were 42.6±20.4ng/ml. These were significantly higher than normal, and there was significant correlation between plasma β-TG values and serum creatinine concentrations (r=0.743, p<0.01) . Urine β-TG values were 0.41±0.23ng/ml in MPD, aug-mented especially in CML and ET. Those in renal disease and nephrotic syndrome were 0.94± 0.96 and 0.93±0.67ng/ml, respectively. These were significantly higher than the controls. There was no correlation between plasma β-TG values and urine β-TG values; also, there was no correlation between urine β-TG values and urine protein concentrations. The present study suggests that high β-TG values are mainly due to platelet counts and platelet dysfunction in MPD and to decreased renal catabolism of β-TG in renal disease. Urine, β-TG values did not always reflect plasma β-TG values in MPD and renal disease.

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The case of multiple gastric cancer has tended to increase in number in recent years, clinically having many important problems such as how to make certain diagnosis of multiple lesions and how to avoid cancerous residue in surgical operation. Histopathologically, factors such as the surrounding mucosa in the development of cancer, multicentric development of cancer and fusion or unification of multiple lesions are of interest in studying the development and growth of gastric cancer. Using 49 cases of multiple cancer which met the criteria by Moertel et al. (4.4%) among 1, 116 cases of primary gastric cancer which we had resected in the past 26 years (1956-1981) as the subjects, we examined clinicopathological features, measured the size (area) of each lesion and the distance between lesions and studied the possibility of these lesions getting fused with one another to become a single lesion in the course of their development and growth and also what lesion is liable to get fused. Results obtained are as follows : The incidence of multiple cancer was higher in early cancer than in progressive cancer, for multiple cancer was 16 (7.0 %) out of 229 cases of early cancer and 33 (3.7 %) out of 887 cases of progressive cancer (P<0.05) . As indicated by the age distribution of 37-81 years (average: 61.6 years) and the male to female ratio of 2.3: 1, multiple cancer, compared with single cancer, tended to be found more in those of the advanced age and males. The number of lesions was 2 in 42 cases (87.8 %), 3 in 5 cases (10.2 %) and 4 in one case (2.0 %) . 43 cases with two lesions were used in the subsequent pathological study. As for the location of cancerous lesion, both the main and sub-lesions mostly belonged to areas A and M, while only 5 (5.8 %) out of 86 lesions belonged to area C. The mean value for the size of lesions measured by the MOP (manual optical picture analyzing system) was 1, 624.3±241.7 mm2 (Mean±S. E.) for the main lesion and 422.8±82.7 mm2 for the sub-lesion. When comparison was made of two groups namely, cases accompanying early cancer and those accompanying progressive cancer, both the main and sub-lesions were larger in the cases accompanying progressive cancer (P<0.005) . By the macroscopic type, the main and sub-lesions were of the same type in many of the cases accompanying early cancer, that is, 11 (73.3 %) out of 15 cases, while no fixed tendency was seen in the cases accompanying progressive cancer. By the histologic type, the proportion of differentiated type of cancer was high with 27 cases (62.8 %) for both the main and sub-lesions, and this tendency was stronger in the sub-lesions. The differentiated type/undifferentiated type ratio was 2.6 in the main lesion and 3.8 in the sub-lesion. By the surrounding mucosa of the lesions, many cases belonged to the intermediate zone with the main lesion 69.8 % and sub-lesion 74.4 %, and this fact suggested association between the intermediate zone and development of cancer. As for the mode of arrangement of the lesion, the oblique arrangement was found the most with 53.5 %, followed by the vertical arrangement with 25.6 % and the horizontal arrangement with 20.9 %. The distance between lesions in each arrangement was 46.0±6.3 mm, 27.0±7.4 mm and 22.9±8.5 mm respectively, the longest distance being in the oblique arrangement (P<0.05) .

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Mitogen-stimulated mononuclear blood cells produce differentiation-inducing factors (DIFs) for the human myeloid leukemia cells. We report here that human fibroblasts also produce a DIF distinguished from leukocyte DIFs. WI-38, a human diploid cell line derived from fetal lung, was used for preparing fibroblast conditioned medium (FCM) . Differntiation inducing activity in the FCM was assayed by determining several differentiation. associated properties of U937, a human monoblastic leukemia cell line derived from a patient with hystiocytic lymphoma. FCM induced NBT reducing activity and phagocytic activity, and the differentiated cells were classified as macrophage-like by morphology and lineage-specific a-naphthyl acetate esterase stain. The factor in FCM was stable at pH 2, at 70°C for 30 min and sensitive to trypsin digestion. The molecular weight was approximately 80, 000 by the analysis of gel filtration, Factor (s) in FCM induced NBT reducing activity remarkably of monocytic leukemic lines, but was almost ineffective on myeloid leukemic lines. These results suggest that fibroblasts produce a proteinaceous factor which induces differentiation of monoblastic leukemia cells to monocyte/macrophage lineage.

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The purpose of this study is to clarify the effect of 1α-OH-D₃on the bone metabolism through the process of the bone graft. Eighty seven male rats of 7 week-old were grafted on the middle of femur from tibial bone and were given 1α-OH-D₃every day. Following biochemical changes in the serum, radiological findings and histological findings of bone tissue were studied. The results are summarized as follows: (1) Serum calcium in the 1α-OH-D₃group was noted at high level, but it was in normal ranges. 1α-OH-D₃elavated the serum level of alkaline phosphatase activity at the early stage. (2) At the early stage of the bone graft, bone resorption in the 1α-OH-D₃group could be seen severely around the grafted bone through the radiological findings and contact microradiograms, and also the bone formation could be observed amply from the grafted bone to endosteal area of femur. (3) Through the histological findings, 1α-OH-D₃could stimulate osteoclasts and osteoblasts and promote the differentiation and function of them. In conclusion, the administration of 1α-OH-D₃during the process of the long bone graft is useful in stimulating the direct bone formation.

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With an increase in the opportunity of a catheter being placed in the central vein, many cases have been reported in which the catheter is fragmented to become a foreign matter in the major blood vessels of the heart.
A 51-year-old patient, after operation on gastric cancer, fell into a restless state and pulled out the IVH catheter by himself, leaving a broken piece of catheter about 15cm long inside. We succeeded in removing it in a non-operative manner.
A piece of broken catheter that wandered into major vessels of the heart, if left as it is, develops many complications or occasionally causes the death.
With the lapse of time after wandering into the major vessel, the broken piece moves from the vena cava to the right ventricle and further to the pulmonary artery. Therefore, it is desirable to remove it as soon as possible.
In removing it, we used a basket catheter. An approach from the right subclavial vein was made for easy removal of the piece since it was difficult to introduce the catheter from the right femoral vein.
Selecting the site of approach carefully appeared to be necessary when removing a broken catheter piece that wandered into the pulmonary artery.

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A 52-year-old housewife visited our clinic with the complaint of a continuous genereal fatigue. She had already been pointed out icterus of the conjunctiva bulbi from her childhood and medicated by a homedoctor, being followed up the slight disturbance of her liver function. Plasma total bilirubin concentration was 4.5mg/dl. Direct bilirubin in plasma was 3.9mg/dl. The other laboratory tests were normal expect for γ-GTP concentration. Diabetus mellitus was diagnosed by employing a 75g OGTT. Free blood sugar concentration was 219mg/dl.
By the laparotomy, the gray-black color of the liver was confirmed. The biopsied liver specimen showed various features, i.e. distinctive dark brown Dubin-Johnson pigments, degeneration of the hepatic cells due to both active hepatitis and Diabetus mellitus, and fibrosis.

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This case, a 72-year-old male, visited our hospital with the chief complaint of dysphagia, and the x-ray examination by barium indicated an abnormal shadow in his oesophagus. He was diagnosed as having oesophageal carcinoma and underwent subtotal oesophageal resection by trans-thoraco-laparotomy and oesophago-gastric anastomosis at the retrosternal left cervical region. According to macroscopical findings of the resected specimen, there was a well-definde, protrudes and nearly globular tumor 3.0×3.6×1.0cm in size. Histologically, the tumor was expansive type and mainly composed of undifferentiated carcinoma of the oesophagus with the depth of cancer invasion limited to the tela submucosa and partly of oat cell carcinoma (small cell carcinoma) . According to the statistics, the incidence of oesophageal adenocarcinoma is 2.3%, and that of undifferentiated carcinoma like this case is as very low as 1.7%. The prognosis of patients with undifferentiated carcinoma of the oesophagus is usually very poor. However, since carcinoma of this case was found at the superficial carcinoma (early carcinoma of the oesophagus), better prognosis will be obtained.

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