Pirenzepine, Dihydrochloride

Pirenzepine dihydrochloride (LS519) is a selective M1 muscarinic receptor antagonist.

Signaling Pathways >> GPCR/G Protein >> mAChR

Signaling Pathways >> Neuronal Signaling >> mAChR

Research Areas >> Inflammation/Immunology

Research Areas >> Neurological Disease

The antisecretory properties of pirenzepine on gastric acid and pepsin secretion may be attributed to the antagonistic activity of the drug on muscarinic M1 receptors of gastric intramural plexuses, whereas the effect on parietal muscarinic M2 receptors seems of less importance. Additional inhibitory mechanisms on gastric secretion may be represented by pirenzepine-induced increase in somatostatin release from gastrointestinal system. Significant cytoprotective properties of pirenzepinehave been observed on a variety of experimentally induced peptic ulcerations[1]. Pirenzepine (5-500 μg/mL) inhibits agonist-(acetylcholine-, carbachol- or nicotine-) induced contractions of the toad isolated rectus abdominis muscle, and depresses electrically provoked twitches of the rat phrenic nerve-hemidiaphragm muscle preparation[2].

Pirenzepine is potent in impairing learning of an avoidance; much higher doses are required to antagonize other central muscarinic effects. Pirenzepine is found to impair passive avoidance learning when given i.c.v. 20 min pre-training. The median latencies in pirenzepine-treated animals are 79.5, 11, 27 and 25.5 seconds with doses of 0.03, 0.1, 0.3 and 1 μg per mouse respectively[3]. Acid and pepsin secretion stimulated by either bethanechol or the vagus are inhibited in a dose-responsive manner by pirenzepine[4]. Pirenzepine (5-25 mg/kg i.v.) depresses indirect electrical stimulation-evoked twitches of the cat tibialis anterior and soleus muscle preparations[2].

Dogs: In three of the Dogs, gastric secretion also is stimulated by bethanechol infused i.v. at the rate of 80 μg (0.4 μM)/kg.hr for 3 hr. Atropine (1.4, 2.8, 5.6 and 11.2 nM/kg) or pirenzepine (6, 12 and 24 nM/kg) are injected at 15-mm intervals, beginning 1 hr after initiation of bethanechol infusion. Heart rate is measured every 7.5 mm during infusion of the drugs and for 75 mins thereafter[4].

[1]. Del Tacca M, et al. A selective antimuscarinic agent: pirenzepine. Review of its pharmacologic and clinical properties. Minerva Dietol Gastroenterol. 1989 Jul-Sep;35(3):175-89.

[2]. Ojewole JA, et al. Effects of pirenzepine (Gastrozepin) on skeletal muscle contractility. Methods Find Exp Clin Pharmacol. 1983 Nov;5(9):619-23.

[3]. Caulfield MP, et al. Central administration of the muscarinic receptor subtype-selective antagonist pirenzepine selectively impairs passiveavoidance learning in the mouse. J Pharm Pharmacol. 1983 Feb;35(2):131-2.

[4]. Hirschowitz BI, et al. Effects of pirenzepine and atropine on vagal and cholinergic gastric secretion and gastrin release and on heart rate in the dog. J Pharmacol Exp Ther. 1983 May;225(2):263-8.

Carbachol | Darifenacin HBr | Arecoline hydrobromide | Glycopyrrolate | Imidafenacin | Benztropine Mesylate | Xanomeline oxalate | Batefenterol | Bethanechol chloride | Cevimeline hydrochloride hemihydrate | Otilonium Bromide | solifenacin | VU0467154 | Anisodamine | Hyoscyamine

MOLECULAR FORMULA :

C19-H21-N5-O2.2Cl-H

MOLECULAR WEIGHT :

424.37

WISWESSER LINE NOTATION :

T C676 BN DN IMVJ BV1- AT6N DNTJ D1 &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 :

5 gm/kg

TOXIC EFFECTS :

Behavioral - ataxia Behavioral - coma Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,328,1980

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

440 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

YAKUD5 Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- Volume(issue)/page/year: 23,1999,1981

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

3 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 19,735,1988

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

92 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 19,735,1988

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2600 mg/kg

TOXIC EFFECTS :

Behavioral - ataxia Behavioral - coma Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,328,1980

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

412 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

PJPPAA Polish Journal of Pharmacology and Pharmacy. (ARS Polona, POB 1001, 00-068 Warsaw 1, Poland) V.25- 1973- Volume(issue)/page/year: 33,615,1981

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2100 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 19,735,1988

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

96 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 19,735,1988

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>3700 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NIIRDN Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) Volume(issue)/page/year: -,900,1990

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

62500 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 19,544,1988

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

3 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 9,377,1975 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

52500 mg/kg/5W-C

TOXIC EFFECTS :

Liver - changes in liver weight Endocrine - changes in spleen weight Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,328,1980

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

182 gm/kg/26W-C

TOXIC EFFECTS :

Endocrine - changes in adrenal weight Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,328,1980 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

6750 mg/kg

SEX/DURATION :

female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,424,1980

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

675 mg/kg

SEX/DURATION :

female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,424,1980

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

810 mg/kg

SEX/DURATION :

female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive) Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,859,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

810 mg/kg

SEX/DURATION :

female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - behavioral

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,859,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

1350 mg/kg

SEX/DURATION :

female 17-22 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - delayed effects

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,859,1986

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1125 mg/kg

SEX/DURATION :

female 8-16 day(s) after conception

TOXIC EFFECTS :

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

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 9,377,1975

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

81250 ug/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - sex ratio

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 11,424,1980