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  • Interestingly a homolog of C


    Interestingly, a homolog of 3 bromopyruvate synthesis C. elegans acr-23 is present in the A. suum 3 bromopyruvate synthesis (Jex et al., 2011). However, A. suum is not susceptible to monepantel treatment in vivo (Tritten et al., 2011). Our research seeks to advance knowledge on the mode of action of monepantel on nAChRs from Clade III (A. suum) and Clade V (Oesophagostomum dentatum) nematodes. This present study therefore is an investigation of the effects of monepantel on nAChRs that are widely and ubiquitously expressed in A. suum (Asu-ACR-16), and those involved in neurotransmission (pyrantel/tribendimidine sensitive and levamisole sensitive nAChRs) in O. dentatum. We find that monepantel also acts selectively as an antagonist on the nematode nAChRs we studied.
    Materials and methods
    Conclusion Our results indicate that monepantel acts as an antagonist of Ascaris muscle contraction, and as a non-competitive antagonist, with subtype selective effects, of expressed nAChR subtypes from A. suum (Clade III) and O. dentatum (Clade V). Non-competitive antagonism of monepantel on expressed nAChRs which we show in our research adds to the reported mode of action of monepantel as a positive allosteric modulator of expressed receptors of the DEG-3/DES-2 group of nAChRs. Thus, illustrating the complexity of the mode of action of the drug; involving more than one target site. Detailed understanding of the mode of action of antinematodal drugs is necessary, especially when considered for use in combination therapy/products, an approach proven to be highly effective for parasite control. As with many pharmacological agents we find that the mode of action of monepantel is complex and the drug is active on multiple nAChR subtypes.
    Statement of conflict of interest
    Acknowledgments We would like to acknowledge NIHR21AI092185-01A1 to APR, NIHRO1 AI047194-15 and the E. A. Benbrook Foundation for Pathology and Parasitology to RJM, Schlumberger Foundation Faculty for the Future Fellowship to MA and NIHT35 OD 012199-13 to JGT. We would also like to thank Dr Michael Kimber of Iowa State University for the gift of Zolvix (monepantel).
    Introduction Coronary artery spasm may concern the pathogenesis of various cardiac disorders, such as acute coronary syndrome, unstable angina, serious fatal arrhythmia, sudden cardiac death, syncope, transient heart failure, atypical chest pain, and so on [1], [2], [3], [4], [5], [6], [7]. In the clinical situations, we finally decided to perform spasm provocation tests of acetylcholine (ACh) and ergonovine (ER) as invasive methods in patients suspected of vasospastic angina (VSA). Hackett et al. and Ishise et al. reported the usefulness of intracoronary injection of ER in diagnosing patients with VSA in 1987 [8], [9]. In contrast, Yasue and Okumura reported the usefulness of intracoronary administration of ACh in patients with variant angina in 1988 [10], [11], [12]. Instead of intravenous injection of ER, cardiologists have employed intracoronary administration methods of ACh and ER. ACh acts through the muscarinic cholinergic receptors, whereas ER probably acts through the serotogenic receptors. Different mediators may have different coronary response even in the same patients. However, the majority of cardiologists use one pharmacologic agent, ACh or ER, to diagnose the presence of coronary artery spasm in the cardiac catheterization laboratory. We performed the ACh and ER spasm provocation tests for 24 years. However, there are some controversies concerning the diagnostic utility, limitations, and complications of pharmacological spasm provocation tests. According to the Japanese Circulation Society (JCS) guidelines for VSA established in 2008, selective methods of ACh and ER tests are recommended as invasive methods to diagnose patients when suspecting coronary spasm [13]. In the JCS guidelines, the pharmacological spasm provocation test is defined as Class I, whereas the European Society of Cardiology (ESC) guideline and the American College of Cardiology (ACC)/American Heart Association (AHA) guideline give the spasm provocation testing Class IIa and Class IIb, respectively [14], [15]. In this article, we summarize the comparisons of clinical usefulness between ACh and ER tests in the clinic.