A novel series of CCK-B/gastrin receptor antagonists—ureidomethylcarbamoylphenylketone derivatives—were designed, synthesized, and evaluated for activity. Structure-activity relationship studies ...revealed the importance of a carboxylic acid at substituent R
2 and a
tert-butoxycarbonyl group at R
1 in structure
A. Compound
7a (
S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of
7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED
50 value of 0.014 mg/kg. Furthermore,
7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus,
S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.
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We report a case of long-term surviving pancreatic somatostatinoma with multiple liver metastases treated by reduction surgery and repeated transcatheter arterial embolization (TAE). A 40-year-old ...woman referred for general fatigue and weight loss, and found to have diabetes and a hypervascular pancreatic tumor and multiple liver tumors in imaging such as abdominal angiography was suspected of having endocrine tumor, so studied for hormone levels in the blood. Serum somatostatin was elevated to 56 pg/ml. Distal pancreatectomy with splenectomy was done to debulk the tumor based on a preoperative diagnosis of pancreatic somatostatinoma.TAE was done every 3 to 4 months after the operation. The metastatic liver tumors have not increased in site and no other metastasis has been detected in CT. The woman remains in good physical condition in the over 5 years since suvgery.
Cisplatin and VP-16 were used to study the induction of apoptosis in Panc-1 cells. Cisplatin and VP-16 inhibited the growth of Panc-1 cells. After 2 hours exposure to cisplatin or VP-16, attached and ...detached cells were subjected to TUNEL staining to calculate the ratio of apoptosis. In detached cells TUNEL positive ratios increased in a time- and dose-dependent manner. In Western blotting, Bax expression was obviously up-regulated, but Bcl-2 remained almost constant. The results suggested that in Panc-1 cells cisplatin and VP-16 induced apoptotic cell death which was mediated through the interaction of Bax expression in the presence of mutated p53.
We examined the association between aortic arch calcification (AAC) area and serum osteoprotegrin (OPG) regulating vascular calcification, and also examined that between serum OPG and factors related ...to renal osteodystrophy. In forty-eight CKD patients including 14 diabetics, without administration of vitamin D, who were investigated before starting dialysis, the average serum Cr was 4.8±3.9mg/dL. Serum corrected Ca, Pi, calcitriol, intact-PTH, BAP and OPG were also examined. The averaged serum corrected Ca, Pi, calcitriol, intact-PTH and BAP was 8.8mg/dL, 4.4mg/dL, 24.8pg/mL, 160pg/mL and 34.0U/L, respectively. Serum OPG correlated with AAC area (p=0.0326). Stepwise regression analysis demonstrated an independent relationship between serum calcitriol or age, and serum OPG (p<0.0001). Furthermore, serum calcitriol negatively correlated with serum OPG (p<0.0001). These results suggest that decreased serum calcitriol relates to vascular calcification in CKD patient before starting dialysis.
We tried to evaluate arterial stiffness in hemodialysis patients based on increased pulse wave velocity (PWV) during noradrenaline (NA) load, since it has been reported that vasoconstriction by NA ...load was accelerated following the development of atherosclerosis. We measured plasma NA level (pNA) and PWV (baPWV, hbPWV) before, 100μg/hr and 200μg/hr NA load during ECUM without ultrafiltration one day after dialysis in 13 patients. In addition, we measured pNA and PWV before and 200μg/hr NA load during ECUM without ultrafiltration one and two days after dialysis in 8 patients. We found a significant positive correlation between the increase of pNA and that of baPWV during 200μg/hr NA load. The % increase of baPWV and hbPWV during 200μg/hr NA load in the dialysis session with larger body weight gain was significantly decreased in that with smaller gain. In conclusion, it was possible to evaluate the degree of arterial stiffness by the increased PWV after 200μg/hr NA load during ECUM without ultrafiltration one day after dialysis.
This report describes a case of bilateral osteonecrosis of the humeral capitellum in an adult patient. A 23-year-old male complaining of right elbow pain visited to our hospital in August 1999 ...several weeks after a slight elbow injury. Roentgenograms of his right elbow demonstrated a radiolucent area in the right humeral capitellum and irregular subcortical bone. The same findings were present in his left elbow. He was treated conservatively for about three months but the condition of his right elbow deteriorated. Upon admission, he underwent continuous epidural anesthesia, physical therapy, arthroscopy of the elbow joint and bone peg grafting. At four months after the operation, the patient had good elbow mobility and was free from elbow pain. Careful follow-up is required to prevent the reccurence of the pain.
Mutation in the mitochondrial gene at position 3243 was recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated ...insulin secretion in pancreatic beta-cells, we therefore searched for such mutations to detect a candidate gene for diabetes. We screened 10 diabetic subjects with clinical features suggesting mitochondrial DNA mutations. An adenine to guanine point mutation in tRNALysin at position 8296 (the 8296 mutation) was newly identified. Subsequently, we screened 1216 diabetic subjects, 44 patients with sensorineural deafness subjects and 300 non-diabetic control subjects for this mutation. We identified the mutation in 11 (0.90%) unrelated diabetic subjects, one (2.3%) patient with deafness and no non-diabetic control subject. Seven of these 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands. Four family pedigrees showed maternal inheritance of diabetes over two or three generations. Subjects carrying the 8296 mutation may develop diabetes and the mutation can explain as high as ca. 1% of the causes of diabetes.
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