Dilazep dihydrochloride

Dilazep dihydrochloride is an inhibitor of adenosine uptake. Dilazep dihydrochloride has cerebral and coronary vasodilating action through enhancement of effect of adenosine. Dilazep dihydrochloride also inhibits the ischemic damage, platelet aggregation, and membrane transport of nucleosides[1][2].

Research Areas >> Cardiovascular Disease

Signaling Pathways >> Others >> Others

Adenosine uptake

The uptake mechanism has been studied extensively in vitro and Dilazep, NBI and Dipyridamole have been reported to inhibit the uptake of adenosine into different cells. Of these compounds, Dilazep and NBI are almost 10 times more potent than Dipyridamole. In addition, only Dilazep is water soluble and no solubility aiding organic solvent is needed for preparing an aqueous solution[1].

After administration of Dilazep, even low doses (0.04-0.1 mg/kg/min) of exogenous adenosine significantly increases superior mesenteric arterial conductance (SMAC) and elevates arterial plasma adenosine concentration. The increased adenosine levels were highly correlated with the increased percentage of change of SMAC and values for Rmax and EC50 were 193.4% change of SMAC and 2.8 μM, respectively. Administration of bolus doses of 8-phenyltheophylline abolishes the ability of Dilazep to potentiate vasodilation, but did not affect isoproterenol-induced relaxation[1]. Dilazep inhibits the phospholipase activation in reperfused heart mitochondria and also inhibits the lipid peroxidation caused by cerebral ischemia and reperfusion. Dilazep may prevent ischemic cerebral injury due to an increase in cerebral blood flow and/or its protective effects on vascular endothelial cell membrane[1].

[1]. Zhang Y, et al. Dilazep potentiation of adenosine-mediated superior mesenteric arterial vasodilation. J Pharmacol Exp Ther. 1991 Sep;258(3):767-71.

[2]. Kawagoe J, et al. Effect of dilazep dihydrochloride against ischemia and reperfusion-induced disruption of blood-brain barrier in rats: a quantitative study. Naunyn Schmiedebergs Arch Pharmacol. 1992 Apr;345(4):485-8.

MOLECULAR FORMULA :

C31-H44-N2-O10.2Cl-H

MOLECULAR WEIGHT :

677.69

WISWESSER LINE NOTATION :

T7N DNTJ A3OVR CO1 DO1 EO1& D3OVR CO1 DO1 EO1 &GH 2

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 :

>2150 mg/kg

TOXIC EFFECTS :

Peripheral Nerve and Sensation - spastic paralysis with or without sensory change Behavioral - convulsions or effect on seizure threshold

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

85200 ug/kg

TOXIC EFFECTS :

Behavioral - tremor Gastrointestinal - changes in structure or function of salivary glands

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

369 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

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: 8,2044,1974

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

13700 ug/kg

TOXIC EFFECTS :

Behavioral - tremor Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - respiratory depression

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: 8,2044,1974

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2860 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - respiratory depression

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: 8,2044,1974

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

161 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

154 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

16800 ug/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - respiratory depression

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: 8,2044,1974

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>316 mg/kg

TOXIC EFFECTS :

Cardiac - pulse rate increase, without fall in BP Gastrointestinal - nausea or vomiting

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

11200 ug/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Behavioral - ataxia Gastrointestinal - changes in structure or function of salivary glands

REFERENCE :

ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 22,667,1972 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

156 gm/kg/26W-I

TOXIC EFFECTS :

Liver - other changes Kidney, Ureter, Bladder - other changes 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: 8,2062,1974

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

30 gm/kg/30D-C

TOXIC EFFECTS :

Liver - changes in liver weight Endocrine - changes in adrenal weight Related to Chronic Data - changes in ovarian weight

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: 8,2050,1974

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

336 mg/kg/28D-I

TOXIC EFFECTS :

Liver - changes in liver weight Blood - normocytic anemia Related to Chronic Data - death

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 18(Suppl 12),S3091,199

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1456 mg/kg/26W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - changes in bladder weight Endocrine - changes in adrenal weight Blood - normocytic anemia

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 18(Suppl 12),S3155,199

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

84 mg/kg/7D-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - urine volume increased Kidney, Ureter, Bladder - other changes in urine composition Nutritional and Gross Metabolic - changes in sodium

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 18(Suppl 12),S3141,199

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

728 mg/kg/26W-I

TOXIC EFFECTS :

Kidney, Ureter, Bladder - other changes in urine composition Blood - changes in platelet count Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 18(Suppl 12),S3193,199 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1750 mg/kg

SEX/DURATION :

female 7-13 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: 8,4368,1974

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

672 mg/kg

SEX/DURATION :

male 9 week(s) pre-mating female 2 week(s) pre-mating - 7 day(s) after conception

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 18(Suppl 12),S3227,199

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

6 gm/kg

SEX/DURATION :

female 7-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

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: 8,2084,1974

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

3 gm/kg

SEX/DURATION :

female 7-12 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: 8,2084,1974