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Annals of Translational Medicine Mar 2021Treatment of cardiac amyloidosis is determined by the amyloid type and degree of involvement. Two types of amyloid commonly infiltrate the heart: immunoglobulin... (Review)
Review
Treatment of cardiac amyloidosis is determined by the amyloid type and degree of involvement. Two types of amyloid commonly infiltrate the heart: immunoglobulin light-chain amyloid (AL), and transthyretin amyloid (ATTR), that encompasses other two forms, a hereditary form (hATTR), and a sporadic, age-related wild-type (wtATTR). The prevalence is expected to increase with aging population. The natural history of ATTR cardiomyopathy includes progressive heart failure (HF), complicated by arrhythmias and conduction system disease. New therapies options have been approved or are under investigation. We performed a narrative literature review, manually-searched the reference lists of included articles and relevant reviews. Treatment for cardiac ATTR should be directed towards alleviation of HF symptoms and to slow or stop progressive amyloid deposition. Conventional HF medications are poorly tolerated and may not alter the disease progression or symptoms, except perhaps with the administration of diuretics. There are three approaches of therapy for ATTR cardiomyopathy: tetramer stabilizers, inhibition of ATTR protein synthesis and clearance of deposited fibrils. Tafamidis diminishes the progression of cardiomyopathy, functional parameters, improves overall outcome in patients with early disease stages, irrespective of ATTR status and is well tolerated. Diflunisal has shown promising results in early studies, but at the expense of significant side effects. Two new agents, antisense oligonucleotides, patisiran and inotersen are under investigation in cardiac amyloidosis. Patisiran appears to be the most effective treatment for hATTR, although evidence is limited, with a relatively small cardiac subpopulation. Therapies considering clearance of amyloid fibrils from tissue remain experimental. In conclusion, tafamidis is the only approved agent for the treatment of ATTR cardiomyopathy although multiple other agents have shown promising early results and are undergoing clinical trials. Careful consideration of the type of ATTR, comorbidities and disease stage will be key in deciding the optimal therapy for ATTR patients.
PubMed: 33850916
DOI: 10.21037/atm-20-4636 -
Pharmaceuticals (Basel, Switzerland) Mar 2021The interaction between drugs and transport proteins, such as albumins, is a key factor in drug bioavailability. One of the techniques commonly used for the evaluation...
Evaluation of the Interactions between Human Serum Albumin (HSA) and Non-Steroidal Anti-Inflammatory (NSAIDs) Drugs by Multiwavelength Molecular Fluorescence, Structural and Computational Analysis.
The interaction between drugs and transport proteins, such as albumins, is a key factor in drug bioavailability. One of the techniques commonly used for the evaluation of the drug-protein complex formation is fluorescence. This work studies the interaction of human serum albumin (HSA) with four non-steroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, naproxen, and diflunisal-by monitoring the fluorescence quenching when the drug-albumin complex is formed. Two approaches-the double logarithm Stern-Volmer equation and the STAR program-are used to evaluate the binding parameters. The results are analyzed considering the binding properties, determined by using other complementary techniques and the available structural information of albumin complexes with NSAID-related compounds. Finally, this combined analysis has been synergistically used to interpret the binding of flurbiprofen to HSA.
PubMed: 33806467
DOI: 10.3390/ph14030214 -
International Journal of Nanomedicine 2021Rheumatoid arthritis is an autoimmune disorder that directly affects joints. However, other body organs including heart, eyes, skin, blood vessels and lungs may also be...
PURPOSE
Rheumatoid arthritis is an autoimmune disorder that directly affects joints. However, other body organs including heart, eyes, skin, blood vessels and lungs may also be affected. The purpose of this study was to design and evaluate a nanoemulgel formulation of diflunisal (DIF) and solubility enhanced diflunisal (DIF-IC) for enhanced topical anti-inflammatory activity.
METHODOLOGY
Nanoemulsion formulations of both DIF and DIF-IC were prepared and incorporated in three different gelling agents, namely carboxymethylcellulose sodium (CMC-Na), sodium alginate (Na-ALG) and xanthan gum (XG). All the formulations were evaluated in term of particle size, pH, conductivity, viscosity, zeta potential and in vitro drug release. The formulation 2 (NE2) of both DIF and DIF-IC which expressed optimum release and satisfactory physicochemical properties was incorporated with gelling agents to produce final nanoemulgel formulations. The optimized nanoemulgel formulation was subjected to three different in vivo anti-inflammatory models including carrageenan-induced paw edema model, histamine-induced paw edema model and formalin-induced paw edema model.
RESULTS
DIF-IC-loaded nanoemulgel formulations yielded significantly enhanced in vitro skin permeation than DIF-loaded nanoemulgel. The nanoemulgel formulation of DIF-IC formulated with XG produced improved in vivo anti-inflammatory activity.
CONCLUSION
It was recommended that DIF-IC-based nanoemulgel formulation prepared with XG could be a better option for effective topical treatment of inflammatory conditions.
Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Carrageenan; Diflunisal; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Drug Liberation; Edema; Electric Conductivity; Emulsions; Hydrogen-Ion Concentration; Male; Nanogels; Particle Size; Permeability; Phase Transition; Polyethylene Glycols; Polyethyleneimine; Rats; Skin; Skin Absorption; Solubility; Surface-Active Agents; Viscosity
PubMed: 33654396
DOI: 10.2147/IJN.S294653 -
Frontiers in Microbiology 2021Increasing antibiotic resistance and diminishing pharmaceutical industry investments have increased the need for molecules that can treat infections caused by dangerous...
Increasing antibiotic resistance and diminishing pharmaceutical industry investments have increased the need for molecules that can treat infections caused by dangerous pathogens such as methicillin-resistant (MRSA). Quorum Sensing (QS) is a signaling mechanism that regulates bacterial virulence in pathogens. A report demonstrating that the anti-inflammatory drug Diflunisal reduces MRSA virulence factors' expression prompted us to design, synthesize and test 16 aza-analogs as inhibitors of virulence factors controlled by the accessory gene regulator () QS system. At first, we evaluated by qRT-PCR the activity of compounds on expression, a QS related gene. Azan-7 was the most active molecule tested and it did not show cytotoxic activity in human cell lines. Moreover, we demonstrated that it did not affect bacterial proliferation. Regulation of MRSA virulence genes by Azan-7 was investigated using qRT-PCR and RNAseq. Azan-7 significantly reduced , α, , , , and gene expression. docking demonstrated that Azan-7 binds the response regulator AgrA. This data was confirmed by electrophoretic mobility shift assay (EMSA) reporting that Azan-7 binding to AgrA protein strongly reduced the AgrA-DNA complex formation at the P3 promoter region involved in the regulation of transcription. Azan-7 inhibited MRSA-mediated haemolysis, reduced survival of the pathogen at low pH levels, and increased macrophage killing. In addition, Azan-7 enhanced MRSA susceptibility to clindamycin both in planktonic growth and biofilm. Azan-7 did not induce resistance over 10 days in culture. It was equally active against all the AgrA MRSA subtypes encountered among clinical isolates, but it was not active against , although the AgrA proteins show an approximate 80% homology. These results demonstrate that Azan-7 inhibits the expression of MRSA virulence factors by interfering in the QS and synergizes MRSA biofilm with clindamycin, indicating the compound as a promising candidate for the treatment of MRSA infections.
PubMed: 33633702
DOI: 10.3389/fmicb.2021.610859 -
Orphanet Journal of Rare Diseases Jan 2021Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years....
BACKGROUND
Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study's objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis.
METHODS
Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016-12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011-2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match.
RESULTS
For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls.
CONCLUSIONS
Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.
Topics: Aged; Amyloid Neuropathies, Familial; Biomarkers; Cohort Studies; Female; Humans; Male; Medicare; Middle Aged; Prealbumin; United States
PubMed: 33430941
DOI: 10.1186/s13023-020-01623-1 -
Journal of Medicinal Chemistry Jan 2021In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically...
In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM () and 3.10 ± 0.11 μM (), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.
Topics: Bacterial Proteins; Binding Sites; Biosynthetic Pathways; Carboxy-Lyases; Catalytic Domain; Crystallography, X-Ray; Diflunisal; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Kynurenine; Molecular Docking Simulation; NAD; Pseudomonas fluorescens; Structure-Activity Relationship; Tryptophan
PubMed: 33369426
DOI: 10.1021/acs.jmedchem.0c01762 -
Journal of Orthopaedic Research :... Feb 2021Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone...
Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone infections and features an arsenal of virulence factors that contribute to bone destruction and counteract immune responses. We previously demonstrated that diflunisal, a nonsteroidal anti-inflammatory drug, decreases S. aureus-induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local diflunisal therapy was complicated by bacterial colonization of the depot's surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is, therefore, critical to develop an alternative drug delivery method for diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle-based parenteral delivery strategy would provide a method for delivering diflunisal to infected tissue while circumventing the complications associated with local delivery. In this study, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering diflunisal to infected bone. Moreover, diflunisal-loaded PPS nanoparticles effectively decrease S. aureus-mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone and Bones; Cell Line; Diflunisal; Drug Delivery Systems; Drug Evaluation, Preclinical; Female; Host-Pathogen Interactions; Mice; Nanoparticles; Osteomyelitis; Polymers; Staphylococcal Infections; Staphylococcus aureus; Sulfides
PubMed: 33300149
DOI: 10.1002/jor.24948 -
Frontiers in Genetics 2020Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now...
Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.
PubMed: 33193567
DOI: 10.3389/fgene.2020.00849 -
JACC. Cardiovascular Imaging Jan 2021The purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV)...
OBJECTIVES
The purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM).
BACKGROUND
Administration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain.
METHODS
Patisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a "TTR-stabilizing" drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results.
RESULTS
Patisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: -6.2% [95% confidence interval [CI]: -9.5% to -3.0%]; p = 0.001) accompanied by a fall in N-terminal pro-B-type natriuretic peptide concentrations (adjusted mean difference between groups: -1,342 ng/l [95% CI: -2,364 to -322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%).
CONCLUSIONS
Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.
Topics: Amyloid Neuropathies, Familial; Humans; Predictive Value of Tests; RNA, Small Interfering; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 33129740
DOI: 10.1016/j.jcmg.2020.07.043