Long-term oral administration of NG is known to produce gastric carcinomas in dogs. This experiment was designed in order to investigate problems concerning the process of the gastric carcinomas. Adult dogs, weighing 7kg on the average, took about 300ml of 80μg/ml NG solution daily for 1, 2, 4, and 6 months, thereafter, they were sacrificed. Histologically, adenocarcinoma tubulare and/or mucocellulare developed in the angular and cardiac portions of the stomach in one of 6-months group dogs. Many erosions and shallow ulcers, including healed scars, were observed as the preceding gastric mucosal damages. Favourite sites of these mucosal defects were on the antro-angular portion near the lesser curvature and on the cardiac portion near the greater curvature. These mucosal defects increased in number in accordance with the duration of NG administration. At the margins of these mucosal defects, cuboidal cells with hyperchromatic nuclei were observed superficially near the neck zones in most cases. Lesions with these cells increased in number in proportion to the length of NG administration. And they were considered to be regenerative atypical cells possibly originated from the neck cells. Other finding was the grandular atrophy in the pyloric portions and in the upper parts of fundic portions. No intestinal metaplasia was seen. Preceding the developement of carcinomas, shallow gastric mucosal defects and regenerative atypical cells were observed at the two common sites as in cancers ever reported. The possibility of occurance of carcinomas from neck cells in the process of regeneration after the repeated mucosal defects were discussed.
To elucidate the role of trypsin inhibitor, inhibitory activity of these drugs in vitro, stability in serum and effect on exocrine pancreatic secretion were studied using clinically applicable trypsin inhibitors-Trasylol, ρ-ethoxycarbonyl-phenyl-guanidinocaproate phosphate (Synthetic I) and 4-(2-carboxyethyl) phenyl-trans-4-aminomethyl cyclohexane carboxylate hydrochloride (Synthetic II). The change in inhibitory activity together with the electrolytes and enzymes in human and canine pancreatic juice was also measured after the administration of these inhibitors. The pattern of dose related curve in inhibitory activity of these trypsin inhibitors in vitro was similar to each, revealing that the dosis of 95% inhibition of standard trypsin solution (0.1mg of Sigma trypsin) was 500KIU in Trasylol, 2mg in Synthetic I and 4mg in Synthetic II. In serum, Trasylol was stable but the inhibitory activity of the synthetic inhibitors was gradually decreased, showing 60% decrease in Synthetic I and 30% decrease in Synthetic II after 120min. By the intravenous administration of these exogenous trypsin inhibitors, inhibitory activity in serum and pancreatic juice was not influenced. The ratio of secreted trypsin inhibitor to trypsin in pancreatic juice was the approximately same in every experiment, indicating significant correlation in some of them. Therefore, it was suggested that the exogenous trypsin inhibitors in the dosis of this study were neither secreted into human or canine pancreatic juice nor enhanced the secretion of the endogenous trypsin inhibitor into pancreatic juice. The volume, electrolytes and enzymes of pancreatic juice were also unchanged, and each enzyme was secreted in parallel fashion before and after the administration of trypsin inhibitors. Then, it was concluded that trypsin inhibitors in the dosis of this study did not play any secretagogous or secretoinhibitory role.
In order to evaluate the usefulness of the peripheral lymphocyte culture method for the diagnosis of drug-induced liver injury, the present study was carried out on 21 cases of druginduced liver injury diagnosed on the basis of histologic, clinical and laboratory data (Group A) and 8 cases with liver cirrhosis of unknown etiology (Group B) as well as 17 healthy controls with normal liver function (Group C). The lymphocytes obtained from peripheral blood of the patients were cultured according to the method of Hirschhorn et al., in presence of serial concentrations of appropriate candidate drugs as a stimulant. Incorporation of C14-thymidine into lymphocytic DNA was measured as an index of lymphocyte stimulation by the method of Shtacher et al., and the uptakes over 75cpm by the total lymphocytes were judged as positive. Nine cases in Group A, 2 in Group B and 1 in Group C showed a positive lymphocytes stimu lation. The drugs which showed the positive stimulation were tetracycline, chlotaon, sigmamycin, ethionamide, PAS, sulpyrin, and ajmaline. Out of 9 cases which showed positive stimulation, six cases were cholestatic type of liver injury, and the remaining three were of hepatitic type. The lymphocyte stimulation was positive in all of 6 cases which showed over 50 units of icterus index and in all of 4 cases which showed over 15 units (Bessey-Lowrey) of serum alkaline phosphatase activity during the course of the disease. The results suggest that peripheral lymphocyte culture method is a useful method for diagnosis of drug-induced liver injury.