Afacifenacin Fumarate

Overactive bladder (OAB) is a term used to describe the symptom syndrome of urgency, with or without urgency incontinence, usually associated with frequency and nocturia. Antimuscarinics are the most widely prescribed class of drugs for OAB, although their systemic adverse effects limit their use in clinical practice as compliance. This has led to developments in the field.

In this review, the authors describe Phase II drugs that target cholinergic receptors. First, the authors present the new antimuscarinics (tarafenacin and afacifenacin). This is followed by reports on a combination drug (tolenix) containing a muscarinic antagonist (tolterodine) associated with a muscarinic agonist (pilocarpine). Further, the authors discuss the trials of well-known drugs in either new combination therapy (solifenacin and mirabegron) or with new routes of delivery (oxybutynin vaginal ring). Finally, the authors examine the option of targeting nicotinic acetylcholine receptors (dexmecamylamine).

Different strategies have been adopted to improve the efficacy and tolerability of therapeutics for OAB. Nicotinic receptors represent a novel therapeutic target; however, it is unlikely that antimuscarinic agents will be replaced as standard first-line therapy in the near future.

With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans (Pomphorhynchus laevis, Neoechinorhynchus agilis,Neoechinorhynchus buttnerae) from four fish species (common barbel, European eel, thinlip mullet, tambaqui).

The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel.

The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URLtinyurl.com/yx72rda7.