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American Journal of Kidney Diseases :... Mar 2024Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as... (Review)
Review
Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as abnormal amyloid fibrils and accumulate throughout the body. The kidney is one of the main organs affected in amyloid light chain (AL) amyloidosis and ATTRv amyloidosis. The most common clinical presentation is proteinuria, which consists mainly of albumin; this is the first step in the natural history of ATTRv nephropathy. Not all TTR mutations are equal in terms of ATTRv kidney involvement. Kidney involvement in ATTRv itself is difficult to define, given the numerous associated confounding factors. There are several treatments available to treat ATTRv, including orthotopic liver transplant (OLT), which is the classic treatment for ATTRv. However, we should be careful regarding the use of calcineurin inhibitors in the setting of OLT because these can be nephrotoxic. New treatments for amyloidosis may have an impact on kidney function, including drugs that target specific pathways involved in the disease. Tafamidis and diflunisal, which are TTR stabilizers, patisiran (RNA interference agent), and inotersen (antisense oligonucleotide inhibitor) have been shown to reduce TTR amyloid. Tafamidis and patisiran are medications that have reduced the progression of kidney disease in amyloidosis, but inotersen and diflunisal may damage kidney function.
PubMed: 38484868
DOI: 10.1053/j.ajkd.2024.01.527 -
Amyloid : the International Journal of... Sep 2018Transthyretin (ATTR) amyloidosis is an under-recognized, progressive disease manifesting as cardiomyopathy and/or polyneuropathy. Diflunisal, a nonsteroidal...
OBJECTIVE
Transthyretin (ATTR) amyloidosis is an under-recognized, progressive disease manifesting as cardiomyopathy and/or polyneuropathy. Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID), has demonstrated transthyretin stabilization in vitro and slowing of polyneuropathy progression in the hereditary ATTR subtype (ATTRm). However, the use of diflunisal has only been described in a small cohort of patients with ATTR cardiac amyloidosis (CA). We hypothesized that selected patients with ATTR-CA, both hereditary and wild-type (ATTRwt), would tolerate diflunisal with limited adverse events.
MATERIALS AND METHODS
This is a retrospective, longitudinal study of 23 patients with ATTR-CA (10 ATTRm and 13 ATTRwt) diagnosed at the Cleveland Clinic from May 2007 to August 2017 who were treated with diflunisal. Patients were prescribed diflunisal, fully informed of the risks of side effects. Patient characteristics and subsequent adverse events were recorded.
RESULTS
The duration of diflunisal therapy ranged from 1-89 months (median 15 months). Average eGFR at diflunisal initiation was 61.9 ± 15.4 mL/min/m. Only one patient had a transient rise in Cr of 0.31 mg/dL. There were no clinically significant bleeding events, despite most of the patients being on anticoagulants or antiplatelet agents. Three of 23 patients (13%) withdrew treatment due to drug side effects (erosive gastritis, epigastric pain and decreased appetite). No patients died or were hospitalized for heart failure.
CONCLUSION
Diflunisal was well-tolerated in both the ATTRm- and ATTRwt-CA populations. Withdrawal due to side effects was related to gastrointestinal complaints, but most patients had no adverse events. Diflunisal can be safely used in a selected group of ATTR-CA patients with appropriate clinical, renal and hematologic monitoring.
Topics: Aged; Amyloidosis; Anti-Inflammatory Agents, Non-Steroidal; Cardiomyopathies; Diflunisal; Female; Humans; Longitudinal Studies; Male; Middle Aged; Prealbumin; Retrospective Studies
PubMed: 30388377
DOI: 10.1080/13506129.2018.1519507 -
MedChemComm Jun 2018Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a...
Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a nonsteroidal anti-inflammatory agent, has recently been repurposed for its anti-virulence properties against methicillin-resistant . Effective synthesis of some aza-analogs of the anti-inflammatory drug diflunisal was carried out following the route involving key oxazole intermediates to obtain - and -hydroxypyridinecarboxylic acid derivatives. The newly synthesized diflunisal aza-analogs did not exhibit cytotoxic activity up to 80 μM and some of them exhibited anti-inflammatory activities, decreasing the levels of pro-inflammatory cytokines and prostaglandins induced by bacterial lipopolysaccharide in human primary macrophages. Ten of the diflunisal aza-analogs were found to have interesting antibacterial activity, sensitizing , , , and to the antibacterial effects of beta-lactam antibiotics and protein synthesis inhibitors.
PubMed: 30108991
DOI: 10.1039/c8md00139a -
Journal of Medicinal Chemistry Feb 2019Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer...
Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer precede amyloid fibril formation, development of a small molecule that binds to TTR and stabilizes the TTR tetramer is an efficient strategy for the treatment of amyloidosis. Here, we report our discovery of the anti-TTR amyloidogenesis activities of crown ethers. X-ray crystallographic analysis, binding assay, and chemical cross-linking assay showed that 4'-carboxybenzo-18C6 (4) stabilized the TTR tetramer by binding to the allosteric sites on the molecular surface of the TTR tetramer. In addition, 4 synergistically increased the stabilization activity of diflunisal, one of the most potent TTR amyloidogenesis inhibitors. These experimental evidences establish that 4 is a valuable template compound as an allosteric inhibitor of TTR amyloidogenesis.
Topics: Allosteric Site; Amyloidogenic Proteins; Crown Ethers; Crystallography, X-Ray; Diflunisal; Drug Discovery; Humans; Prealbumin; Protein Binding; Protein Multimerization
PubMed: 30688456
DOI: 10.1021/acs.jmedchem.8b01700 -
Journal of Clinical Medicine Apr 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them.
PubMed: 35456241
DOI: 10.3390/jcm11082148 -
Antibiotics (Basel, Switzerland) May 2023Virulence factor expression is integral to pathogenicity of . We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates...
Virulence factor expression is integral to pathogenicity of . We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates virulence phenotypes in vitro and in vivo. We compared salicylate metabolites and a structural analogue for their ability to modulate virulence factor expression and phenotypes: (i) acetylsalicylic acid (ASA, aspirin); (ii) ASA metabolites, salicylic acid (SAL), gentisic acid (GTA) and salicyluric acid (SUA); or (iii) diflunisal (DIF), a SAL structural analogue. None of these compounds altered the growth rate of any strain tested. ASA and its metabolites SAL, GTA and SUA moderately impaired hemolysis and proteolysis phenotypes in multiple strain backgrounds and their respective deletion mutants. Only DIF significantly inhibited these virulence phenotypes in all strains. The kinetic profiles of ASA, SAL or DIF on expression of (alpha hemolysin), (V8 protease) and their regulators (, , (RNAIII)) were assessed in two prototypic strain backgrounds: SH1000 (methicillin-sensitive ; MSSA) and LAC-USA300 (methicillin-resistant ; MRSA). DIF induced expression which is coincident with the significant inhibition of RNAIII expression in both strains and precedes significant reductions in and expression. The inhibited expression of these genes within 2 h resulted in the durable suppression of hemolysis and proteolysis phenotypes. These results indicate that DIF modulates the expression of key virulence factors in via a coordinated impact on their relevant regulons and target effector genes. This strategy may hold opportunities to develop novel antivirulence strategies to address the ongoing challenge of antibiotic-resistant .
PubMed: 37237805
DOI: 10.3390/antibiotics12050902 -
Journal of Molecular Graphics &... Jul 2023An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel... (Review)
Review
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Alzheimer Disease; Molecular Docking Simulation; Diflunisal; Drug Repositioning; Reproducibility of Results; Cholinesterase Inhibitors; Acetylcholinesterase
PubMed: 37087882
DOI: 10.1016/j.jmgm.2023.108471 -
Biological & Pharmaceutical Bulletin 2018Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the... (Review)
Review
Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. In this review, we summarized the natural products and synthetic compounds that have been shown to inhibit the amyloidogenesis of TTR. The stabilizers and/or the amyloid fibril disrupters isolated from natural sources may become lead compounds for the treatment of TTR-related amyloidosis.
Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents, Non-Steroidal; Benzoxazoles; Biological Products; Diflunisal; Humans; Mutation; Prealbumin
PubMed: 29962408
DOI: 10.1248/bpb.b18-00166 -
Expert Opinion on Pharmacotherapy 2016Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the... (Review)
Review
INTRODUCTION
Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.
AREAS COVERED
We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.
EXPERT OPINION
Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Clinical Trials, Phase III as Topic; Diflunisal; Disease Progression; Gene Silencing; Humans; Liver Transplantation; Prealbumin; Receptors, Albumin
PubMed: 26800456
DOI: 10.1517/14656566.2016.1145664 -
Journal of the American Dental... Apr 2018Effective pain management is a priority in dental practice. Government and private agencies highlight the need to provide optimal pain relief, balancing potential... (Review)
Review
BACKGROUND
Effective pain management is a priority in dental practice. Government and private agencies highlight the need to provide optimal pain relief, balancing potential benefits and harms of both opioid and nonopioid analgesic agents. The purpose of this study is to summarize the available evidence on the benefits and harms of analgesic agents, focusing on preexisting systematic reviews.
TYPES OF STUDIES REVIEWED
An overview of systematic reviews was conducted to evaluate the efficacy or reported adverse events associated with orally administered medication or medication combinations for relief of acute pain. Reviews were inclusive of all age populations but were limited to those that evaluated medication and medication combinations marketed in the United States and had moderate or high methodological quality according to the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 tool.
RESULTS
Five reviews were found eligible for inclusion. The data identified combinations of ibuprofen and acetaminophen as having the highest association with treatment benefit in adult patients and the highest proportion of adult patients who experienced maximum pain relief. Diflunisal, acetaminophen, and oxycodone were found to have the longest duration of action in adult patients. Medication and medication combinations that included opioids were among those associated most frequently with acute adverse events in both child and adult-aged patient populations.
PRACTICAL IMPLICATIONS
The best available data suggested that the use of nonsteroidal medications, with or without acetaminophen, offered the most favorable balance between benefits and harms, optimizing efficacy while minimizing acute adverse events.
Topics: Acetaminophen; Acute Pain; Adult; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Child; Dentistry; Humans; Pain, Postoperative; Systematic Reviews as Topic
PubMed: 29599019
DOI: 10.1016/j.adaj.2018.02.012