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Effect of WAL-801, a new antiallergic drug, on chemical mediator-induced bronchoconstrictions in guinea pigs
227
pharmacokinetic parameters were examined in guinea pig. The absorption rates of a-Terpineol by aerosol inhalation and oral administration were rapid. The drug was distributed widely in vivo. It was found in tracheal smooth muscle, lung, heart, liver and kidney with rather high concentrations. The elimination rate of a-Terpineol was fast, its biological half-lives were 5.92 and 8.45 hours for inhalation and oral administration, respectively. a-Terpineol mainly excreted in urine as unchanged form. a-Terpineol were given by aerosol to treat 400 cases of bronchial asthma FEV, and MMEF were increased after treatment. Total effectiveness was 98% of cases. It had very low frequency of increase in heart rate. I P.mo.017 I
Antiallergic effect and its mechanism of te
e
Bian, R.-L. Institute of Clinical Pharmacology, Zhejiang Medical University, People’s Republic of China
Tetrandrine (5 mg/kg and 30 mg/kg, i.v.; 100 mg/kg and 300 mg/kg, i.g.) inhibited passive cutaneous anaphylaxis, reversed cutaneous anaphylaxis of rats, Forssman cutanous vasculitis reaction of guinea pigs, Arthus reaction of rabbits, foot pod delayed anaphylaxis of mice induced by red blood cells of sheep and contact dermatitis induced by dinitrofluorobenzene, respectively. It also inhibited Schultz-Dale reaction of Ileum tracheal smooth muscle and lung strip of guinea pigs at 3-15 pg/rnl concentration. IC,, for histamine and acetylcholine were 50 ag/ml and 66 pg/ml on the ileum of guinea pigs, respectively. IC,, for SRS-A was 6-6.6 pg/ml on the tracheal and lung strip of guinea pig. Tetrandrine (0.25 nM) provented the degranulation of rat peritoneal mast cells induced by antigen (redix trichosanthis; 10 as/ml), ionophore calcimycin (A23187,lSO nM) or compound 48/80 1 pg,/ml under transmission and scanning electron microscopes, and inhibited the release of histamine from mast cells induced by antigen or dextran. The cyclooxygenase of sheep vesicular glands and lipoxygenase of pig leukocytes were inhibited by 0.25 mM tetrandrine. Tetrandrine (0.25 mM) suppressed the 45Ca influx via the histamine-opened channel and the high K-opened channel in dog and guinea pig tracheal smooth muscle Tetrandrine (32 pM or 65 PM) inhibited the increase by calcimycin (25 PM), leukotriene B4 (60 CM) platelet activating factor (10 PM) of intracellular Ca in rat neutrophils exposed to Hank’s solution containing Ca.
1P.mo.018 1
Effect of WAL-
1, a new antiallergic drug, on the bronchoconstrictions irbguinea pigs
iator-in
Kanai, Y. and Misawa, M. Department of Applied Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebaro, Shinagawa-ku, Tokyo 142. Japan
WAL-801 (3-amino-9,13b-dihydro-lH-dibenz-(c,f)imidazo(lJ-a)azepine hydrochloride) is a new antiallergic drug with HI-receptor blocking activity, devoid of central depression such as sedation and drowsiness. WAl-801 is known to inhibit the release of chemical mediators from mast cells. In the present study, the effects of WAL-801 on the bronchoconstrictor actions of chemical mediators probably playing a role in bronchial asthma, such as histamine, substance P, bradykinin and U-46619, a thromboxane AZ mimetic, were studied in comparison with those of other antiallergic drugs, such as ketotifen, azelastine and oxatomide. Male Hartley guinea pigs (250-420 g) were orally administered the antiallergic drugs 1 hr before i.v. administrations of the above chemical mediators. Water (vs. WAL-801, ketotifen and azelastine) and 0.3% CMC-Na (vs. oxatomide) were given to the control groups. The animals anesthetized with pentobarbital-Na (48 rng/-kg, i.p.), were immobilized with decamethonium bromide (2 mg/kg, i.v.) and ventilated artificially through a tracheal cannula at a frequency of
Systemic arterial blood pressure was monitored from a cannula inserted into the left carotid artery. measured by a modification of Konzett-Riissler method. The lung was inflated at a nstant pressure (5 cm H,O), and ventilation overflow (VO) was continuously recorded as strattons of histamine (3,10, 30 nM/kg), substance P (3, 10, 30 nM/kg), bradykinin (30, 100 10, 30 nM/kg) caused an increase in VO in a dose-dependent manner, accompanied by decrease by histamine, substance P and bradykinin; increase by U-46619). WAG801 (0.01, the histamine-induced bronchoconstriction, markedly and dose-dependently. The antiof WAL-801 was almost equivalent to those of ketotifen and azelastine, and more potent than that ne of the antiallergic agents used including WAL-801 had no effect on the substance P-induced nstrtctton. WAL-801, ketotifen and azelastine significantly inhibited and oxatomide tended to inhibit the bronchoconstriction. The inhibition rates of WAL-801 to the response to bradykinin (30 nM/kg) mg/kg (p 60.01) and 79.2% for 10 mg/kg (p 6 0.01); WAL-801 showed the most potent acnvity among the antiallergic agents used. WAL-801 (10 mg/kg, p.o.) significantly inhibited the I9 (10 nlvl/kg)-induced bronchoconstriction, the inhibition rate being 38.8% (p a 0.05). On the other hand, the other drugs had no effect on the action of U-46619. From the above results, it is suggested that WAL-801 possesses interesting antimediator effects, and that the agent is promising .S a new antiasthma drug without central depression. Table 1 Effect of WAL-801 on chemicai mediator-induced bronchoconstrictions WAL-801 D@x (nrg/lrg, P-0.)
Inhibition rate(W) SP (10 nM/kg)
BK (30 nM/kg)
U-46619 (10 nM/kg)
1
18.4
10
9.8
59.3 * * 79.2 * *
8.5 38.8 *
* p
** p c 0.01 vs. control group. SP: substance P, BK: bradykinin.
P.mo.019
effect of tranilast, mast cell Hiroshi, M. and Akihide, Dept. OfPha~cv&Y,
Gifu Pharmceutical
University, 5-6-l.
K. Mitahom-higad&
(ii@ 502, Japan
There are many papers describing that mast cells may participate in the development of fibrosis in various tissues. Recently, it has been reported that tranilast, which is an inhibitor of mediator release from mast cells, has curative effect on fibrosis of scar keloid in human skin. However, the role of mast cells is not known in the development of fibrosis. In the present paper, we tried to clarify the role of mast cells as well as the mechanism of the effect of tranilast on the development of bleomycin (BLM)-induced lung fibrosis. 1) By i.v. injections of 5 mg/kg of BLM for 10 days, ICR mice caused a severe fibrosis 5 weeks after the final treatment of BLM, and C3H/He and C5?BL/6 mice did a moderate fibrosis. But, BALB/c mice did not. Mast cell counts increased in lung parenchyma of mice having lung fibrosis, but BALB/c mice did not show significant change in the mast cell counts. The severity of the fibrosis was evaluated from the histological findings and the hydroxyproline content in the lung. 2) ICR mice, which are high responders for BLM to induce lung fibrosis, were treated with varying doses of BLM i.p. The severity of lung fibrosis depended on the dose of BLM. An increase of mast cell counts in the lung parenchyma was demonstrable in mice showing lung fibrosis, and an increase of histamine content in the lung was proportional to
pharmacokinetic parameters were examined in guinea pig. The absorption rates of a-Terpineol by aerosol inhalation and oral administration were rapid. The drug was distributed widely in vivo. It was found in tracheal smooth muscle, lung, heart, liver and kidney with rather high concentrations. The elimination rate of a-Terpineol was fast, its biological half-lives were 5.92 and 8.45 hours for inhalation and oral administration, respectively. a-Terpineol mainly excreted in urine as unchanged form. a-Terpineol were given by aerosol to treat 400 cases of bronchial asthma FEV, and MMEF were increased after treatment. Total effectiveness was 98% of cases. It had very low frequency of increase in heart rate. I P.mo.017 I
Antiallergic effect and its mechanism of te
e
Bian, R.-L. Institute of Clinical Pharmacology, Zhejiang Medical University, People’s Republic of China
Tetrandrine (5 mg/kg and 30 mg/kg, i.v.; 100 mg/kg and 300 mg/kg, i.g.) inhibited passive cutaneous anaphylaxis, reversed cutaneous anaphylaxis of rats, Forssman cutanous vasculitis reaction of guinea pigs, Arthus reaction of rabbits, foot pod delayed anaphylaxis of mice induced by red blood cells of sheep and contact dermatitis induced by dinitrofluorobenzene, respectively. It also inhibited Schultz-Dale reaction of Ileum tracheal smooth muscle and lung strip of guinea pigs at 3-15 pg/rnl concentration. IC,, for histamine and acetylcholine were 50 ag/ml and 66 pg/ml on the ileum of guinea pigs, respectively. IC,, for SRS-A was 6-6.6 pg/ml on the tracheal and lung strip of guinea pig. Tetrandrine (0.25 nM) provented the degranulation of rat peritoneal mast cells induced by antigen (redix trichosanthis; 10 as/ml), ionophore calcimycin (A23187,lSO nM) or compound 48/80 1 pg,/ml under transmission and scanning electron microscopes, and inhibited the release of histamine from mast cells induced by antigen or dextran. The cyclooxygenase of sheep vesicular glands and lipoxygenase of pig leukocytes were inhibited by 0.25 mM tetrandrine. Tetrandrine (0.25 mM) suppressed the 45Ca influx via the histamine-opened channel and the high K-opened channel in dog and guinea pig tracheal smooth muscle Tetrandrine (32 pM or 65 PM) inhibited the increase by calcimycin (25 PM), leukotriene B4 (60 CM) platelet activating factor (10 PM) of intracellular Ca in rat neutrophils exposed to Hank’s solution containing Ca.
1P.mo.018 1
Effect of WAL-
1, a new antiallergic drug, on the bronchoconstrictions irbguinea pigs
iator-in
Kanai, Y. and Misawa, M. Department of Applied Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebaro, Shinagawa-ku, Tokyo 142. Japan
WAL-801 (3-amino-9,13b-dihydro-lH-dibenz-(c,f)imidazo(lJ-a)azepine hydrochloride) is a new antiallergic drug with HI-receptor blocking activity, devoid of central depression such as sedation and drowsiness. WAl-801 is known to inhibit the release of chemical mediators from mast cells. In the present study, the effects of WAL-801 on the bronchoconstrictor actions of chemical mediators probably playing a role in bronchial asthma, such as histamine, substance P, bradykinin and U-46619, a thromboxane AZ mimetic, were studied in comparison with those of other antiallergic drugs, such as ketotifen, azelastine and oxatomide. Male Hartley guinea pigs (250-420 g) were orally administered the antiallergic drugs 1 hr before i.v. administrations of the above chemical mediators. Water (vs. WAL-801, ketotifen and azelastine) and 0.3% CMC-Na (vs. oxatomide) were given to the control groups. The animals anesthetized with pentobarbital-Na (48 rng/-kg, i.p.), were immobilized with decamethonium bromide (2 mg/kg, i.v.) and ventilated artificially through a tracheal cannula at a frequency of
Systemic arterial blood pressure was monitored from a cannula inserted into the left carotid artery. measured by a modification of Konzett-Riissler method. The lung was inflated at a nstant pressure (5 cm H,O), and ventilation overflow (VO) was continuously recorded as strattons of histamine (3,10, 30 nM/kg), substance P (3, 10, 30 nM/kg), bradykinin (30, 100 10, 30 nM/kg) caused an increase in VO in a dose-dependent manner, accompanied by decrease by histamine, substance P and bradykinin; increase by U-46619). WAG801 (0.01, the histamine-induced bronchoconstriction, markedly and dose-dependently. The antiof WAL-801 was almost equivalent to those of ketotifen and azelastine, and more potent than that ne of the antiallergic agents used including WAL-801 had no effect on the substance P-induced nstrtctton. WAL-801, ketotifen and azelastine significantly inhibited and oxatomide tended to inhibit the bronchoconstriction. The inhibition rates of WAL-801 to the response to bradykinin (30 nM/kg) mg/kg (p 60.01) and 79.2% for 10 mg/kg (p 6 0.01); WAL-801 showed the most potent acnvity among the antiallergic agents used. WAL-801 (10 mg/kg, p.o.) significantly inhibited the I9 (10 nlvl/kg)-induced bronchoconstriction, the inhibition rate being 38.8% (p a 0.05). On the other hand, the other drugs had no effect on the action of U-46619. From the above results, it is suggested that WAL-801 possesses interesting antimediator effects, and that the agent is promising .S a new antiasthma drug without central depression. Table 1 Effect of WAL-801 on chemicai mediator-induced bronchoconstrictions WAL-801 D@x (nrg/lrg, P-0.)
Inhibition rate(W) SP (10 nM/kg)
BK (30 nM/kg)
U-46619 (10 nM/kg)
1
18.4
10
9.8
59.3 * * 79.2 * *
8.5 38.8 *
* p
** p c 0.01 vs. control group. SP: substance P, BK: bradykinin.
P.mo.019
effect of tranilast, mast cell Hiroshi, M. and Akihide, Dept. OfPha~cv&Y,
Gifu Pharmceutical
University, 5-6-l.
K. Mitahom-higad&
(ii@ 502, Japan
There are many papers describing that mast cells may participate in the development of fibrosis in various tissues. Recently, it has been reported that tranilast, which is an inhibitor of mediator release from mast cells, has curative effect on fibrosis of scar keloid in human skin. However, the role of mast cells is not known in the development of fibrosis. In the present paper, we tried to clarify the role of mast cells as well as the mechanism of the effect of tranilast on the development of bleomycin (BLM)-induced lung fibrosis. 1) By i.v. injections of 5 mg/kg of BLM for 10 days, ICR mice caused a severe fibrosis 5 weeks after the final treatment of BLM, and C3H/He and C5?BL/6 mice did a moderate fibrosis. But, BALB/c mice did not. Mast cell counts increased in lung parenchyma of mice having lung fibrosis, but BALB/c mice did not show significant change in the mast cell counts. The severity of the fibrosis was evaluated from the histological findings and the hydroxyproline content in the lung. 2) ICR mice, which are high responders for BLM to induce lung fibrosis, were treated with varying doses of BLM i.p. The severity of lung fibrosis depended on the dose of BLM. An increase of mast cell counts in the lung parenchyma was demonstrable in mice showing lung fibrosis, and an increase of histamine content in the lung was proportional to