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The Journal of Evidence-based Dental... Dec 2023Recurrent aphthous ulceration (RAU) is an oral condition cavity affecting 2.5 billion people worldwide. We aimed to assess the comparative efficacy and safety of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recurrent aphthous ulceration (RAU) is an oral condition cavity affecting 2.5 billion people worldwide. We aimed to assess the comparative efficacy and safety of available interventions in the management of RAU.
MATERIALS AND METHODS
An electronic search of 3 databases (Medline, CENTRAL, Scopus) was performed to identify randomized control trials evaluating the efficacy of RAU interventions published until December 2022. A network meta-analysis (NMA) was conducted on 4 outcomes: reduction in pain, duration of ulceration, the diameter of ulceration, and area of ulceration. The interventions are then arranged using the surface area under cumulative ranking (SUCRA).
RESULTS
A total of 38 trials involving 2773 patients were included were included in quantitative synthesis by NMA. Our analysis showed that Diode laser [MD, -4.865 ± 1.951 (95%CI = (-8.690, -1.041)] was the most effective in reducing the pain score followed by Amlexanox [MD, -2.673 ± 1.075 (95%CI = -4.779, -0.566)]. Iralvex performed the best in reducing the duration of ulceration [MD, -6.481 ± 1.841 (95%CI = -10.090, -2.872)]. Diode laser, acacia nilotica with licorice formulation, and amlexanox were the most effective interventions for reduction of ulcer diameter. Majority of the trials reported absence of any adverse effects and those reported were mild.
CONCLUSION
Our NMA has identified several interventions to be more effective than a placebo. Laser therapy may be an option for promoting pain management, however, most have only been tested in 1 or 2 trials. Further studies with rigorous methodology on larger samples are recommended to strengthen the current evidence.
Topics: Humans; Stomatitis, Aphthous; Network Meta-Analysis; Aminopyridines; Pain
PubMed: 38035895
DOI: 10.1016/j.jebdp.2023.101918 -
European Journal of Pharmacology Jan 2023The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature...
The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute promising pharmacotherapies acting on the fundamental cause of the disease. Here, we screened a collection of triazole compounds to identify novel F508del-CFTR correctors. The functional primary screen identified four hit compounds (LSO-18, LSO-24, LSO-28, and LSO-39), which were further validated and demonstrated to rescue F508del-CFTR processing, plasma membrane trafficking, and function. To interrogate their mechanism of action (MoA), we examined their additivity to the clinically approved drugs VX-661 and VX-445, low temperature, and genetic revertants of F508del-CFTR. Rescue of F508del-CFTR processing and function by LSO-18, LSO-24, and LSO-28, but not by LSO-39, was additive to VX-661, whereas LSO-28 and LSO-39, but not LSO-18 nor LSO-24, were additive to VX-445. All compounds under investigation demonstrated additive rescue of F508del-CFTR processing and function to low temperature as well as to rescue by genetic revertants G550E and 4RK. Nevertheless, none of these compounds was able to rescue processing nor function of DD/AA-CFTR, and LSO-39 (similarly to VX-661) exhibited no additivity to genetic revertant R1070W. From these findings, we suggest that LSO-39 (like VX-661) has a putative binding site at the NBD1:ICL4 interface, LSO-18 and LSO-24 seem to share the MoA with VX-445, and LSO-28 appears to act by a different MoA. Altogether, these findings represent an encouraging starting point to further exploit this chemical series for the development of novel CFTR correctors.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Mutation; Triazoles
PubMed: 36410419
DOI: 10.1016/j.ejphar.2022.175396 -
Bioorganic & Medicinal Chemistry Sep 2022A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino...
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino sidechain is reported. A rapid and simple protocol was developed to access these inhibitors in excellent yields. Neuronal nitric oxide synthase (nNOS) is a novel therapeutic target for the treatment of various neurological disorders. The major challenges in designing nNOS inhibitors in humans focus on potency, selectivity over other isoforms of nitric oxide synthases (NOSs), and blood-brain barrier permeability. In this context, we discovered a promising inhibitor, 6-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-methylpyridin-2-amine dihydrochloride, that exhibits excellent potency for rat (K = 46 nM) and human nNOS (K = 48 nM), respectively, with 388-fold human eNOS and 135-fold human iNOS selectivity. It also displayed excellent permeability (P = 17.3 × 10 cm s) through a parallel artificial membrane permeability assay, a model for blood-brain permeability. We found that increasing lipophilicity by incorporation of fluorine atoms on the backbone of the inhibitors significantly increased potential blood-brain barrier permeability. In addition to measuring potency, isoform selectivity, and permeability of NOS inhibitors, we also explored structure-activity relationships via structures of key inhibitors complexed to various isoforms of nitric oxide synthases.
Topics: Aminopyridines; Animals; Enzyme Inhibitors; Humans; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Protein Isoforms; Rats
PubMed: 35772285
DOI: 10.1016/j.bmc.2022.116878 -
Endocrine-related Cancer Apr 2021The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data...
The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.
Topics: Aminopyridines; Everolimus; Humans; Middle Aged; Neuroendocrine Tumors; Purines
PubMed: 33640871
DOI: 10.1530/ERC-20-0446 -
Chest Jul 2015
Topics: Albuterol; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Bronchodilator Agents; Female; Humans; Male; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives
PubMed: 26149563
DOI: 10.1378/chest.15-0664 -
Toxicology and Applied Pharmacology Nov 2019Through synthesis of two rare phosphoinositides, PtdIns(3,5)P and PtdIns5P, the ubiquitously expressed phosphoinositide kinase PIKfyve is implicated in pleiotropic... (Review)
Review
Through synthesis of two rare phosphoinositides, PtdIns(3,5)P and PtdIns5P, the ubiquitously expressed phosphoinositide kinase PIKfyve is implicated in pleiotropic cellular functions. Small molecules specifically inhibiting PIKfyve activity cause cytoplasmic vacuolation in all dividing cells in culture yet trigger non-apoptotic death through excessive vacuolation only in cancer cells. Intriguingly, cancer cell toxicity appears to be inhibitor-specific suggesting that additional targets beyond PIKfyve are affected. One PIKfyve inhibitor - apilimod - is already in clinical trials for treatment of B-cell malignancies. However, apilimod is inactivated in cultured cells and exhibits unexpectedly low plasma levels in patients treated with maximum oral dosage. Thus, the potential widespread use of PIKfyve inhibitors as cancer therapeutics requires progress on multiple fronts: (i) advances in methods for isolating relevant cancer cells from individual patients; (ii) delineation of the molecular mechanisms potentiating the vacuolation induced by PIKfyve inhibitors in sensitive cancer cells; (iii) design of PIKfyve inhibitors with favorable pharmacokinetics; and (iv) development of effective drug combinations.
Topics: Aminopyridines; Animals; Antineoplastic Agents; Heterocyclic Compounds, 3-Ring; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Binding; Translational Research, Biomedical
PubMed: 31628917
DOI: 10.1016/j.taap.2019.114771 -
Leukemia Research Nov 2022Enasidenib was approved by the Food and Drug Administration in 2017 for the treatment of patients with relapsed or refractory (RR) acute myeloid leukemia (AML) with an...
Enasidenib was approved by the Food and Drug Administration in 2017 for the treatment of patients with relapsed or refractory (RR) acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Given limited data in clinical practice, this study assessed real-world clinical outcomes and healthcare resource use in patients with RR AML. Physicians performed chart abstraction of patients with RR IDH2-mutated AML treated with enasidenib (between 1/2018 and 6/2019) or other first-line (1 L) RR therapy (between 1/2016 and 7/2017). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and adjusted risk of progression and death were estimated by multivariable Cox proportional hazard models. Among 124 patients treated with enasidenib and 76 patients treated with other 1 L RR therapy, overall response rate was higher among patients treated with enasidenib vs. other 1 L RR therapies (77% vs. 52%, p < 0.01). After a median follow-up of 9 and 6 months, median PFS was 8 months in enasidenib-treated patients and 5 months in patients receiving other 1 L RR therapy, respectively (adjusted HR=0.36, 95% CI: 0.23-0.57, p < 0.01). Median OS was 11 and 6 months in enasidenib-treated patients and patients receiving other 1 L RR therapy, respectively (adjusted HR=0.37, 95% CI: 0.22-0.60, p < 0.01). Fewer enasidenib-treated patients were hospitalized during 1 L RR therapy vs. those receiving other therapies (14% vs. 46%, p < 0.01). Results from this real-world study confirm the effectiveness of enasidenib among patients with IDH2-mutated RR AML and demonstrate that hospitalizations were significantly lower vs. other 1 L RR treatment in clinical practice.
Topics: Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Aminopyridines; Triazines; Mutation
PubMed: 36108427
DOI: 10.1016/j.leukres.2022.106946 -
Bioorganic Chemistry Dec 2022A series of novel 2-aminopyridine derivatives 1-26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds...
A series of novel 2-aminopyridine derivatives 1-26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.
Topics: Humans; Ubiquitin-Specific Peptidase 7; Aminopyridines; HCT116 Cells; Tumor Suppressor Protein p53; Antineoplastic Agents; Cell Proliferation; Cell Line, Tumor
PubMed: 36113266
DOI: 10.1016/j.bioorg.2022.106128 -
Bioorganic & Medicinal Chemistry Apr 2023We report the design, synthesis and evaluation of five o‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5...
We report the design, synthesis and evaluation of five o‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5 with the fluoroethoxy group at the meta- or para-position of the phenyl ring possessed nanomolar inhibitory potency against CSF-1R with IC values of 7.6 nM and 2.3 nM, respectively. Radioligands [F]4 and [F]5 were obtained in radiochemical yields of 17.2 ± 5.3% (n = 5, decay-corrected) and 14.0 ± 4.3% (n = 4, decay-corrected), with radiochemical purity of > 99% and molar activity of 9-12 GBq/μmol (n = 5) and 6-8 GBq/μmol (n = 4), respectively. In biodistribution studies, radioligands [F]4 and [F]5 showed moderate brain uptake in male ICR mice with 1.52 ± 0.15 and 0.91 ± 0.07% ID/g, respectively, at 15 min. Metabolic stability studies in mouse brain revealed that [F]4 exhibited high stability while [F]5 suffered from low stability. Higher accumulation of [F]4 in the brain of lipopolysaccharide (LPS)-treated mice was observed, and further pretreatment of BLZ945 or CPPC led to remarkable reduction, indicating specific binding of [F]4 to CSF-1R.
Topics: Animals; Male; Mice; Fluorine Radioisotopes; Mice, Inbred ICR; Neuroinflammatory Diseases; Positron-Emission Tomography; Tissue Distribution; Aminopyridines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
PubMed: 36933438
DOI: 10.1016/j.bmc.2023.117233 -
Clinical Pharmacology and Therapeutics Jun 2022
Topics: Aminopyridines; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles
PubMed: 35394660
DOI: 10.1002/cpt.2579