Effects of S-0509, a novel CCKB/gastrin receptor antagonist, on acid secretion and experimental duodenal ulcers in rats

Background:

S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ureidomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and selective CCK_B/gastrin receptor antagonist that does not affect the central nervous system.

Methods:

We evaluated the effects of S-0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L-365,260, another CCK_B/gastrin receptor antagonist.

Results:

S-0509 (0.1~10 mg/kg, i.d.) was able to dose-dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 μg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 μg/kg/h, i.v.). L-365,260 (10 and 30 mg/kg, i.d.) caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including peptone treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/kg, s.c.) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 weeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole when it was given as a pre-treatment. It also promoted significantly the healing of these ulcers (> 3 × 2 mg/kg, p.o.) when it was given twice daily for 14 days. In contrast, L-365,260 (30 mg/kg) tended to reduce the severity of mepirizole-induced duodenal ulcers, with a slight inhibition of acid secretion, but it caused no influence on the healing response of these ulcers.

Conclusion:

These results confirmed that S-0509 is a selective CCK_B/gastrin receptor antagonist with potent antisecretory action in vivo conditions, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCK_B/gastrin receptors.

     

Comprehensive treatment of advanced neuroblastoma involving autologous bone marrow transplant

Encouraging results are reported with high-dose chemotherapy and total body irradiation followed by autologous bone marrow transplantation in the treatment of advanced neuroblastoma. However, relapse remains a significant problem. We used high-dose chemotherapy, surgery, intraoperative radiation and an autologous bone marrow transplant treated in vitro to remove tumor cells followed by 13-cis-retinoic acid to treat 36 children with advanced neuroblastoma. This comprehensive treatment appears to improve the survival rate of patients with advanced neuroblastoma, including those with N-myc amplification and bony involvement. The disease-free survival rate was 66% (95% confidence interval, 49–84%) at 3 years. All patients who received 13-cis-retinoic acid developed cheilitis, but no bone marrow depression occurred in these patients. Five patients developed hemolytic uremic syndrome (HUS) post-transplant. This may have been related to the procedure used for total body irradiation. Patients who had their kidneys shielded during this procedure did not develop this syndrome. Patients who received local irradiation at the primary site showed no evidence of relapse in this region, indicating that such therapy may help to prevent a relapse. These data suggest a high rate of 3 year disease-free survival with this treatment strategy. The nonrandomized nature of the study and use of multiple modalities precludes analysis of the specific contribution of each.     

High incidence of papillary renal cell tumours in patients on chronic haemodialysis

Papillary and nonpapillary renal cell tumours can be differentiated according to their genetic constitution. In this study, their incidence in end stage kidney disease has been investigated histologically. Nonpapillary renal cell carcinoma was observed in 22 cases (51.2%) whereas papillary renal cell tumours were diagnosed in 21 (48.8%) of the 43 patients with end stage kidney disease. The incidence of papillary renal cell tumours in end stage kidney disease is significantly higher (χ²= 31.9; P <0.001) than in the general population (4.8%). Haemodialysis patients with nonpapillary and papillary renal cell tumours did not show significant differences in age, sex or size of tumour. However, patients with papillary renal cell tumours had received longer duration of haemodialysis than patients with nonpapillary renal cell carcinomas. These data suggest that not only different genetic events but also different aetiological factors are involved in the development of the two types of tumour in end stage kidney disease.     

Neonatal alloimmune thrombocytopenia involving HPA-5b (Bra): A rare Japanese Case

Neonatal alloimmune thrombocytopenia (NAIT) is caused by platelet antigen incompatibility between the mother and fetus. The frequency of NAIT varies among ethnic groups. In Caucasians, HPA-5b (Br^a) is the antigen that is second most frequently implicated. In Japan, NAIT due to anti-HPA-5b antibody is quite rare. The present case is the second case of Br^a-NAIT in Japanese and the first case serologically confirmed by monoclonal antibody-specific immobilization of platelet antigens.     

An early onset of hereditary progressive dystonia with marked diurnal fluctuation: Determining clinical status using gait analysis

We report on a 5 year old girl who has hereditary progressive dystonia with marked diurnal fluctuation that improved remarkably after treatment with L-dopa. A gait analysis of the patient was done and we compared her gait patterns with those of a normal child. The following results were obtained. Before L-dopa treatment: (i) knee extension time was prolonged with genu recurvatum; (ii) the flexors and the extensors were simultaneously activated in the stance phase, and reciprocity between them was impaired; and (iii) recorded sole contact was a toe-only pattern. After L-dopa treatment: (i) the step cycle was shorter mainly due to a shorter knee extension time; (ii) genu recurvatum improved; (iii) reciprocal activities of the flexors and the extensors were observed; and (iv) a normal sole contact pattern was also observed. The data from the gait analysis were useful in stabilizing the subject's clinical condition and in evaluating changes to it.     

Disaccharide analysis of the skin glycosaminoglycans in systemic sclerosis

The disaccharides constituting chondroitinase-digestible glycosaminoglycan (GAG) in the skin lesions of patients with systemic sclerosis were determined using high-performance liquid chromatography (HPLC). In scleroderma there was an increase in the amount of delta Di-4S(DS), the main disaccharide unit of dermatan sulphate, and a decrease in delta Di-HA, the disaccharide unit of hyaluronic acid, as compared with normal skin from a similar site. The distribution pattern of the main disaccharides constituting chondroitin sulphate and dermatan sulphate in scleroderma differed from that in scars or scleredema.     

Mixed tumour of the vagina

A 33-year-old Japanese woman presented with a polypoid 2.5 × 2.5 × 1.9 cm mass located in the posterior wall of the lower vagina. Microscopically, the tumour was composed of benign epithelial and stromal-type elements. Predominant epithelial elements were mucinous glands with squamous metaplasia and islands of mature squamous epithelium. The stromal-type cells showed reticular or short fascicular patterns with a transition to the epithelial elements. There was no dual epithelial-myoepithelial combination in the glands as seen in so-called mixed tumours (pleomorphic adenomas) of the salivary gland. Immunohistochemically, the epithelial elements were strongly positive for cytokeratin, PKK1 and epithelial membrane antigen, while the stromal-type cells co-expressed PKK1 and vimentin. Staining for S-100 protein, muscle actin, alpha-smooth muscle actin, desmin, and CD34 was uniformly negative in the tumour cells. The DNA pattern was diploid. The patient is alive and well without recurrence for 50 months after excision. These results indicate that an epithelial cell proliferation, probably of the remnant vestibular gland, plays a major role in the development of mixed tumours of the vagina.     

Acute Gastric Mucosal Lesion in the Aged

Abstract: Over a period of 3 years between August 1985 and July 1988, 110 patients (male/female ratio, 64: 46, age range 22–89 years, mean 48.1 years) were diagnosed endoscopically as having acute gastric mucosal lesion (AGML). These patients were divided into an elderly group (60 years or more, 26 patients) and a younger group (less than 60 years, 84 patients). The chief complaint, the precipitating factors, the location of the lesion, the disease type, the background gastric mucosa and the state of bleeding were compared between the groups. AGMLs in elderly patients were found to have the following characteristic features. The chief complaints included hematemesis and melena, and oral drugs were the precipitating factor in many patients. The lesion often occurred in the body or whole area of the stomach, and was found to be relatively rare in the vestibule. An acute gastric ulcer was the most frequent clinical finding. The background gastric mucosa was rated C-II or more severe in most cases. Overt bleeding was present in many cases, requiring endoscopic hemostasis.     

Growing cavernous haemangioma of the liver: 11-fold increase in volume in a decade

A 57 year old Japanese male was incidentally found to have a 7.5 cm diameter hepatic haemangioma. Eleven years later he was operated on because the haemangioma had grown into a 17 cm mass causing upper abdominal fullness. Volumetry on computerized tomograms disclosed that the haemangioma had grown from 123 cm3 to 1343 cm3 in volume. Quantitative documentation on growing hepatic haemangioma has been rare.