Effect of orally administered beta-glucan on macrophage function in mice

The effect of orally administered SSG, a beta-1,3-glucan obtained from the culture filtrate of the fungus Sclerotinia sclerotiorum IFO 9395, on the function of peritoneal macrophages in CDF1 mice was examined. Oral administration of SSG (20, 40, 80 or 160 mg/kg, daily for 10 consecutive days) enhanced the acid phosphatase activity of peritoneal macrophages. The greatest enhancing effect was observed at 80 mg/kg of SSG. Relatively long periods of administration (more than 10 consecutive days) were needed to induce significant enhancing effects. Phagocytic activity, candidacidal activity, hydrogen peroxide (H2O2) production and interleukin-1 (IL-1) production of peritoneal macrophages were also enhanced after the administration of SSG by the oral route (80 or 160 mg/kg). However, the durations of the activated state after completion of administration differed depending on the activity. Enhanced activity of lysosomal enzyme (acid phosphatase) was also shown in peritoneal macrophages taken from C3H/HeJ mice, which is a nonresponder strain to bacterial lipopolysaccharide (LPS). These results demonstrate that SSG given by the oral route can activate peritoneal macrophages in mice.     

Immunomodulation by orally administered beta-glucan in mice

Orally administered SSG, a beta-1,3-glucan obtained from the culture filtrate of the fungus Sclerotinia sclerotiorum IFO 9395, was examined for effects on immune responses in mice. The proliferative responses of spleen cells from SSG-administered mice (40 or 80 mg/kg, daily for 5 or 10 consecutive days) to a T-cell mitogen, concanavalin A (Con A), or a B-cell mitogen, lipopolysaccharide (LPS), were higher than those from normal mice. Oral administration of SSG (80 mg/kg) to mice also enhanced the activities of both natural killer (NK) cells in spleen and the lysosomal enzyme of peritoneal macrophages. Furthermore, significant inhibition of tumor growth was observed in syngeneic tumor systems when SSG was administered directly after tumor implantation. The inhibiting effect required high doses of SSG (over 80 mg/kg). These results demonstrate that SSG can potentiate the immune response of mice following oral administration.     

Oral administration of SSG, a beta-glucan obtained from Sclerotinia sclerotiorum, affects the function of Peyer's patch cells.

The effect of orally administered SSG, a beta-1,3-glucan obtained from the culture filtrate of a fungus, Sclerotinia sclerotiorum IFO 9395, on the function of Peyer's patch (PP) cells was investigated in comparison with that on spleen cells in mice. Oral administration of SSG enhanced the proliferative response of PP cells to a T-cell mitogen, concanavalin A (Con A), and a B-cell mitogen, lipopolysaccharide (LPS), although the response of spleen cells was not affected. Peyer's patch cells taken from mice which had received oral administration of SSG two days before, showed enhanced plaque-forming cell (PFC) response to sheep red blood cells (SRBC) after antigen (SRBC) stimulation for 5 days in vitro. These results suggest that oral administration of SSG can modulate the mucosal immune response.     

Effects of propranolol on the pharmacokinetics of cyclosporine after intravenous and oral administration to control rats and rats with uranyl nitrate-induced acute renal failure.

Effects of propranolol on the pharmacokinetics of cyclosporine were investigated after intravenous and oral administration of the drugs to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF). Effects of intravenous propranolol, 3 mg/kg, on the pharmacokinetics of intravenous cyclosporine, 3 and 30 mg/kg, to control rats, and 30 mg/kg, to rats with U-ARF seemed to be negligible. However, the effects of orally administered propranolol, 10 mg/kg, on the area under the blood concentration-time curve (AUC) of oral cyclosporine were significant after oral administration of cyclosporine, 10 and 100 mg/kg, to control rats. For example, the AUC of cyclosporine increased significantly (33.1 versus 24.7 microg h/ml) at cyclosporine oral dose of 10 mg/kg, however, the value decreased significantly (167 versus 235 microg h/ml) at cyclosporine oral dose of 100 mg/kg. Effects of orally administered propranolol, 10 mg/kg, on the pharmacokinetics of orally administered cyclosporine, 100 mg/kg, seemed to be negligible in rats with U-ARF.     

Efficacy of mangiferin against Cryptosporidium parvum in a neonatal mouse model

The inhibitory activity of mangiferin (50 mg/kg/die and 100 mg/kg/die) on Cryptosporidium parvum was evaluated in a neonatal mouse model and its activity was compared with that of paromomycin (100 mg/kg/die). At 4 days of age, neonatal Swiss conventional outbred mice were experimentally infected by oral administration of 10⁴ oocysts/animal of C. parvum and treated orally for 10 consecutive days, starting 7 days after the experimental infection. One group of mice was left untreated. To evaluate the efficacy of mangiferin, from euthanised mice, 3-μm-thick tissue sections of the intestine were stained with haematoxylin–eosin and periodic acid Schiff. Immunohistochemistry was also used by employing a monoclonal anti-C. parvum antibody. Oocysts were counted and results were expressed as mean oocysts number/intestine. Results obtained show that mangiferin at 100 mg/kg/die has a significant anticryptosporidial activity and that its activity is similar to that showed by the same dose (100 mg/kg/die) of paromomycin. However, both mangiferin and paromomycin were not able to completely inhibit intestinal colonization of C. parvum but only to reduce it. This reduction was calculated at over 80% for both mangiferin and paromomycin with respect to the untreated control. A significant activity was found also for mangiferin at 50 mg/kg/die only after the end of treatment.     

Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs.

Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Previous animal safety studies with Qinghaosu derivatives revealed dose-dependent neurotoxicity with movement disturbances and neuropathic changes in the hindbrain of intramuscularly treated dogs, rats and monkeys. Such effects have not been seen in man. The objective of our present studies was to compare the effects of high levels of AM administered to dogs p.o. versus i.m. In a pilot study 20 mg/kg/day of AM was given i.m. to groups of 3 male Beagle dogs for 5 and 30 days, respectively. Clinical signs of neurotoxicity were noted in some individual dogs from test day 23 on. One dog had to be sacrificed pre-term. Hematologic findings indicated a hypochromic, microcytic anemia. Microscopic examination demonstrated neuropathic changes only at 30 days, but not at 5 days. The animals had neuronal and secondary axonal damage, most prominent in the cerebellar roof, pontine and vestibular nuclei, and in the raphe/paralemniscal region. The affected neurons showed loss of Nissl substance, cytoplasmic eosinophilia, shrinkage of the nucleus and in advanced stages scavenging by microglia. In a subsequent experiment, AM was administered to groups of 4 male and 4 female dogs, respectively, at 8 daily doses of 0, 20, 40 and 80 mg/kg i.m., or 0, 50, 150 and 600 mg/kg p.o. Neurologic signs were seen at high i.m. doses only. In most animals they were inconspicuous and consisted of reduced activity with convulsions seen in single dogs shortly before death. Neuronal damage occurred in all animals at 40 and 80 mg/kg following i.m. treatment. At 20 mg/kg minimal effects occurred in 5/8 dogs only, indicating that this level was close to tolerated exposure. No comparable lesions were observed after oral administration. Both i.m. and p.o. exposure at high dose levels was associated with a prolongation of mean QT interval of ECG, suggesting slowing of repolarization of the myocardium. Individual data indicated that in 1 of 4 females at 80 mg/kg i.m. this prolongation was above the 25% level considered as threshold for concern. After intramuscular administration pharmacokinetics indicated peak plasma levels of AM at 2 to 4 hours post-dose, slow elimination and a tendency to accumulate after repeated administration. Only low levels of the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the cerebrospinal fluid (CSF) were < 10% of plasma levels. After oral administration AM concentrations were considerably lower than after i.m. administration. The concentration of DHA was high on day 1 but almost nil on day 7 indicating its fast inactivation in dogs. Two hours after the 8th oral administration neither AM nor DHA was detected in CSF which may explain the absence of neurotoxicity in dogs after oral administration of AM.     

Chai-ling-tang (Japanese name: sairei-to) as an oral adjuvant.

Immunomodulating and anti-tumor activities of orally administered Chai-Ling-Tang (Japanese name: sairei-to, ST) were investigated. The oral administration of ST into mice augmented the antibody response to intraperitoneally administered 2, 4, 6-trinitrophenyl-haptenated sheep red blood cells (TNP-SRBC). Orally administered ST showed also an enhancing effect on the antibody response to TNP-SRBC administered by the oral route. In addition, orally administered ST markedly activated the peritoneal macrophages to enhanced phagocytic and lysosomal enzyme activities. A significant inhibition of tumor growth was observed in a syngeneic tumor-mouse system when ST was administered orally. These results suggest that ST has an efficiency as an oral adjuvant or an oral biological response modifier (BRM).     

Radioprotection by oral administration of Aegle marmelos (L.) Correa in vivo.

The radioprotective effect of an extract of Aegle marmelos (L.) Correa (AME), family Rutaceae, was investigated in mice exposed to different doses of gamma-radiation. Mice were administered orally AME 250 mg/kg b.wt. orally daily for 5 consecutive days before exposure to 6, 7, 8, 9, 10, or 11 Gy of gamma-radiation. The animals were monitored daily up to 30 days after irradiation for the development of symptoms of radiation sickness or death. Treatment of mice with AME before irradiation reduced the symptoms of radiation sickness and delayed death compared to the irradiated controls given sterile physiological saline (SPS). AME provided protection against both gastrointestinal and hematopoietic toxicities. Reducing the administration schedule of AME to 1 or 3 consecutive days or increasing the schedule to 7 consecutive days was not as effective as 5 consecutive days of preradiation schedule. The administration of AME after irradiation was not effective, and no survivors could be reported 30 days after irradiation. The LD50/30 was found to be 8.1 Gy for the SPS + irradiation group and 9.7 Gy for the AME + irradiation group. The oral administration of AME resulted in an increase in radiation tolerance by 1.6 Gy, and the dose reduction factor was found to be 1.2. Preradiation treatment of mice with AME caused a significant depletion in lipid peroxidation followed by a significant elevation in glutathione concentration in the liver of mice 31 days after irradiation. The drug was nontoxic up to a dose of 6000 mg/kg b.wt., the highest drug dose that could be tested for acute toxicity.     

Oral naloxone reduces constipation but not antinociception from oral morphine in the rat.

Oral administration of naloxone (10 mg/kg) antagonized the slowing of the intestinal transit caused by oral morphine (1, 2.5 and 5 mg/kg) in rats. Oral administration of naloxone (10 mg/kg) did not prevent the antinociceptive effect of orally administered morphine (2.5 mg/kg) in the tail-flick test carried out on rats. It is concluded that oral naloxone locally blocks the constipating effect of morphine, while it fails to reduce the central action of morphine due to extensive metabolization after oral administration.     

Enzyme replacement therapy in alpha-mannosidosis guinea-pigs

alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal alpha-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in alpha-mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for alpha-mannosidosis. Intravenous recombinant human lysosomal alpha-mannosidase, administered at a dose of 1mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4x normal levels) detected in circulation one week post-injection. alpha-Mannosidase administered to alpha-mannosidosis guinea-pigs at 1mg/kg (onset at birth or approximately 30 days) and 10mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10mg/kg dose, compared with untreated alpha-mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1mg/kg recombinant enzyme in alpha-mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.     

Diphenyldisulfide inhibits indomethacin-induced ulcerogenesis in rats

Indomethacin was administered subcutaneously to rats, 4 mg/kg/day for 4 consecutive days in order to produce erosions of the small intestine which were scored at necropsy on day 5. Orally administered phenidone (up to 250 mg/kg/day), a mixed cycloocygenase-lipoxygenase inhibitor, failed to produce intestinal erosions, but tended to exacerbate indomethacin-induced erosions. A 5-LO inhibitor, diphenyldisulfide, provided significant protection at 10–100 mg/kg when given orally to indomethacin-treated rats. Sulfasalazine, auranofin and cyproheptadine, but not cimetidine, also protected, suggesting a role for mast cell activation and leukotriene generation in indomethacin-induced ulcerogenesis.     

Effects of progesterone on open field behavior of food deprived ovariectomized female rats

The effects of intraperitoneal progesterone administration on the open field behavior of ovariectomized female Wistar rats were studied in two experiments. Subjects were challenged with 5 different doses of progesterone (0, 10, 20, 40, 80 mg/kg body weight) during 5 successive days of open field testing (5 min a day) in the first experiment. Progesterone dose-dependently decreased rearing and object inspection, but did not affect total ambulation. In the second experiment food pellets were presented in the open field and subjects were repeatedly tested at regular intervals after progesterone administration on each of 5 consecutive testing days. Three doses of progesterone (0, 40, 80 mg/kg body weight) were administered during the final 3 days of the second experiment. Eighty mg/kg progesterone decreased rearing activity, but increased ambulation; motivation to retrieve food pellets was not affected. These effects of 80 mg/kg progesterone were observed at least as long as 2 hours after injection. Forty mg/kg progesterone did not produce such effects. These results, in conjunction with those of other experiments show that progesterone affects open field behavior in a way similar to central depressant drugs.     

Effect of orally administered heat-killed Enterococcus faecalis FK-23 preparation on neutropenia in dogs treated with cyclophosphamide

Dogs injected intravenously for 3 days with cyclophosphamide (CY) at a dose of 10 mg/kg were given 100 mg/kg of Enterococcus faecalis FK-23 preparation (FK-23) perorally for 14 days to confirm the beneficial effects of the latter drug in neutropenic dogs when orally administered. Although FK-23 treatment did not inhibit CY-induced neutropenia, it augmented neutrophil-reconstituting capacity in these dogs. Increases in the myeloid/ erythroid ratio and neutrophilic lineages were found in the bone marrow of FK-23 administered dogs. The oral administration significantly restored the reduced activity of neutrophil phagocytosis and chemiluminescence in dogs treated with CY. These findings indicate that FK-23 administered perorally not only augments neutrophil reconstitution through the activation of bone marrow but also functions in dogs treated with CY. It may thus be a useful supportive agent to reduce the adverse side-effects associated with the administration of chemotherapeutic agents such as CY.     

Effect of FTY720, a novel immunosuppressant,on adjuvant-induced arthritis in rats

OBJECTIVE AND DESIGN: Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats. MATERIAL: Male LEW rats. TREATMENT: FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adjuvant inoculation. In addition, the anti-arthritic effect of FTY720 (0.3 mg/kg) and cyclosporin A (10 mg/kg) were evaluated by administration to animals for 5 consecutive days (days 2-6, 6-10, and 10-14). METHODS: Adjuvant-induced arthritis was produced by intradermal injection of 0.5 mg heat-killed Mycobacterium tuberculosis. Hindpaw edema was measured plethysmographically. The day of arthritis onset was determined macroscopically. Bone degradation was determined by radiography. Peripheral blood leukocytes were classified microscopically. RESULTS: All test compounds inhibited the incidence of arthritis, hindpaw edema and bone destruction. In addition, FTY720 but not cyclosporin A or tacrolimus markedly decreased the number of peripheral blood lymphocytes. FTY720 treatment on days 6 to 10 inhibited the bone destruction and hindpaw edema. CONCLUSION: These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.     

Pathological evaluation of WR-151327 administered orally in irradiated and non-irradiated male mice.

Studies were made on the radioprotective and toxic effects of orally administered WR-151327 in male CD2F1 mice. The lowest dose of orally administered drug permitting probit analysis of data was 450 mg per kg. The calculated radioprotective dose reduction factors (DRF) at 450 mg per kg and 900 mg per kg of body weight (BW) WR-151327 were 1.2 and 1.3, respectfully. Pathological examination at 8, 30 or 90 days post administration of 100, 450, or 900 mg per kg of the drug demonstrated that the major target organ for orally dosed mice was the testes. There was a decrease in the number of cells in the germinal cell layers of testes from animals administered 450 mg per kg WR-151327 or 10 Gy whole body irradiation after eight days. Moreover, there was a dramatic reduction in the germinal cells in mice seminiferous tubules treated with a combination of 450 mg per kg WR-151327 plus 10 Gy radiation after eight days.     

Effects of cyclosporin A and cyclophosphamide on Peyer's patches in rat, exposed in utero and neonatally or during adult age

The effects of cyclosporin A (CY) and cyclophosphamide (CPS) on Peyer's patches (PP) were studied in Wistar rats, exposed in utero and neonatally or during adult age. In one study, pregnant dams received 5 or 15 mg/kg bw/day CY from gestation day 6 to day 21 of lactation. In two other studies, animals were exposed at young adult age: female rats received orally 5 or 20 mg/kg/day CY or 5 or 10 mg/kg bw CPS for 4 weeks; males received orally 5 mg/kg bw CPS for 4 weeks, or a single i.v. injection of 50 mg/kg bw CPS. Upon in utero and neonatal exposure, the numbers of grossly observed PP were increased in male pups from the high-dose CY dams at 70 days of age. Exposure to high-dose CY at adult age only tended to decrease the numbers of PP; germinal center development was reduced in the PP from the middle segment of the small intestines, as examined microscopically. Exposure to both doses CPS at adult age reduced the numbers of PP and reduced germinal centre development and the number of lymphocytes in all compartments of PP. It was concluded that the effects of CPS and CY could be established by counting the number of grossly visible PP and by microscopic observation of PP, provided that regional differences of PP were taken into account. Moreover, the type of effects of an immunotoxic agent may vary with age of exposure.     

Murine delayed-type hypersensitivity granuloma: an improved model for the identification and evaluation of different classes of anti-arthritic drugs

The present study examined the effects of five different classes of anti-inflammatory/immunoregulatory drugs using a mouse model of mBSA-induced delayed-type hypersensitivity granuloma (DTH GRA) to measure immune-mediated chronic inflammatory tissue formation. The compounds were administered orally daily following induction of DTH GRA (days 0 to 4); granulomata were quantitated gravimetrically on day 5. NSAIDs, with the exception of flurbiprofen, showed little activity in comparison with the steroids dexamethasone (1-3 mg/kg/day, orally) and prednisolone (3-10 mg/kg/day, orally), which caused significant suppression of DTH GRA tissue (65-76% and 26-68%, respectively). The "immunoregulatory" compounds levamisole and D(-)penicillamine were inactive, whereas cyclophosphamide (5-50 mg/kg/day, orally) reduced the response by 24-83%. The "interferon alpha-inducers" Tilorone, U-54,461, and U-56,499 were also potent inhibitors of the DTH GRA response; U-54,462, a weak interferon alpha-inducer, was inactive. Cyclosporin A (50-100 mg/kg/day, orally) suppressed DTH GRA most effectively when administered on days 3 and 4 (66% and 97%) of the five-day granuloma response (treatment was ineffective when given on days 1 and 2). We conclude that the DTH GRA response described above may be useful for evaluating different types of unique therapeutic agents that are effective in the treatment of chronic immuno-inflammatory disease such as rheumatoid arthritis.     

Amiodarone- and desethylamiodarone-induced pulmonary phospholipidosis, inhibition of phospholipases in vivo, and alteration of [14C]amiodarone uptake by perfused lung

Amiodarone (AM) pulmonary phospholipidosis in patients receiving this drug is well recognized. We investigated the in vivo phospholipidosis-inducing potency of AM and its major nonpolar metabolite, desethylamiodarone (DEA), in rats, their ability to inhibit phospholipases, and also the effects on pulmonary uptake of [14C] AM. Fisher-344 male rats (200 to 250 g) were given AM or DEA (100 mg/kg/d orally) for 2, 7, or 21 d. Food consumption and body weight gain were significantly reduced by both AM and DEA treatment. The control rats, therefore, were pair-fed. Both drugs increased the number of cells in lavage during the treatment. Lung/body weight ratio increased after 21 d of treatment in AM rats. Mortality increased to 100% by day 10 in DEA-treated rats, unlike in AM-treated rats, where 20 to 30% of the animals died during this period and thereafter. No further mortality occurred during 21 d of treatment. Levels of phospholipids increased in lavaged lung, alveolar lavage cells, and surfactant material in AM- as well as DEA-treated rats. However, there was no significant difference between the two treatment groups. Phospholipases A and C were measured in lysosomal soluble fractions of lavaged lung and sonicated lung lavage cells. Both drugs exerted inhibitory action on phospholipases in the lavage cells but, to some extent, spared phospholipases in lysosomal plus mitochondrial soluble fraction isolated from lavaged lung with reversibility in enzyme inhibition despite continuous treatment. [14C] AM uptake by perfused lung, lavage cells as well as surfactant supernatant was increased in AM- and DEA-treated rats. Again, increase in pulmonary uptake of [14C]AM was similar in AM- and DEA-treated rats. These results thus suggest: (1) DEA is more toxic to rats than is AM, at the dose level used. The ability to sequester AM and the parameters related to phospholipidosis revealed no significant differences between these two analogs. (2) Both drugs are inhibitors of lavage cell phospholipases and also are inhibitory to lung lysosomal phospholipases to a lesser extent. Recovery of lung phospholipases occurred despite continuous treatment. (3) AM- and DEA-induced phospholipidosis increased the uptake of [14C]AM by perfused lung. (4) The mechanism of AM-induced pulmonary phospholipidosis includes selective in vivo inhibition of phospholipases.     

Uterotrophic assay,Hershberger assay,and repeated 28-day oral toxicity study of flumorph based on the Organization for Economic Co-operation and Development draft protocols

To evaluate the endocrine-mediated effects of flumorph, we performed the uterotrophic assay, the Hershberger assay, and the repeated 28-day oral toxicity study based on the OECD draft protocols. In the uterotrophic assay, female ovariectomized SD rats were subcutaneously injected with flumorph at doses of 0, 50, 150, and 500 mg/kg on each of 3 days, and no changes were observed. In the Hershberger assay, castrated male SD rats were administered with flumorph by oral gavage at doses of 0, 50, 150, and 500 mg/kg/day for 10 consecutive days, and no abnormal changes were observed. However, in the repeated 28-day oral toxicity study , flumorph was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days, a significantly increase in T₄ value in male rats and TSH value in female rats were detected in the highest dosage group, respectively. Besides, the flumorph administration increase liver weights, produce hepatocellular diffuse fatty degeneration, and effect biochemical parameters related to liver function in male and/or female rats in dosed groups. Therefore, flumorph is concluded to have thyroid disruption effects and is likely a thyroid disrupter, but the further studies are needed for hazard identification.     

Inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action,on compound 48/80-induced gastric mucosal lesions in rats

We evaluated the inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a peptidoleukotriene antagonist) and cimetidine (a histamine H₂ receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its peptidoleukotriene antagonistic activity.