Abstract:The M1-selective antimuscarinic drugs pirenzepine and telenzepine moderately reduce gastric acid secretion without inhibiting smooth-muscle activity as much as nonselective antimuscarinics, e.g. atropine and 1-hyoscyamine. They hasten peptic ulcer healing and improve the symptoms of reflux oesophagitis. In combination with H2 receptor antagonists they abolish gastric acid secretion almost completely and can therefore be used in high-risk peptic conditions. Long-term trials have to show wh… Show more
“…Strategies to mitigate side effects of anti-muscarinics include development of receptor sub-type specific (or highly selective) compounds that have limited distribution and tissue penetration profiles. For example, oral delivery of the hydrophilic M 1 R selective antagonist pirenzepine was developed to allow local delivery to the alimentary tract for treatment of ulcers (Carmine and Brogden, 1985;Stockbrugger, 1988). Similarly, the development history of oxybutynin to treat overactive bladder shows progression from oral to topical transdermal gel and patch formulations to avoid first pass metabolism in the upper GI tract and liver, thereby reducing production of metabolites associated with side effects while maintaining systemic therapeutic levels of the parent compound (Sand, 2009).…”
Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M 1 receptor selective muscarinic antagonist pirenzepine when delivered by sub-cutaneous injection, oral gavage or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6hr postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of streptozotocin-diabetic mice dosedependently (0.1-10.0%) prevented tactile allodynia, thermal hypoalgesia and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia while withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 days per week. Similar local effects were noted with the non-selective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies.
“…Strategies to mitigate side effects of anti-muscarinics include development of receptor sub-type specific (or highly selective) compounds that have limited distribution and tissue penetration profiles. For example, oral delivery of the hydrophilic M 1 R selective antagonist pirenzepine was developed to allow local delivery to the alimentary tract for treatment of ulcers (Carmine and Brogden, 1985;Stockbrugger, 1988). Similarly, the development history of oxybutynin to treat overactive bladder shows progression from oral to topical transdermal gel and patch formulations to avoid first pass metabolism in the upper GI tract and liver, thereby reducing production of metabolites associated with side effects while maintaining systemic therapeutic levels of the parent compound (Sand, 2009).…”
Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M 1 receptor selective muscarinic antagonist pirenzepine when delivered by sub-cutaneous injection, oral gavage or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6hr postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of streptozotocin-diabetic mice dosedependently (0.1-10.0%) prevented tactile allodynia, thermal hypoalgesia and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia while withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 days per week. Similar local effects were noted with the non-selective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies.
“…Telenzepine is an analogue of pirenzepine, and moderately reduces gastric acid secretion with no effect on blocking smooth muscle activity compared to atropine. 136 Due to its low efficacy and undesirable anticholinergic side effects, coupled with the success of omeprazole as a more effective acid suppressant, telenzepine is no longer available for clinical use. 137 Finally, umeclidinium was discarded from this model because it has a high molecular weight, low lipophilicity, and low solubility ( f Csp 3 ) ( Table 3 ; ESI, Fig.…”
“…Furthermore, pirenzepine acts as a lead structure for the development of novel mAChR ligands. The most notable examples which arose from this strategy are the mAChR M1 antagonist telenzepine 24 , the M2/M4 antagonist AF-DX-384 25 and the M2 antagonists AF-DX 116 26 and AQ-RA 741 27 . Figure 1 Overview of synthetic routes of pirenzepine dihydrochloride.…”
Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.
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