BOSTON, Oct. 20, 2011 /PRNewswire/ -- Additional data will be presented on the mechanistic characterization of adverse events reported with the azole antifungal, voriconazole, and the ketolide antibiotic, telithromycin, at the 49th Annual Meeting of the Infectious Diseases Society of America (IDSA). The data will be presented during a poster abstract session at 12:15 to 2:15 p.m. EDT on October 21 in Poster Hall B1.
Bertrand et al. had previously shown that inhibition of neuronal nicotinic acetylcholine receptors (nAChRs) by telithromycin, which contains a pyridine side chain, may be responsible for the "Ketek effect" observed with the compound. In this study, Bertrand et al. (Abst. # 644), characterized the reason for the "curare-like" effect at the neuromuscular junction seen in myasthenia gravis patients treated with telithromycin. Voriconazole was also tested in nAChR assays because visual effects observed in patients treated with voriconazole are similar to those observed with telithromycin and the voriconazole molecule includes a heterocyclic N in its pyrimidine side chain.
The compounds were assayed by expressing human nAChRs in Xenopus oocytes. Telithromycin inhibited the presynaptic alpha-3-beta-2 nAChR and its metabolite, telithromycin-N-oxide, inhibited the post-synaptic neuromuscular junction nAChR. A telithromycin metabolite lacking the pyridine side chain generated minimal nAChR inhibition. The alpha-3-beta-4 nAChR receptor found in the ciliary ganglion of the eye was strongly inhibited by both telithromycin-N-oxide and voriconazole. Fluconazole, which has had no visual side effects, caused no significant nAChR inhibition. The authors concluded that the cumulative effects of telithromycin and its metabolite at the pre- and postsynaptic neuromuscular junction receptors, combined with an inherent defect in acetylcholine transmission in myasthenia gravis patients, can explain the curare-like neuromuscular effects after telithromycin administration. The visual effects of telithromycin and voriconazole may be attributed to both molecules' inhibitory effects on nAChRs. CEM-101, a next-generation oral and intravenous fluoroketolide in clinical development for the treatment of community-acquired bacterial pneumonia, and available macrolides, azithromycin and clarythromycin, do not have the pyridine side chain and do not significantly inhibit nAChRs.
About Cempra Pharmaceuticals
Founded in 2006, Cempra Pharmaceuticals is a clinical-stage pharmaceutical company focused on developing antibiotics to meet critical unmet medical needs in the treatment of bacterial infectious diseases, particularly respiratory tract infections and skin and skin structure infections. Our two lead product candidates have both completed oral Phase 2 clinical trials and seek to address the need for new treatments targeting drug-resistant bacterial infections in the hospital and in the community. The company also intends to use its proprietary macrolide library and chemistry technology to develop novel macrolides without antibacterial activity for non-antibiotic uses such as inflammatory and GI disorders. Additional information about Cempra can be found at www.cempra.com.
Robert E. Flamm, Ph.D.
Russo Partners, LLC
Tony Russo, Ph.D.
Russo Partners, LLC
Prabhavathi Fernandes, Ph.D.
President and Chief Executive Officer
SOURCE Cempra Pharmaceuticals