ABSTRACT
The Coronavirus Disease 2019 (COVID-19) pandemic curtailed clinical trial activity. Decentralized clinical trials (DCTs) can expand trial access and reduce exposure risk but their feasibility remains uncertain. We evaluated DCT feasibility for atrial fibrillation (AF) patients on oral anticoagulation (OAC). DeTAP (Decentralized Trial in Afib Patients, NCT04471623) was a 6-month, single-arm, 100% virtual study of 100 AF patients on OAC aged >55 years, recruited traditionally and through social media. Participants enrolled and participated virtually using a mobile application and remote blood pressure (BP) and six-lead electrocardiogram (ECG) sensors. Four engagement-based primary endpoints included changes in pre- versus end-of-study OAC adherence (OACA), and % completion of televisits, surveys, and ECG and BP measurements. Secondary endpoints included survey-based nuisance bleeding and patient feedback. 100 subjects (mean age 70 years, 44% women, 90% White) were recruited in 28 days (traditional: 6 pts; social media: 94 pts in 12 days with >300 waitlisted). Study engagement was high: 91% televisits, 85% surveys, and 99% ECG and 99% BP measurement completion. OACA was unchanged at 6 months (baseline: 97 ± 9%, 6 months: 96 ± 15%, p = 0.39). In patients with low baseline OACA (<90%), there was significant 6-month improvement (85 ± 16% to 96 ± 6%, p < 0.01). 86% of respondents (69/80) expressed willingness to continue in a longer trial. The DeTAP study demonstrated rapid recruitment, high engagement, and physiologic reporting via the integration of digital technologies and dedicated study coordination. These findings may inform DCT designs for future cardiovascular trials.
ABSTRACT
RATIONALE AND OBJECTIVE: Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. RESULTS: EVP-5141 bound to α7 nAChRs in rat brain membranes (K i = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i = 880 nM) but had low affinity for α4ß2 nAChRs (K i > 100 µM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3ß4, α4ß2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg(-1), p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg(-1), p.o.). CONCLUSIONS: EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.
Subject(s)
Memory/physiology , Nicotinic Agonists/metabolism , Nicotinic Agonists/pharmacology , Quinolines/metabolism , Quinolines/pharmacology , Quinuclidines/metabolism , Quinuclidines/pharmacology , Serotonin 5-HT3 Receptor Antagonists/metabolism , Serotonin 5-HT3 Receptor Antagonists/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Dose-Response Relationship, Drug , Female , HEK293 Cells , Humans , Male , Memory/drug effects , Mice , Mice, Inbred C57BL , Nicotinic Agonists/chemistry , Protein Binding/physiology , Quinolines/chemistry , Quinuclidines/chemistry , Rats , Rats, Wistar , Xenopus laevisABSTRACT
The relative contribution of alpha4beta2, alpha7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the alpha7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to alpha7 nAChR in rat brain membranes (Ki=62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki=60 nM). ABBF was a potent agonist at the recombinant rat and human alpha7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT3 receptor and alpha3beta4, alpha4beta2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3-1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the alpha7 nAChR antagonist methyllycaconitine at 10 microg, indicating that it is mediated by alpha7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the alpha7 nAChR and that selective alpha7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that alpha7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.
Subject(s)
Benzofurans/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Memory/drug effects , Nicotinic Agonists/pharmacology , Quinuclidines/pharmacology , Receptors, Nicotinic/drug effects , Animals , Cognition Disorders/drug therapy , Exploratory Behavior/drug effects , Generalization, Psychological/drug effects , Male , Maze Learning/drug effects , Mice , Rats , Rats, Inbred BN , Rats, Inbred F344 , Rats, Wistar , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A general method for the stereocontrolled synthesis of cyclopropanes is described. Various, highly stable, enantiomerically pure alkenylboronic esters 13 have been conveniently synthesized by the direct hydroboration of alkynes 11 using the new chiral 1,3,2-dioxaborolane 15. The high stability was also demonstrated by the selective deprotection of a tert-butyldimethylsilyl protecting group without hydrolyzing the boronic ester. The diastereoselective cyclopropanation of the olefins was achieved by the palladium(II) acetate catalyzed decomposition of diazomethane. This process was optimized giving cyclopropylboronic esters 20/21 in high yield (89-99%) and with good to excellent diastereomeric ratios (up to 95:5). The diastereomers were separated by means of MPLC and their configurations determined by X-ray crystallography (compound 21c), by transformation to known cyclopropanols, and by correlation of NMR data. Treatment with LiAlH(4) followed by acidic hydrolysis yielded the enantiomerically pure cyclopropylboronic acid 27 for the first time and allowed the nearly quantitative recovery of the chiral auxiliary 3. Different protocols for the Suzuki coupling reaction of compound 27 were investigated.
