Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro.
Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors expressed on human TE671 cells. Telithromycin decreased the twitch contraction force of the rat diaphragm muscle in response to phrenic nerve stimulation in a concentration-dependent manner with an IC(50) of 22.3 microM and a maximal inhibition of approximately 70%. The trans-membrane current from the ACh receptors expressed in the TE671 neuromedulloblastoma cells was recorded in the whole-cell patch-clamp configuration. When applied to the TE671 cells, telithromycin caused a dose-dependent inhibition of the nicotinic ACh current with an IC(50) of 3.5 microM and maximal inhibition of nearly 100%. These results indicate that telithromycin inhibits postsynaptic nicotinic ACh receptors in vitro and partially blocks neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Based on these findings, we propose that exacerbation of myasthenia gravis reported in some patients taking telithromycin results in part from postsynaptic neuromuscular transmission block.
Liu
Chang-Ning
CN
Department of Investigative Toxicology, Drug Safety Research & Development, Pfizer Global R&D, Groton, CT 06340, USA.
Somps
Chris J
CJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002460:Cell Line; D017291:Clarithromycin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048628:Ketolides / Q000633:toxicity*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects*; D009466:Neuromuscular Blocking Agents / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D055366:Synaptic Potentials / Q000187:drug effects; D014403:Tubocurarine / Q000633:toxicity
D000900:Anti-Bacterial Agents; D048628:Ketolides; D009466:Neuromuscular Blocking Agents; D018733:Nicotinic Antagonists; D017291:Clarithromycin; C106791:telithromycin; D014403:Tubocurarine