ICI 153110

ICI 153110 is an orally active phosphodiesterase inhibitor with both vasodilating and inotropic properties which is designed for the treatment of congestive cardiac failure.

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

Research Areas >> Cardiovascular Disease

Phosphodiesterase[1]

ICI 153110 is an orally active phosphodiesterase inhibitor with both vasodilating and inotropic properties which is designed for the treatment of congestive cardiac failure. Fourteen animals have died as a direct or indirect consequence of ICI 153110 administration in the high-dose main test and reversibility groups. In the female rat dosed at 10 mg/kg/day ICI 153110 a mild focal arteritis is characterized by a predominantly and diffusely adventitial infiltration of mixed cells and early formation of fibrous tissue. The two rats dosed at 250 mg/kg/day ICI 153110 die prematurely from intratracheal intubation of dosing solution. Arteries from two further animals (dosed at 5 and 250 mg/kg/day ICI 153110) show minimal focal arteritis with medial necrosis, and medial and adventitial inflammation[1].

Alderley Park APfSD rats are used in this study. In all, 150 male rats and 150 female rats are assigned to four groups (one control and three treatment) in the two separate studies; 30 per sex representing the main (regular) test groups and 15 per sex for investigating reversibility of effects following treatment at the highest dose employed (withdrawal studies). The dose levels are 5, 10, and 250 mg/kg/day of ICI 153110. All animals are dosed orally, by gavage, using a plastic syringe and a flexible catheter. Equal numbers of animals per sex in the four groups are necropsied necropsied at each of two time points; following at least 28 consecutive days dosing (1 month) and 182 consecutive days of dosing (6 months). All animals are observed at least twice daily for any abnormal signs, all of which are recorded. Body weights, food consumption, water consumption, clinical pathology, and pharmacokinetics are also measured[1].

[1]. Westwood FR, et al. Pathologic changes in blood vessels following administration of an inotropic vasodilator (ICI 153,110) to the rat. Fundam Appl Toxicol. 1990 May;14(4):797-809.

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MOLECULAR FORMULA :

C11-H11-N3-O

MOLECULAR WEIGHT :

201.25

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

7 gm/kg/28D-I

TOXIC EFFECTS :

Vascular - BP lowering not characterized in autonomic section Nutritional and Gross Metabolic - body temperature decrease Related to Chronic Data - death

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 14,797,1990

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

45500 mg/kg/26W-I

TOXIC EFFECTS :

Vascular - structural changes in vessels Vascular - other changes Related to Chronic Data - death

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 14,797,1990