Yoshiya Aze

Involvement of cysteinyl leukotrienes in biphasic increase of nasal airway resistance of antigen-induced rhinitis in guinea pigs.

We examined the effect of a specific cysteinyl leukotriene (LT) receptor antagonist, 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzopyran hemihydrate (pranlukast), on a novel model of allergic rhinitis induced by repeated intranasal ovalbumin challenge in actively sensitized guinea pigs. Repeated intranasal ovalbumin challenge caused a biphasic increase of nasal airway resistance, peaking 0.5 and 4 h after the final challenge. The early-phase response was accompanied by an increase in sneezing and nasal secretion, while that in the late phase was associated with edema and eosinophil infiltration of the nasal mucosa. Analysis of nasal lavage fluid showed that cysteinyl LTs increased in both phases. Pranlukast, when administered 1 h before every ovalbumin challenge, dose-dependently suppressed the increase of nasal airway resistance in the early- and late phase with evidence of histopathological improvements in the late phase. Pranlukast, however, failed to suppress sneezing and nasal secretion. We suggest that cysteinyl LTs play an important role in allergic rhinitis especially in the nasal obstruction due to edema of the nasal mucosa membrane.

The rat urinary bladder as a new target of heterocyclic amine carcinogenicity: tumor induction by 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate.

In order to examine the carcinogenicity of 3‐amino‐l‐methyl‐5H‐pyrido[4,3‐β]indole acetate (Trp‐P‐2), 30 male and 30 female F344 rats were maintained on diet containing 0, 30, or 100 ppm Trp‐P‐2 for 112 weeks. The overall mean chemical intakes in the 100 ppm and 30 ppm groups were 3.84 and 1.14 mg/kg/day in males, and 4.57 and 1.34 ing/kg/day in females, respectively. Females of the 100 ppm group showed increased mortality in the late period of the study. In the 100 ppm group, significant increases in the incidences of neoplastic lesions were found in the liver, urinary bladder and mammary gland in males, and in the mammary gland, hematopoietic system and clitoral gland in females. Histologically, tumors induced by Trp‐P‐2 were hepatocellular adenomas, transitional cell tumors (papillomas and carcinomas) of the urinary bladder, fibroadenomas/fibromas of the mammary gland, malignant lymphomas and clitoral gland tumors (adenomas and adenocarcinomas). These results indicate multi‐target carcinogenicity of Trp‐P‐2 in F344 rats and provide evidence that the urinary bladder is also a target for heterocyclic amine action.

Restoration of immune responses in tumor-bearing mice by ONO-4007, an antitumor lipid A derivative

ONO-4007, a synthetic lipid A derivative, has been found to exhibit potent antitumor activity in several animal models. In the present study, we examined the effects of ONO-4007 on delayed-type hypersensitivity (DTH) reaction and antibody production in Meth A sarcoma-bearing BALB/c mice. The DTH reaction to sheep red blood cells (SRBC) and the IgG production against keyhole limpet hemocyanin (KLH), were depressed in tumor-bearing mice as well as in normal mice given Mitomycin C (MMC). However, ONO-4007 restored these immune responses to normal levels. In addition, in vitro studies showed that ONO-4007 induced the production of tumor necrosis factor-alpha (TNF-alpha) in splenic adherent cells of tumor-bearing mice more than those in normal mice. Though ONO-4007 alone had little effect on the induction of IL-2 production in spleen cells, it augmented the Concanavalin A (Con A)-stimulated IL-2 production. Moreover, ONO-4007 had a mitogenic effect on spleen cells. These results suggest that ONO-4007 may improve immunocompetence in tumor-bearing hosts and contribute to the induction of antitumor immunity and prevention of bacterial infections.

Lysozyme activity of cystic mucosal and submucosal glands in the stomal area of the gastric remnant.

In order to study the lysozyme activity in the cystic mucosal and sub‐ucosal glands in the stomal area of the gastric remnant, which is one of the components of gastritis cystica polyposa, we carried out a pathological and immunohistochemical examination of 55 patients with gastric remnants, including 19 with stomal carcinoma, after partial gastrectomy for benign gastro‐duodenal diseases. These stomach specimens were examined im‐munohistochemically for lysozyme. The cytoplasm of some epithelial cells of cystic mucosal and submucosal glands, which showed characteristic changes in the gastro‐intestinal stoma as well as background changes in the stomal carcinoma, showed a strongly positive reaction for lysozyme. These strongly lysozyme‐positive cells in the cystic mucosal glands appeared more frequently in the cases of stomal carcinoma than in the non‐cancerous controls.

Blocking effects of synthetic trypsin inhibitor (camostat) on pancreatic carcinogenesis in hamsters initiated with N-nitrosobis(2-oxopropyl)amine

The effects of concomitant administration of a synthetic trypsin inhibitor (camostat) on pancreatic carcinogenesis in hamsters treated with N-nitrosobis(2-oxopropy1)amine (BOP) were investigated. Thirty-two female Syrian golden hamsters were given weekly 10 mg/kg S.C. injections of BOP for 5 weeks while simultaneously receiving a 500 ppm camostat diet (BOP + camostat group). Additional groups of 30 animals received either the S.C. injections of BOP (BOP group), or the 500 ppm camostat diet (camostat group) during the same 5-week period. Thirty weeks after the first BOP administration, the incidence of pancreatic adenocarcinomas in the BOP + camostat group was significantly lower than in the group administered BOP only (p < 0.05). Similarly, the total numbers of pancreatic adenocarcinomas or dysplas-tic lesions were significantly decreased in the BOP + camostat group as compared with the BOP group (p < 0.01). None of the animals receiving camostat alone developed any adenocarcinomas or dysplastic lesions of the pancreas. The results of the present experiments clearly show that camostat can inhibit induction of hamster pancreatic ductal neoplasms when administered simultaneously with BOP.

TOXICITY STUDIES OF LANDIOLOL HYDROCHLORIDE (ONO-1101)(1) SINGLE INTRAVENOUS TOXICITY STUDY IN RATS AND DOGS

Single dose toxicity studies of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, were conducted in Sprague-Dawley (SD) rats and beagle dogs. ONO-1101 was administered intravenously at a dose level of 37.5, 75, 150 or 300 mg/kg to rats of both sexes and 25, 50 or 100 mg/kg to male dogs. In the rat study, 5/6 males in the 150 mg/kg group and all animals in the 300 mg/kg group died during or right after administration. Survivors in the 150 mg/kg group showed temporal hypoactivity, bradypnea, dyspnea, tremor, loss of righting reflex and reddish lacrimation up to 5 min after injection. One male in the 150 mg/kg group had a tendency of suppression on body weight gain. No effects on clinical signs and body weight gain were seen in the 75 mg/kg group or lower. Necropsy findings showed only red tear in the majority of the decedents. In the dog study, all animals died within 6 min after administration in the 100 mg/kg group, showed ataxic gait, rolling and tachypnea followed by bradypnea and gasping/apnea. Incontinence of urine, defecation and vocalization were also seen in each one of two animals before death. Temporal hypoactivity was seen 1 min after administration in the 50 mg/kg group. No clinical signs were seen in the 25 mg/kg group. ONO-1101 did not affect bodyweight or food consumption. Necropsy findings of the decedents showed no abnormalities. It is indicated that the minimum lethal doses are 150 mg/kg in rats and 100 mg/kg in dogs.