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Biomedicines Feb 2019Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has... (Review)
Review
Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.
PubMed: 30764529
DOI: 10.3390/biomedicines7010011 -
Molecules (Basel, Switzerland) Jul 2021Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis.... (Review)
Review
Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.
Topics: Alzheimer Disease; Amyloid; Amyloid Neuropathies, Familial; Benzoxazoles; Diflunisal; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Myocardium; Neuroprotective Agents; Oligonucleotides; Peripheral Nerves; Prealbumin; Prion Diseases; RNA, Small Interfering
PubMed: 34361762
DOI: 10.3390/molecules26154611 -
Journal of AOAC International Dec 2021Diflunisal (DIF) has analgesic and anti-inflammatory activity. It is a pharmacopeial drug found in the British Pharmacopoeia (BP), and its major pharmacopeial impurity...
BACKGROUND
Diflunisal (DIF) has analgesic and anti-inflammatory activity. It is a pharmacopeial drug found in the British Pharmacopoeia (BP), and its major pharmacopeial impurity is biphenyl-4-ol (BPL).
OBJECTIVE
DIF has not previously been determined together with BPL. The presence of BPL could significantly affect the dose of DIF in its dosage forms; hence it is crucial to determine DIF and BPL in each other's presence.
METHODS
TLC is the first proposed method, where DIF and BPL were separated on silica gel TLC F254 plates. The eluent was toluene-acetone-acetic acid solution (3.5:6.5:1, v/v). Reversed-phase (RP) HPLC is the second suggested method, where a mixture of DIF and BPL was separated on a C18 (5 µm ps, 250 mm and 4.6 id) column using phosphate buffer pH 4 (0.05 M)-acetonitrile (40:60, v/v). Detection was carried out at 254 nm in both methods.
RESULTS
For the TLC method, concentration ranges of 0.5-3 and 0.3-1.7 µg/band were used, with mean percentage recoveries of 100.22% (SD 0.893) and 100.52% (SD 0.952) for DIF and BPL, respectively. The RP-HPLC method was carried out over a concentration range of 5-30 and 2-9 μg/mL, with mean percentage recoveries of 100.10% (SD 1.259) and 98.88% (SD 0.822) for DIF and BPL, respectively.
CONCLUSION
The TLC and RP-HPLC methods were successfully applied for the determination of DIF and BPL, quantitatively, whether in bulk powder or in pharmaceutical formulations.
HIGHLIGHTS
Two chromatographic methods were developed and validated according to International Council on Harmonization guidelines for the assay of DIF and its pharmacopeial impurity.
Topics: Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Densitometry; Diflunisal; Reproducibility of Results
PubMed: 34051091
DOI: 10.1093/jaoacint/qsab076 -
Journal of Biomolecular Structure &... Feb 2022Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or...
Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or oxamniquine but there are reported cases of treatment failures due to resistance or tolerance. Again, derivatives of praziquantel and oxamniquine have not shown significant activities than their parent compounds. The study predicted approved drugs with possible antischistosomal activities. Four schistosomal drug targets were obtained from Protein Data Bank and six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, [(2S,3S,4S,5S,6S)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl] methyl acetate, [propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The selected drugs and drug targets were obtained and prepared for molecular docking simulations. The molecular docking simulations were performed using AutoDockvina-1.1.2 after validation of docking protocols while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area). Tolmetin was predicted as potential antischistosomal drug with binding energies of -231.064 ± 18.550 and -338.636 ± 36.900 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) respectively. Also diflunisal was predicted as potential antischistosomal drug with binding energies of -168.641 ± 20.370 and -290.117 ± 43.800 KJ/mol for sulfotransferase and TGR respectively. Non-covalent interactions and conformational changes were responsible for molecular recognitions and specificities and average bond measurement showed that carboxylic functional groups in diflunisal and tolmetin may interact covalently with -SH group of Cys159 in TGR. Confirmation of covalent interactions and validations are recommended.Communicated by Ramaswamy H. Sarma.
Topics: Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Oxamniquine; Schistosomiasis; Schistosomicides
PubMed: 32924851
DOI: 10.1080/07391102.2020.1820382 -
ELife May 2016Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms,...
Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.
Topics: Acetyl Coenzyme A; Acetylation; Animals; Antineoplastic Agents; Binding, Competitive; Catalytic Domain; Cell Line, Tumor; Core Binding Factor Alpha 2 Subunit; Diflunisal; Enzyme Inhibitors; Gene Expression Regulation, Leukemic; HEK293 Cells; Humans; Leukemia, Myeloid, Acute; Leukocytes; Mice; Mice, SCID; Oncogene Proteins, Fusion; Protein Binding; RUNX1 Translocation Partner 1 Protein; Salicylic Acid; Signal Transduction; Structure-Activity Relationship; Xenograft Model Antitumor Assays; p300-CBP Transcription Factors
PubMed: 27244239
DOI: 10.7554/eLife.11156 -
Brain and Behavior Sep 2019Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant... (Review)
Review
INTRODUCTION
Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR.
METHODS
A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR.
RESULTS
Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities.
CONCLUSIONS
Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.
Topics: Amyloid Neuropathies, Familial; Female; Humans; Oligonucleotides; RNA, Small Interfering; Treatment Outcome
PubMed: 31368669
DOI: 10.1002/brb3.1371 -
Expert Opinion on Investigational Drugs Sep 2014Transthyretin (TTR)-related hereditary amyloidosis is an adult-onset, dominantly inherited, systemic neurodegenerative disease endemic in some populations. Stabilization... (Review)
Review
INTRODUCTION
Transthyretin (TTR)-related hereditary amyloidosis is an adult-onset, dominantly inherited, systemic neurodegenerative disease endemic in some populations. Stabilization of the native structure of TTR by small-molecule ligands has recently proved effective in slowing neurological progression. Two drugs, tafamidis and diflunisal, are now available for most patients, particularly in the early stage of the disease. However, this disorder remains life threatening with several unmet needs. There are great expectations for a number of novel agents undergoing investigation.
AREAS COVERED
The authors review the current investigational drugs for the treatment of TTR amyloidosis according to the different steps of the fibrillogenesis process they target. Innovative approaches include suppression of TTR secretion, prevention of TTR misfolding by stronger stabilizers identified through structure-based design and high-throughput screening methodologies as well as the redirection of pathogenic aggregates toward nontoxic species and reabsorption of deposits through amyloid disrupters and immunotherapy.
EXPERT OPINION
Suppression of TTR synthesis by antisense oligonucleotides and small-interfering RNA is presently one of the most promising therapeutic approaches. However, well-designed clinical trials are required to establish their safety and efficacy compared with liver transplantation, tafamidis and diflunisal. With a longer time frame, it may be possible to develop combination therapies that target multiple steps of the aggregation process that could provide the best long-life effective treatments for this devastating disease.
Topics: Adult; Age of Onset; Amyloid Neuropathies, Familial; Animals; Clinical Trials as Topic; Drug Design; Drugs, Investigational; High-Throughput Screening Assays; Humans; Oligonucleotides, Antisense; Protein Folding; RNA, Small Interfering
PubMed: 25003808
DOI: 10.1517/13543784.2014.922541 -
Clinical Autonomic Research : Official... Sep 2019Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis... (Review)
Review
PURPOSE
Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40-60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen).
METHODS
Literature review.
RESULTS
Orthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition.
CONCLUSIONS
When recognized, neurogenic orthostatic hypotension can be treated. Discontinuation of potentially aggravating medications, patient education and non-pharmacologic approaches should be applied first. Droxidopa (Northera), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.
Topics: Amyloid Neuropathies, Familial; Humans; Hypotension, Orthostatic
PubMed: 31452021
DOI: 10.1007/s10286-019-00623-x -
EMBO Reports Oct 2019Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states:...
Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of diflunisal and open the way to the rational design of functionally specific anti-inflammatory drugs.
Topics: 3T3 Cells; Animals; Chemokine CXCL12; Chemotaxis; Diflunisal; Disulfides; Glycyrrhizic Acid; HMGB1 Protein; Humans; Inflammation; Leukocytes; Macrophages; Magnetic Resonance Spectroscopy; Mice
PubMed: 31418171
DOI: 10.15252/embr.201947788 -
Transplant International : Official... 2022To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a...
To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of ≥2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs. Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for ≥12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months ( = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients. Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.
Topics: Amyloid Neuropathies; Diflunisal; Humans; Longitudinal Studies; Retrospective Studies; Transplant Recipients
PubMed: 35497887
DOI: 10.3389/ti.2022.10454