Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment

Sci Rep. 2018 Jan 10;8(1):304. doi: 10.1038/s41598-017-18307-9.

Abstract

Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG. We found that at dose effectively reducing MG symptoms, C547 did not affect activity of rat urinary bladder. In contrast, at equipotent dose, pyridostigmine caused a significant increase in tonus and force of spontaneous contractions of bladder wall. We also found that this profile of ChEs inhibitors translates into the preparation of human urinary bladder. The difference in action observed for C547 and pyridostigmine we attribute to a high level of pharmacological selectivity of C547 in inhibiting acetylcholinesterase as compared to butyrylcholinesterase. These results raise reasonable hope that selective acetylcholinesterase inhibitors should show efficacy in treating MG in human patients with a significant reduction in adverse effects related to hyperactivation of smooth muscles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinesterase Inhibitors / adverse effects*
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Humans
  • Intestines / drug effects
  • Muscle Contraction
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Myasthenia Gravis, Autoimmune, Experimental / drug therapy*
  • Pyridostigmine Bromide / adverse effects
  • Pyridostigmine Bromide / pharmacology
  • Quaternary Ammonium Compounds / adverse effects*
  • Quaternary Ammonium Compounds / pharmacology
  • Quaternary Ammonium Compounds / therapeutic use
  • Rats
  • Uracil / adverse effects
  • Uracil / analogs & derivatives*
  • Uracil / pharmacology
  • Uracil / therapeutic use
  • Urinary Bladder / drug effects

Substances

  • C-547 compound
  • Cholinesterase Inhibitors
  • Quaternary Ammonium Compounds
  • Uracil
  • Pyridostigmine Bromide