Pirenzepine dihydrochloride

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

In Vitro: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].

In Vivo: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].

References:
[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.

Controlled double-blind study of the therapeutic effect of pirenzepine dihydrochloride in duodenal ulcer. Phase III study.[Pubmed:3527182]

Arzneimittelforschung. 1986 Jun;36(6):980-3.

A controlled double-blind study was performed in 17 institutes using gefarnate as a control drug in order to investigate the therapeutic effect and safety of Pirenzepine dihydrochloride (LS 519) in duodenal ulcer. A total of 233 subjects were studied, 110 in the pirenzepine group (LS group) and 123 in the gefarnate group (GF group). Final improvement rate of ulcer lesions (8 weeks) of LS group showed the highly significant superiority over the GF group. Cumulative healing rates based on endoscopic findings of 17.9, 49.4, 67.0, 84.2 and 91.2% were found for the LS group at the 2nd, 4th, 6th, 8th, 10th and 12th weeks, respectively; the respective values for the GF group being 14.7, 33.0, 51.5, 66.7, 70.5 and 72.4%. Thus, the LS group showed a significantly superior acceleration of healing to that of the GF group on all occasions but the 2nd week. The improvement rate of subjective symptoms for moderately and markedly improved cases together totalled 98.9% for the LS group and 81.2% for the GF group, indicating the significant superiority of the former. These results proved the excellent therapeutic effect of pirenzepine. No significant difference in safety was found between the two drug groups. Gastric analysis was carried out before the start of drug administration and of its termination. In the healed subjects treated with pirenzepine there were a significant decrease in the secretion volume and acid output, and also a tendency to decrease in the acidity in basal secretion; and further a tendency to decrease in the acidity in maximally stimulated secretion.

HPLC determination of pirenzepine dihydrochloride in rabbit aqueous humor.[Pubmed:16002348]

J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Aug 5;822(1-2):300-3.

Pirenzepine was considered as a pharmacologic agent of preventing form-deprivation myopia. To assess the ocular bioavailability of pirenzepine, a HPLC method for determination of pirenzepine in rabbit aqueous humor was developed. An HPLC system was used in the reverse phase mode for the determination of pirenzepine. A Luna RP18 5 microm 4.6 mm x 150 mm column was employed at 35 degrees C. The mobile phase was methanol/0.02 M KH2PO4/sodium 1-pentanesulfonate (350/650/1, v/v/m, pH was adjusted to 8.0 by dropping 1M NaOH). The flow rate was 1 ml/min. Pirenzepine was monitored at 280 nm. Sample treatment procedure consists of deproteinisation with methanol. Calibration curves fitted by plotting the peak area versus concentration were linear in the range 20-400 ng/ml. The limit of quantification (LOQ) of present method was 20 ng/ml. Within-day and inter-day coefficient of variation was lower than 10%. Analytical recoveries were determined as 92.4, 95.4 and 101.4% at concentrations of 40, 200 and 400 ng/ml. In conclusion, this HPLC method using a simple sample treatment procedure appears suitable for monitoring ocular concentration of pirenzepine.

Treatment of Campylobacter pylori gastritis: a pilot study using pirenzepine dihydrochloride (Gastrozepin) and three formulations of colloidal bismuth subcitrate (De-Nol).[Pubmed:3054641]

N Z Med J. 1988 Oct 26;101(856 Pt 1):651-4.

Antral biopsies were obtained to detect Campylobacter pylori infection in 382 patients referred for gastroscopy. One hundred and seventy four patients (46%) were infected. Infection was strongly associated with histological gastritis (p less than 0.001), but there was no association between histological antral gastritis and the appearance of the gastric antrum during gastroscopy. Because it has been suggested that the lower relapse rate for duodenal ulcer following colloidal bismuth subcitrate (CBS) is due to suppression of C pylori we investigated different formulations and dosing of CBS for their efficacy in clearing C pylori. Seventy four infected patients were prospectively assigned to therapy with pirenzepine (11 patients) or one of four regimens of CBS; one swallow tablet 4 times a day (11 patients); two swallow tablets twice daily (16 patients); two buffered swallow tablets twice daily (14 patients); or two chew tablets twice daily (22 patients). All patients treated with pirenzepine and one CBS swallow tablet 4 times a day were still infected after treatment. Infection was not detected in 16 patients taking twice daily doses of CBS; 8 (50%), 3 (21%) and 5 (23%) patients taking two standard, buffered or chew tabs twice daily respectively. Improvement of histological gastritis was observed only in those patients apparently cleared of C pylori (p less than 0.01) and this was due to a decrease in polymorphonuclear leukocytes. Nine patients apparently cleared of the infection were rebiopsied 44-137 days following treatment and 6 (66%) were found again to be infected. This study suggests that suppression of C pylori may vary with the formulation and dosing of CBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Inverse agonist activity of pirenzepine at M2 muscarinic acetylcholine receptors.[Pubmed:10205015]

Br J Pharmacol. 1999 Mar;126(5):1246-52.

1. The intrinsic properties of muscarinic ligands were studied through their binding properties and their abilities to modulate the GTPase activity of G proteins coupled to muscarinic M2 receptors in pig atrial sarcolemma. 2. Competition binding experiments were performed with [3H]-oxotremorine-M to assess the affinity of receptors coupled to G proteins (R*), with [3H]-N-methylscopolamine ([3H]-NMS) to estimate the affinities of coupled and uncoupled receptors (R*+R) and with [3H]-NMS in the presence of GppNHp to assess the affinity of uncoupled receptors (R). 3. The ranking of Ki values for the agonist carbachol was R*<R*+R>R (174, 155, 115 nM), suggesting inverse agonism. 4. The Vmax of the basal high affinity GTPase activity of pig atrial sarcolemma was increased by mastoparan and decreased by GPAnt-2 indicating the relevance of this activity to G proteins coupled to receptors (R*). The K(M) value (0.26-0.33 microM) was not modified by mastoparan or GPAnt-2. 5. Carbachol increased the Vmax of GTP hydrolysis (EC50 8.1+/-0.3 microM), whereas atropine and AF-DX 116, up to 1 mM, did not modify it. Pirenzepine decreased the Vmax of GTP hydrolysis (EC50 77.5+/-10.3 microM). This effect was enhanced when KCI was substituted for NaCl (EC50 11.0+/-0.8 microM) and was antagonized by atropine and AF-DX 116 (IC50 0.91+/-0.71 and 197+/-85 nM). 6. Pirenzepine is proposed as an inverse agonist and atropine and AF-DX 116 as neutral antagonists at the muscarinic M2 receptor.

Pharmacological profile of selective muscarinic receptor antagonists on guinea-pig ileal smooth muscle.[Pubmed:8200421]

Eur J Pharmacol. 1994 Mar 3;253(3):275-81.

The present study examined the effects of a series of tricyclic muscarinic receptor antagonists on muscarinic receptors present in the guinea-pig ileum, both in vitro and in vivo. The selectivity profiles of these antagonists and that of atropine were determined by their affinity for cortical muscarinic M1, cardiac M2 and submandibular M3 receptors and for m4 receptors expressed in CHO cells. The compounds pirenzepine, UH-AH 37, AQ-RA 391 and AQ-RA 618 possessed high affinity (pKi 7.94-8.22) for muscarinic M1 receptors. Pirenzepine exhibited the most pronounced muscarinic M1 selectivity. AF-DX 384 and AQ-RA 741 possessed an approximately 10-fold higher affinity for the cardiac muscarinic M2 receptor than AF-DX 116. However, both compounds also exhibited high affinity for muscarinic m4 receptors. High affinity for muscarinic M3 and m4 receptors was observed for UH-AH 37, AQ-RA 391 and AQ-RA 681. The antagonists were then tested for their interaction with the muscarinic receptors which are responsible for the methacholine-induced contraction of longitudinal muscle in vitro, circular muscle in vivo and muscarinic receptors which mediate the distension-evoked ascending reflex contraction of circular muscle in vitro. Compounds showing high affinity for muscarinic M3 receptors (e.g. AQ-RA 618) were the most potent antagonists in the functional experiments. Comparison of the binding displacement data with the functional results indicates that the effects of methacholine on the longitudinal and circular muscle of the guinea-pig ileum were predominantly mediated by muscarinic M3-type receptors. In contrast, the correlation between muscarinic M2 receptor affinity and antagonism of muscarinic receptors in the ileum was very weak.

Pirenzepine distinguishes between different subclasses of muscarinic receptors.[Pubmed:7350532]

Nature. 1980 Jan 3;283(5742):90-2.

Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not deviate significantly from the simple Langmuir isotherm, indicating apparent homogeneity of the receptor population in any given region. In contrast, heterogeneity has been detected by agonist binding studies but this may arise from different environmental or coupling restraints on the agonist-induced conformational change and cannot be taken as evidence for different receptor subtypes. We report here binding studies using a new anti-muscarinic drug, pirenzepine, in which we found heterogeneity of binding that correlates well with the pharmacological activity.