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Biomacromolecules Jul 2022Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries....
Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications.
Topics: Biocompatible Materials; Electricity; Polymers; Pyrroles
PubMed: 35748772
DOI: 10.1021/acs.biomac.2c00516 -
World Journal of Gastroenterology Mar 2024() infects over half the global population, causing gastrointestinal diseases like dyspepsia, gastritis, duodenitis, peptic ulcers, G-MALT lymphoma, and gastric... (Meta-Analysis)
Meta-Analysis
BACKGROUND
() infects over half the global population, causing gastrointestinal diseases like dyspepsia, gastritis, duodenitis, peptic ulcers, G-MALT lymphoma, and gastric adenocarcinoma. Eradicating is crucial for treating and preventing these conditions. While conventional proton pump inhibitor (PPI)-based triple therapy is effective, there's growing interest in longer acid suppression therapies. Potassium competitive acid blocker (P-CAB) triple and dual therapy are new regimens for eradication. Initially used in Asian populations, vonoprazan (VPZ) has been recently Food and Drug Administration-approved for eradication.
AIM
To assess the efficacy of regimens containing P-CABs in eradicating infection.
METHODS
This study, following PRISMA 2020 guidelines, conducted a systematic review and meta-analysis by searching MEDLINE and Scopus libraries for randomized clinical trials (RCTs) or observational studies with the following command: [("" OR "H pylori") AND ("Treatment" OR "Therapy" OR "Eradication") AND ("Vonaprazan" OR "Potassium-Competitive Acid Blocker" OR "P-CAB" OR "PCAB" OR "Revaprazan" OR "Linaprazan" OR "Soraprazan" OR "Tegoprazan")]. Studies comparing the efficacy of P-CABs-based treatment to classical PPIs in eradicating were included. Exclusion criteria included case reports, case series, unpublished trials, or conference abstracts. Data variables encompassed age, diagnosis method, sample sizes, study duration, intervention and control, and eradication method were gathered by two independent reviewers. Meta-analysis was performed in R software, and forest plots were generated.
RESULTS
A total of 256 references were initially retrieved through the search command. Ultimately, fifteen studies (7 RCTs, 7 retrospective observational studies, and 1 comparative unique study) were included, comparing P-CAB triple therapy to PPI triple therapy. The intention-to-treat analysis involved 8049 patients, with 4471 in the P-CAB intervention group and 3578 in the PPI control group across these studies. The analysis revealed a significant difference in eradication between VPZ triple therapy and PPI triple therapy in both RCTs and observational studies [risk ratio (RR) = 1.17, 95% confidence interval (CI): 1.11-1.22, < 0.0001] and (RR = 1.13, 95%CI: 1.09-1.17, < 0.0001], respectively. However, no significant difference was found between tegoprazan (TPZ) triple therapy and PPI triple therapy in both RCTs and observational studies (RR = 1.04, 95%CI: 0.93-1.16, = 0.5) and (RR = 1.03, 95%CI: 0.97-1.10, = 0.3), respectively.
CONCLUSION
VPZ-based triple therapy outperformed conventional PPI-based triple therapy in eradicating , positioning it as a highly effective first-line regimen. Additionally, TPZ-based triple therapy was non-inferior to classical PPI triple therapy.
Topics: Humans; Anti-Bacterial Agents; Clarithromycin; Helicobacter pylori; Proton Pump Inhibitors; Drug Therapy, Combination; Helicobacter Infections; Pyrroles; Amoxicillin; Treatment Outcome; Randomized Controlled Trials as Topic; Observational Studies as Topic; Benzene Derivatives; Imidazoles; Sulfonamides
PubMed: 38577188
DOI: 10.3748/wjg.v30.i9.1213 -
Journal of Pharmacy & Pharmaceutical... 2022With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents... (Review)
Review
With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents need to be taken. Pyrrole moiety has been found in various active compounds with anti-inflammatory, antiseptic, antibacterial, lipid-lowering and anticancer properties. Recent advances in the exploration of highly active and selective cytotoxic structures containing pyrrole motifs have shown promising data for future investigations. Accordingly, this review presents an overview of recent developments in the pyrrole derivatives as anticancer agents, with a main focus towards the key moieties required for the anti-tumor activities. Pyrrole molecules comprising prominent targeting capacities against microtubule polymerization, tyrosine kinases, cytochrome p450 family 1, histone deacetylase and bcl-2 proteins were reported. In addition, several mechanisms of action, such as apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others were analyzed. Furthermore, in most of the discussed cases we provided synthesis schemes of the mentioned molecules. Overall, the utilization of pyrrole scaffold for the design and synthesis of novel anticancer drugs could be a promising approach for future investigations.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cytochrome P-450 Enzyme System; Genes, bcl-2; Histone Deacetylases; Humans; Microtubules; Protein-Tyrosine Kinases; Pyrroles; Structure-Activity Relationship
PubMed: 34995473
DOI: 10.18433/jpps32417 -
Molecules (Basel, Switzerland) Sep 2022Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the... (Review)
Review
Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole-pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.
Topics: Benzimidazoles; Ligands; Pyridines; Pyrroles; Thiones
PubMed: 36234805
DOI: 10.3390/molecules27196268 -
Cancer Medicine May 2023FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and...
BACKGROUND
FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102.
METHODS
Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy.
RESULTS
Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95).
CONCLUSIONS
Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.
Topics: Adult; Humans; Young Adult; East Asian People; Neoplasms; Morpholines; Pyrimidines; Pyrroles
PubMed: 37000035
DOI: 10.1002/cam4.5798 -
Cancer Medicine Jun 2023Imatinib is the standard first-line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Imatinib is the standard first-line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance, leading to considerable clinical challenges. Few direct comparisons have been made between different post-first-line therapies on clinical efficacy in advanced GIST following imatinib failure.
METHODS
Databases including PubMed, Embase, Scopus, Google Scholars, and Cochrane Library from inception to February 2023 were retrieved for randomized controlled trials evaluating the clinical efficacy of different post-first-line agents for advanced GIST following imatinib failure. Network and conventional meta-analysis were carried out using Stata/MP 16.0.
RESULTS
Ripretinib showed significant improvement in progression-free survival (PFS) rates from the 2nd to the 12th month compared to placebo, while there was virtually no evidence that the rest active agents had a significant benefit at the 12th month. Masitinib, ripretinib, sunitinib, regorafenib, and pimitespib exhibited significantly longer median PFS than placebo, and pairwise comparisons indicated there were no significant differences among masitinib, ripretinib, and sunitinib. These post-first-line agents decreased the risk of disease progression or death by 65% (HR = 0.35, 95% CI: 0.26-0.47) compared to placebo. Ripretinib and sunitinib came into effect earlier and exhibited more consistent overall survival (OS) rate improvements than masitinib and pimitespib, while pairwise comparisons revealed no significant differences in these four active agents concerning the improvement in OS rate. These post-first-line agents decreased the risk of death by 39% (HR = 0.61, 95% CI: 0.44-0.83) over placebo for advanced GIST following imatinib failure.
CONCLUSION
The active agents in our analysis as post-first-line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post-first-line treatment for advanced GIST following imatinib failure.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Sunitinib; Network Meta-Analysis; Gastrointestinal Neoplasms; Indoles; Pyrroles; Antineoplastic Agents; Protein Kinase Inhibitors
PubMed: 37084005
DOI: 10.1002/cam4.5912 -
Molecules (Basel, Switzerland) Feb 2020Nitroxides are broadly used as molecular probes and labels in biophysics, structural biology, and biomedical research. Resistance of a nitroxide group bearing an...
Nitroxides are broadly used as molecular probes and labels in biophysics, structural biology, and biomedical research. Resistance of a nitroxide group bearing an unpaired electron to chemical reduction with low-molecular-weight antioxidants and enzymatic systems is of critical importance for these applications. The redox properties of nitroxides are known to depend on the ring size (for cyclic nitroxides) and electronic and steric effects of the substituents. Here, two highly strained nitroxides, 5-(-butyl)-5-butyl-2,2-diethyl-3-hydroxypyrrolidin-1-oxyl () and 2-(-butyl)-2-butyl-5,5-diethyl-3,4-bis(hydroxymethyl)pyrrolidin-1-oxyl (), were prepared via a reaction of the corresponding 2--butyl-1-pyrroline 1-oxides with butyllithium. Thermal stability and kinetics of reduction of the new nitroxides by ascorbic acid were studied. Nitroxide showed the highest resistance to reduction.
Topics: Antioxidants; Biomedical Research; Electron Transport; Nitrogen Oxides; Organometallic Compounds; Oxidation-Reduction; Oxides; Pyrroles
PubMed: 32075085
DOI: 10.3390/molecules25040845 -
Journal of the American Chemical Society Aug 2021Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores,...
Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.
Topics: Azirines; Carbon; Density Functional Theory; Indoles; Molecular Structure; Pyrroles
PubMed: 34286965
DOI: 10.1021/jacs.1c06287 -
Journal of Crohn's & Colitis Aug 2020Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised,... (Review)
Review
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.
Topics: Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Triazoles
PubMed: 32160283
DOI: 10.1093/ecco-jcc/jjaa014 -
ACS Applied Bio Materials Jul 2023The low endogenous regenerative capacity of the heart, added to the prevalence of cardiovascular diseases, triggered the advent of cardiac tissue engineering in the last...
The low endogenous regenerative capacity of the heart, added to the prevalence of cardiovascular diseases, triggered the advent of cardiac tissue engineering in the last decades. The myocardial niche plays a critical role in directing the function and fate of cardiomyocytes; therefore, engineering a biomimetic scaffold holds excellent promise. We produced an electroconductive cardiac patch of bacterial nanocellulose (BC) with polypyrrole nanoparticles (Ppy NPs) to mimic the natural myocardial microenvironment. BC offers a 3D interconnected fiber structure with high flexibility, which is ideal for hosting Ppy nanoparticles. BC-Ppy composites were produced by decorating the network of BC fibers (65 ± 12 nm) with conductive Ppy nanoparticles (83 ± 8 nm). Ppy NPs effectively augment the conductivity, surface roughness, and thickness of BC composites despite reducing scaffolds' transparency. BC-Ppy composites were flexible (up to 10 mM Ppy), maintained their intricate 3D extracellular matrix-like mesh structure in all Ppy concentrations tested, and displayed electrical conductivities in the range of native cardiac tissue. Furthermore, these materials exhibit tensile strength, surface roughness, and wettability values appropriate for their final use as cardiac patches. experiments with cardiac fibroblasts and H9c2 cells confirmed the exceptional biocompatibility of BC-Ppy composites. BC-Ppy scaffolds improved cell viability and attachment, promoting a desirable cardiomyoblast morphology. Biochemical analyses revealed that H9c2 cells showed different cardiomyocyte phenotypes and distinct levels of maturity depending on the amount of Ppy in the substrate used. Specifically, the employment of BC-Ppy composites drives partial H9c2 differentiation toward a cardiomyocyte-like phenotype. The scaffolds increase the expression of functional cardiac markers in H9c2 cells, indicative of a higher differentiation efficiency, which is not observed with plain BC. Our results highlight the remarkable potential use of BC-Ppy scaffolds as a cardiac patch in tissue regenerative therapies.
Topics: Polymers; Myocytes, Cardiac; Pyrroles; Cell Differentiation
PubMed: 37342003
DOI: 10.1021/acsabm.3c00303