Hirofumi Miyake

Clinical course and prognosis of chronic pancreatitis.

Course and prognosis of 125 patients with chronic pancreatitis (CP) were evaluated. Follow-up period ranged from 1–20 years with a median of 6.3 years. The following conclusions were obtained. Recent increase of CP in our clinics was ascribed to alcoholic CP and idiopathic CP in the aged. Of 106 patients with pain, 74 showed improvement or disappearance of pain. Drinking habit and observation period were the main factors determining the rate of pain relief. Serial endoscopic retrograde pancreatography (ERP) showed aggravation in 17/47 patients, cholecystokinin-pancreozymin (CCK-PZ) secretin test in 4/40 patients, and oral glucose tolerance test (OGTT) in 7/25 patients. Exocrine function showed improvement in five patients, whereas endocrine function showed none. Improvement or aggravation of exocrine function was closely related to drinking habit. Main complications included 15 cases of peptic ulcer, 19 of pancreatic pseudocyst, and 15 of bile duct stenosis. Twenty-six patients died, often due to malignant neoplasms and diabetic complications. Those who continued drinking as much showed a lower survival rate than those who discontinued or decreased alcohol intake. The socioeconomic status deteriorated often due to pain or alcoholism. Three patients had to degrade jobs and six fell into inactive social life.

Clinical Trial with a Protease Inhibitor Gabexate Mesilate in Acute Pancreatitis

SummaryTo evaluate whether early administration of protease inhibitors could improve mortality and morbidity in acute pancreatitis (AP), we made a retrospective analysis of 23 patients with severe AP and 88 with mild to moderate AP who were treated in our institute and four affiliated medical centers during the 10-y period from 1980 to 1990. Intravenous infusion of a protease inhibitor, Gabexate Mesilate (FOY), was started within 24 h from onset of AP (early administration) in 17 patients with severe AP and 51 with mild to moderate AP. The remaining patients were put on FOY later than 24 h from onset of AP (late administration). Comparison of the mortality and morbidity between the two groups, early vs late administration of FOY, led to the following conclusions: (1) Early administration of FOY significantly improved mortality (29.4 vs 83.3%) in severe AP, although the improvement in mortality was not directly proportional to the shortening of the time lag between the onset of AP and the start of FOY, and (2) earlier administration of FOY brought about significantly earlier recovery of abdominal pain, hyperamylasemia, and leucocytosis in mild to moderate AP.

A potent antimalarial activity of 5-fluoroorotate in combination with sulfamonomethoxine against Plasmodium falciparum in vitro and Plasmodium berghei in mice

Abstract The antimalarial activity of 5-fluoroorotate and sulfamonomethoxine, 4-amino- N -(6-methoxy-4-pyrimidinyl)benzenesulfonamide, was evaluated against Plasmodium falciparum in vitro and P. berghei in vivo. The concentrations of 5-fluoroorotate and sulfamonomethoxine required for 50% inhibition of growth (IC 50 ) of P. falciparum were 4.8 nM and 1.2 μM, respectively. In vitro, a combination of 5-fluoroorotate with sulfamonomethoxine showed potent synergy: the required concentrations in combination for 5-fluoroorotate and sulfamonomethoxine were as low as 1/12 and 1/15 of the respective IC 50 values. In vivo, although either 5-fluoroorotate or sulfamonomethoxine given orally reduced parasitemia, neither completely eliminated parasites from mice. In contrast, a combination of 5-fluoroorotate and sulfamonomethoxine produced a rapid decrease in parasitemia within 24 h and achieved complete cure of mice, with no parasite recrudescence or toxicity. These results suggest that a combination of 5-fluoroorotate and sulfamonomethoxine could form the basis of a new antimalarial combination for the treatment of human malaria.

A Colorimetric DNA Diagnostic Method for Falciparum Malaria and Vivax Malaria: A Field Trial in the Solomon Islands

Abstract We have developed a colorimetric assay, “microtiter plate-hybridization”, for the detection of malaria parasites Plasmodium falciparum and P. vivax in human blood, in which the target DNA sequences (18s small subunit ribosomal RNA gene) amplified by polymerase chain reaction (PCR) are hybridized with the species-specific probes immobilized on a microtiter well. This assay system was tested in Guadalcanal, Solomon Islands, where malaria is highly endemic. We obtained blood samples by finger puncture from 130 asymptomatic donors. Among the 130 samples, 30 (23 %) were P. falciparum positive, 28 (22 %) were P. vivax positive, and 8 (6 %) were mixed infections. The results of our DNA diagnostic method showed good correlation with those of acridine orange microscopy. §This paper is dedicated to Dr. Yoshihisa Mizuno, Emeritus Professor of Hokkaido University, on the celebration of the 75th birthday.

Role of endoscopic elimination of protein plugs in the treatment of chronic pancreatitis

SummaryThe purpose of this report is to evaluate the role of endoscopic elimination of protein plugs in the treatment of chronic pancreatitis (CP) and suspected CP. Endoscopic aspiration of pure pancreatic juice (PPJ) was performed on 69 patients with CP or suspected CP. PPJ was collected from within the main pancreatic duct by endoscopie retrograde catheterization of the papilla after a rapid intravenous injection of secretin and CCKPZ. Following results were obtained. (1) Various numbers of protein plugs were obtained along with PPJ in 26 of the 69 patients. (2) Endoscopie elimination of protein plugs provided 17 of the 26 patients with dramatic relief from abdominal pain and back pain, indicating that the procedure was often useful, at least, for relieving pain in patients with protein plugs in the pancreatic duct system. (3) Follow-up studies suggested that the procedure could be an effective therapeutic tool in selected cases of CP or suspected CP in which no prominent stenotic lesions were noted in the major pancreatic duct system and abstinence from alcohol bevarage was strictly observed. (4) In 43 patients with no protein plugs in the pancreatic juice, in contrast, transient or partial relief from abdominal pain was provided in only one patient, respectively.

Exocrine pancreatic function test by endoscopic retrograde aspiration of pure pancreatic juice

SummaryThe validity of endoscopic retrograde aspiration of pure pancreatic juice (PPJ) as an exocrine pancreatic function test was evaluated in terms of coefficients of variation in control subjects, reproducibility on repeated examinations, and sensitivity for detecting patients with chronic pancreatitis (CP). PPJ was obtained from, nine control subjects, four patients with suspected CP and 13 with CP. PPJ was collected from within the pancreatic duct by endoscopie retrograde catheterization of the papilla at 2-min intervals for 20 minutes after a bolus intravenous injection of secretin (lU/kg) and then for further 20 minutes after a bolus intravenous injection of CCK-PZ (lU/kg). It was recognized that endoscopie aspiration of PPJ was at least as useful and reliable as the traditional pancreozymin secretin test. Useful parameters included 10-min secretory volume and 10-min bicarbonate output after secretin stimulation, and 10-min enzyme output after CCK-PZ stimulation (lipase output showed higher sensitivity than amylase output). Maximal bicarbonate concentration showed poorer reproducibility and sensitivity despite better coefficients of variation. Lower limits in controls (mean-1.5SD) were 22.5ml for 10-min secretory volume, 2.7mEq for 10-min bicarbonate output, 24.5×103U for 10-min amylase output and 3.4x103IU for 10-min lipase output.

Free fatty acids in human pure pancreatic juice.

Human pure pancreatic juice (PPJ) and serum were analyzed for free fatty acids (FFAs) to study whether the damage to pancreatic cell membranes in pancreatitis is reflected as abnormal FFAs concentration and composition. Patients consisted of 13 normal controls, 7 patients with acute pancreatitis (AP) in remission, and 27 with chronic pancreatitis (CP). PPJ was collected at 2-min intervals after secretin and then cholecystokinin pancreozymin stimulation by endoscopic cannulation of the pancreas. The following results were obtained: (a) serum FFAs concentration and composition showed no significant difference between the three groups. (b) FFAs concentration in PPJ was significantly raised in CP through all secretory phases. The rise was significant only in “secretin phase” in AP. In many of the cases with raised FFAs concentration in PPJ, the FFAs composition was similar to that in serum. (c) Arachidonic acid, undetected in normal PPJ, was disproportionately high in concentration and composition in PPJ of eight patients with CP. Two mechanisms were proposed to explain these abnormalities: transudation of serum FFAs into the pancreatic duct and local production of arachidonic acid as a result of the damage to pancreatic cell membranes.

Studies on etiology and treatment of peptic ulcer

The etiology of peptic ulcer and the mechanisms of action of anti-ulcer agents were investigated by measurement of gastric blood flow. I t has been found that there are differences of blood flow between the regional border of the corpus ana antrum, and between the anterior wall and the posterior wall of corpus. The gastric blood flow was max imum in the anterior wail of corpus and min imum in the antrum. These results suggest that there are the warps of Mood flow between each gastric regions. A change in blood flow occured by some vasoactive agents and anti-ulcer agents. The remarkable increase of blood flow by histamine occured in the corpus with the exception of the lesser curvature. On the other hand, atropine caused a reduction of mucosal blood flow in the corpus. In the group of animals in which acetylcholine was administered, a remarkable increase in blood flow occured at the corpus, especially at the muscular layer of the lesser curvature, I t is known that acetylcholine is closely related to gastric motility, while the effect of histamine closely influences on gastric secretion. These results mean that there are relationship between the gastric Mood flow and gastric functions. Regarding the mechanisms of action of some anti-ulcer agents, a study was made from the standpoint of the relationship between the gastric functions and the variations of blood flow. The effects of anti-ulcer agents on the variations of blood flow between each gastric regions were investigated in the groups of animals which were administered acetylcholine and histamine. It has been found that atropine, scopolamine butylbromide, gefarnate and prostaglandin E x showed the normalizing effects of the variations of blood flow induced by acetylcholine and histamine, whereas the normalizing effect of sulpiride was not significant. On the other hand, proxazole citrate corrected the change of blood flow due to the effect of acetylcholine, while it did not prevent the effect of histamine.

The relationship between the etiology of peptic ulcer and the blood flow and metabolism in the gastric mucosa

The incidence of human peptic ulcer differs greatly by the site of the stomach. Therefore, we have conducted a series of studies on the etiology of peptic ulcer by measurements of blood flow and enzymes in the gastric mucosa. The distribution of gastric blood flow are max imum in the anterior corpus and min imum in the an t rum. Histamine, acetylcholine, epirenamine, norepinephrine and prostaglandine E affect the distribution of blood flow in the s tomach, and the blood volume shifts from an t rum to corpus. Fur thermore , the characteristic changes of blood flow are the increase in corpus except lesser curvature and the decrease in muscle layer of lesser curvature by the injection of histamine, and was the increase in the muscle layer of lesser curvature by acetylcholine. These results suggest tha t there are warps of blood flow between an t rum and corpus, and between anterior corpus and posterior. The activities of aldolase, isocitric dehydrogenase and lactic dehydrogenase are higher in the mucosa of corpus than ant rum. The ratio of HfM of lactic dehydrogenase isozyme are larger in the mucosa of greater curvature of corpus than an t rum. It is suggested that these differences in the blood flow and the specificity of metabolism account for more frequent development of peptic ulcer in the area covering lesser curvature between an t rum and corpus.