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We examined the effects of SS320A ((-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid), a new cysteine derivative, on the change in the number of goblet cells induced by isoproterenol in rat tracheal epithelium. Four types of goblet cells were characterized in tracheal epithelium according to their size and staining affinity with Alcian blue (AB) / periodic acid Schiff (PAS). When each rat was given a single daily injection of isoproterenol (0.05 mg/kg, i.p.) for 14 days, a significant increase was observed in AB/PAS-positive cells that were recognizable as goblet cells in tracheal epithelium. When SS320A (10-100 mg/kg, p.o.) or propranolol (1 mg/kg, s.c.) was administered before each injection of isoproterenol, the increase in the number of goblet cells induced by isoproterenol was significantly inhibited. There was no difference between male and female rats with regard to this inhibitory action. On the other hand, ambroxol, bromhexine, L-cysteine ethyl ester and S-carboxymethylcysteine (100 mg/kg, p.o., respectively), which are used as expectorants, had no inhibitory effects on the isoproterenol-induced change in the number of goblet cells. Four metabolites (M1-M4) of SS320A in rats also failed to inhibit the change induced by isoproterenol. These data suggest that SS320A itself may have a beneficial effect against mucus hypersecretion in chronic respiratory diseases.

To examine whether cysteinyl leukotrienes (cysLTs: LTC4, LTD4 and LTE4) induce symptoms of allergic rhinitis via their receptors, we studied the following: i) the specific binding of radiolabeled cysLTs to guinea pig nasal mucosa membrane and ii) effects of nasal LTD4 challenge in normal guinea pigs. The binding study indicated that there was a single population of binding sites for LTC4, LTD4 and LTE4 with Kd and Bmax values of 34.9+/-2.0, 0.252+/-0.015 and 0.589+/-0.039 nM and 10, 140+/-490, 122+/-11 and 306+/-23 fmol/mg protein, respectively. The in vivo study showed that topical nasal challenge of LTD4 (0.1-30 microg/nose) increased nasal secretion, nasal airway resistance and nasal eosinophil infiltration without inducing sneezing. While the increases in nasal secretion and nasal airway resistance were transient, peaking 10 to 20 min after LTD4 challenge, nasal eosinophil infiltration persisted at least until 24 hr post-challenge. These nasal symptoms were dose-dependently suppressed by oral administrations of pranlukast (0.3-3 mg/kg). The results suggest that cysLTs cause not only early-phase symptoms but also nasal eosinophil migration, a characteristic associated with the late-phase symptom of allergic rhinitis, via a receptor-mediated mechanism. Cysteinyl leukotrienes, thus, may be important mediators in allergic rhinitis.

To examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclooxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas thromboxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indomethacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.

The effects of muscarinic antagonists on acetylcholine (ACh)- and histamine-induced nasal secretion were investigated in guinea pigs. Inhalations of flutropium (0.01 to 0.3%) and atropine (0.03 to 0.3%) into the nasal cavities dose-dependently inhibited the nasal secretion induced by ACh. The inhibitory action of flutropium was slightly stronger than that of atropine. Inhalations of pirenzepine (0.3%) and gallamine (0.3%) had no effect on the ACh-induced nasal secretion. However, 4-DAMP dose-dependently inhibited the nasal secretion induced by ACh. Inhalations of flutropium (0.3%) and diphenhydramine (0.3%) showed a similar inhibitory action on the histamine-induced nasal secretion. These results suggest that 1) inhalation into the nasal cavities of flutropium was effective in experimental model of ACh- and histamine-induced nasal secretion, 2) M3-cholinergic receptors may be dominant in the nasal secretion induced by ACh and 3) the experimental model of drug-induced nasal secretion in guinea pigs used in the present study can be employed to develop therapeutic drugs for nasal secretion.

The effects of flutropium on histamine (Hist)-induced increase in intranasal pressure in non-sensitized guinea pigs and nasal mucosa capillary permeability in passively sensitized guinea pigs were investigated. Flutropium (0.3%), atropine (0.3%), diphenhydramine (0.01%) and cimetidine (0.1%) were directly inhaled into the nasal cavities by an ultrasonic nebulizer for 20 min, followed by inhalation of Hist (0.1%) for 10 min. Flutropium, atropine and diphenhydramine had an inhibitory action on the Hist-induced increase in intranasal pressure in guinea pigs. Cimetidine had no effect on this system. In passively sensitized guinea pigs (the challenge was performed 48 hr after sensitization), a 0.1-1.0 mg/kg injection of flutropium (i.v.) dose-dependently inhibited the allergic nasal mucosa capillary permeability. Atropine (10 mg/kg, i.v.) had no inhibitory action on this system. These results suggest that inhalation into the nasal cavities and i.v. injection of flutropium are effective in experimental models of drug- and allergy-induced rhinitis of the guinea pig.

Higher plasma concentrations of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) were obtained after administration of FT (100 mg/kg, i.v.) combined with L-cysteine (CySH, 500 mg/kg, p.o.). The volume of distribution (Vd) and body fluid volumes significantly decreased. These results suggest that the increase of the plasma concentrations of FT can be attributed to the decrease of the Vd of FT, which is considered to be based on the decrease of body fluid volumes by the combined administration of CySH.

Elcatonin is a newly synthetized peptide that prevents experimental ulcer formation. In this study, we examined the influence of elcatonin on endogenous prostaglandin biosynthesis by the gastric mucosa with respect to its antiulcer activity. Control levels of PGE2 generation for the fundic and antral mucosa were 302 +/- 12 and 465 +/- 28 ng/g tissue/min, respectively. Pretreatment with elcatonin resulted in a dose-dependent increment in gastric mucosal PGE2 generation. We conclude that the antiulcer effect of elcatonin is probably due to its ability to enhance endogenous prostaglandin synthesis in the gastric mucosa.

A water-soluble polysaccharide, D-II with marked antitumor activity was isolated from the cultured mycelium of Coriolus versicolor by extraction with hot-water, fractional precipitation with ethanol and ion-exchange chromatography. D-II strongly inhibited the growth of Sarcoma-180 transplanted subcutaneously in mice by intraperitoneal, intravenous, subcutaneous or intra-muscular administration at a dose of 5 mg/kg. the molecular weight was estimated to be 2,000,000 by gel-filtration or 6,500,000 by light scattering analysis. The chemical structure of D-II was then investigated by periodate oxidation, methylation analysis, Smith degradation, and a combination of controlled Smith degradation and methylation analysis. These studies proposed that D-II is composed of a unit structure of four D-glucose residues, and is a glucan consisting of beta-D-1,3-linked main chain in which one for every three D-glucose residues is branched at C-6 with beta-D-1,6-linkage.

The effect of ONO-3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate), a new protease inhibitor, was studied on various proteases in vitro and in an experimental thrombosis model in vivo. ONO-3307 competitively inhibited trypsin, thrombin, plasma kallikrein, plasmin, pancreatic kallikrein and chymotrypsin; and their Ki values were 0.048 microM, 0.18 microM, 0.29 microM, 0.31 microM, 3.6 microM and 47 microM, respectively. In addition, ONO-3307 inhibited both elastase release from N-formyl-Met-Leu-Phe (fMLP)-stimulated leukocytes and tissue thromboplastin release from endotoxin-stimulated leukocytes. To examine the effects of ONO-3307 on disseminated intravascular coagulation (DIC), we developed an experimental thrombosis model. ONO-3307 (10 mg/kg/hr) completely inhibited the deposition of radioactive fibrin in kidney and lung. Gabexate mesilate (50 mg/kg/hr) was also effective in this model, but the effect of nafamostat mesilate was unclear. These results indicate that ONO-3307 exhibits a wide range of inhibitory effects on various proteases, and ONO-3307 may be useful for the treatment of protease-mediated diseases such as thrombosis and DIC.

The antiulcer action of elcatonin, an analogue of natural eel calcitonin, was compared with that of cimetidine, secretin and solcoseryl. Elcatonin (3 to 10 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. Moreover, once daily injections of elcatonin (1 to 10 mu/kg/day, s.c.) promoted the healing of acetic acid-induced chronic gastric ulcers not only in rats but in dogs. The healing effect persisted after the cessation of administrations. Cimetidine (30 to 100 mg/kg, p.o.) inhibited the development of gastric ulcers induced by water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. However, once daily administrations of cimetidine (30 to 100 mg/kg/day, p.o.) did not show significant effect on acetic acid-induced chronic gastric ulcers in rats. Secretin (30 to 100 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine in rats, but was not effective on cysteamine-induced duodenal ulcers and acetic acid-induced chronic gastric ulcers in rats. Solcoseryl (2 ml/kg, s.c.) inhibited only the development of water-immersion stress-induced gastric ulcers in rats. These results suggest that elcatonin is different from these reference drugs in its properties of action on experimental ulcers. Mechanisms of the antiulcer action of elcatonin which has a superior effect on experimental ulcers are discussed.