Tazanolast

Tazanolast is a selective mast-cell-stabilizing drug, on ozone-induced airway hyperresponsiveness in guinea pigs.

Signaling Pathways >> Others >> Others

Research Areas >> Inflammation/Immunology

Tazanolast, an orally active mast-cell-stabilizing drug, which has been shown to suppress passive cutaneous anaphylaxis, Schultz-Dale reaction in isolated tracheal muscle, and experimental asthma without antagonistic actions upon histamine- and leukotriene-D4-induced contraction, IgE-mediated or compound 48/80-induced histamine release from mast cells and lung fragments, compound 48/80-induced Ca2+ uptake into mast cells from extracellular medium, compound 48/80-induced translocation of protein kinase C from the cytosol to the membrane fraction of mast cells, and inositol trisphosphate production without directly inhibiting phospholipase C in mast cells[1].

Tazanolast administered before ozone exposure at doses of 30, 100, or 300 mg/kg inhibits ozone-induced airway hyperresponsiveness in a dose-dependent manner. Tazanolast administered after ozone exposure does not inhibit the airway hyperresponsiveness. Tazanolast does not significantly change the cell distribution of bronchoalveolar lavage (BAL) cells at 2 h after the exposure. Tazanolast significantly inhibits ozone-induced airway hyperresponsiveness in guinea pigs[1].

Pigs[1] The 10 guinea pigs are also exposed to 2 ppm ozone for 2 h and then are orally administered 300 mg/kg of Tazanolast (T-300 post group). At 2 h after exposure PC200-MCh of each animal is determined. Thereafter, BAL is performed for each animal. On Day 1, preexposure PC200-MCh is determined for 50 guinea pigs. On Day 2, guinea pigs in groups of 10 are orally administered Tazanolast at a dose of 30 mg/kg (T-30 group), 100 mg/kg (T-100 group), or 300 mg/kg (T-300 group), or vehicle alone (vehicle group). After 30 min, the animals are exposed to 2 ppm ozone for 2 h. In addition, the other 10 guinea pigs are also exposed to 2 ppm ozone for 2 h and then are orally administered 300 mg/kg of Tazanolast (T-300 post group). At 2 h after exposure PC200-MCh of each animal is determined. Thereafter, BAL is performed for each animal.

[1]. Igarashi A, et al. Tazanolast inhibits ozone-induced airway hyperresponsiveness in guinea pigs. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1531-5.

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MOLECULAR FORMULA :

C13-H15-N5-O3

MOLECULAR WEIGHT :

289.33

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>4 gm/kg

TOXIC EFFECTS :

Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1423 mg/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - effect, not otherwise specified Lungs, Thorax, or Respiration - dyspnea Gastrointestinal - hypermotility, diarrhea

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>4 gm/kg

TOXIC EFFECTS :

Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1119 mg/kg

TOXIC EFFECTS :

Behavioral - altered sleep time (including change in righting reflex) Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - other changes

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>4 gm/kg

TOXIC EFFECTS :

Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1120 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

USXXAM United States Patent Document. (U.S. Patent Office, Box 9, Washington, DC 20231) Volume(issue)/page/year: #4778816

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>4 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1121 mg/kg

TOXIC EFFECTS :

Behavioral - altered sleep time (including change in righting reflex) Lungs, Thorax, or Respiration - cyanosis Lungs, Thorax, or Respiration - other changes

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,5,1989

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>4 gm/kg

TOXIC EFFECTS :

Gastrointestinal - ulceration or bleeding from stomach Gastrointestinal - hypermotility, diarrhea Gastrointestinal - nausea or vomiting

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,11,1989 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

57600 mg/kg/13W-I

TOXIC EFFECTS :

Gastrointestinal - hypermotility, diarrhea Blood - changes in bone marrow (not otherwise specified) Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol)

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,53,1989

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

14840 mg/kg/53W-I

TOXIC EFFECTS :

Gastrointestinal - hypermotility, diarrhea

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,177,1989 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

24 gm/kg

SEX/DURATION :

female 13 day(s) pre-mating - 7 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,255,1989

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

13200 mg/kg

SEX/DURATION :

female 7-17 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - behavioral Reproductive - Effects on Newborn - delayed effects

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,265,1989

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

30 gm/kg

SEX/DURATION :

female 17-20 day(s) after conception lactating female 22 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :

KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 23,283,1989