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  • AG-126 australia Concerning asthma in a study evaluating


    Concerning asthma, in a study evaluating the effect of tiotropium in severe asthma, the sputum eosinophil count and exhaled nitric oxide were also assessed. However, evaluation of the anti-inflammatory effect of tiotropium was difficult because these markers were low at baseline and thereafter. In another study, tiotropium treatment also did not change the levels of exhaled nitric oxide after 48 weeks add-on treatment in AG-126 australia treated with inhaled corticosteroid plus a long-acting beta 2 agonist, which suggests that LAMA might have no inhibitory effect on the eosinophilic airway inflammation in asthma patients. However, the effect of anticholinergic drugs on the airway remodeling is still unknown. To clarify the anti-inflammatory effect of anti-muscarinic drugs in human airway inflammation and airway remodeling, further studies including evaluations by bronchial biopsy are still needed.
    Conflict of interest AK received a research grant from Terumo Foundation for Life Sciences and Arts. MI received lecture fees from Nippon Boehringer Ingelheim, Kyorin and Novartis Pharma.
    Introduction Soil-Transmitted Helminth (STH) infections in humans and animals cause significant disease (morbidity & mortality) globally. At least 1.2 billion people suffer from STH infections, with an estimated at-risk population of 4.5 billion (Bethony et al., 2006, Brooker et al., 2006, Lammie et al., 2006). Control of these infections is heavily reliant on the use of anthelmintics as there are no effective vaccines and sanitation is often sub-optimal (Kaminsky et al., 2013). There are a limited number of drugs used to treat helminth infections (Keiser and Utzinger, 2008). Antinematodal (anthelmintic) drugs can be classified on the basis of similarity in chemical structure; benzimidazoles, imidazothiazoles, tetrahydopyrimidines, macrocyclic lactones, amino-acetonitrile derivatives, spiroindoles and cyclooctadepsipeptides. The benzimidazoles, imidazothiazoles, tetrahydopyrimidines and macrocyclic lactones are older anthelmintic drug classes. Increasing reports of resistance to the ‘older’ anthelmintic drugs has encouraged the development of newer drug classes: amino-acetonitrile derivatives, spiroindoles and cyclooctadepsipeptides. Zolvix® (Novartis Animal Health, Greensboro, NC, USA) is a recently developed anthelmintic for control of gastro-intestinal (GI) nematodes in sheep. It was first introduced in New Zealand in 2009, and contains 25 mg/ml monepantel (mptl) as the active ingredient (Fig. 1). Monepantel is the first member of the amino-acetonitrile derivative (AAD) group of anthelmintics. It has a wide range of activity against nematodes in sheep, including those resistant to benzimidazoles, imidazothiazoles and macrocyclic lactones (Ducray et al., 2008, Kaminsky et al., 2008a, Kaminsky et al., 2008b). Disappointingly, resistance has developed in infected goats and sheep following treatment with monepantel. The first field report of monepantel resistance was observed in Teladorsagia circumcincta and Trichostrongylus colubriformis in goats and sheep on a farm in the lower North Island in New Zealand <2 years after its initial use on that farm (Scott et al., 2013). Subsequent cases of resistance to monepantel have been reported for H. contortus in sheep (Mederos et al., 2014, Van den Brom et al., 2015). The emergence of field resistance to monepantel within very short periods following treatment underscores the pressing need to understand the full mode of action of the drug and thus possible mechanisms of resistance. Monepantel has a site of action reported to involve ACR-23, a member of the DEG-3/DES-2 group of nicotinic acetylcholine receptors (nAChRs) (Lecova et al., 2014). Kaminsky et al. (2008a) showed AADs to cause hypercontraction of body wall muscles in Caenorhabditis elegans and Haemonchus contortus, leading to spastic paralysis and subsequent death of the worms. These authors further revealed C. elegans treated with AADs display molting deficits and characteristics of necrosis (Kaminsky et al., 2008a). Subsequent mutagenesis screens in H. contortus led to the identification of the nAChR subunit gene, mptl-1 (acr-23), as a target for AADs (Rufener et al., 2009). Comparative genomics of all ligand-gated ion channel (LGIC) genes from different clades of nematodes reported nematode species lacking the ACR-23/MPTL-1 nAChR subunits to be insensitive to monepantel. On the contrary, nematode species having ACR-23/MPTL-1 were susceptible to monepantel, thus promoting ACR-23/MPTL-1 nAChR as a principal target for the AADs (Rufener et al., 2010b). To further elucidate the mode of action of monepantel, Rufener et al. (2010b) showed that monepantel on its own did not activate heterologously expressed H. contortus DEG-3/DES-2 receptors but acted as a type 2 positive allosteric modulator when co-applied with choline (Rufener et al., 2010a). In heterologously expressed C. elegans ACR-23 receptors, monepantel caused potentiation following activation by betaine (Peden et al., 2013). Monepantel also acted as a positive allosteric modulator of H. contortus MPTL-1 and C. elegans ACR-20 receptors at low concentrations (<1 nM) but as a direct agonist at high concentrations (>0.1 μM) (Baur et al., 2015).