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Journal of Neurology, Neurosurgery, and... Jun 2022Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic... (Review)
Review
Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.
Topics: Amyloid Neuropathies, Familial; Heart Diseases; Humans; Polyneuropathies; Prealbumin; Quality of Life
PubMed: 35256455
DOI: 10.1136/jnnp-2021-327909 -
Amyloid : the International Journal of... Jun 2022Diflunisal is a non-steroidal anti-inflammatory drug that stabilises transthyretin (TTR) and reduces neurologic deterioration in patients with polyneuropathy caused by...
Diflunisal treatment is associated with improved survival for patients with early stage wild-type transthyretin (ATTR) amyloid cardiomyopathy: the Boston University Amyloidosis Center experience.
BACKGROUND
Diflunisal is a non-steroidal anti-inflammatory drug that stabilises transthyretin (TTR) and reduces neurologic deterioration in patients with polyneuropathy caused by hereditary transthyretin amyloidosis (ATTRv).
METHODS
We conducted a retrospective cohort study of patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) treated with diflunisal for at least one year between 2009 and 2016 at the Boston University Amyloidosis Centre. Baseline and one year follow up characteristics were measured, including plasma chemistries and echocardiography. Cox proportional hazards analysis assessed the primary outcome of all-cause mortality.
RESULTS
A total of 104 ATTRwt-CM patients were evaluated with 35 patients receiving diflunisal. Patients in the diflunisal group were younger (73.8 vs 76.8 years, = 0.034), with lower B-type natriuretic peptide (BNP, 335 +/- 67 vs. 520 +/- 296 pg/mL, = 0.006), similar troponin I (0.1 +/- 0.1 vs 0.2 +/- 0.3 ng/mL, = 0.09), and better renal function (eGFR 67 +/- 17 vs 53 +/- 18 mL/min/1.73m2, = 0.0002) at baseline. Over a median follow-up of 3.2 years, 52 deaths occurred. Diflunisal administration was associated with improved survival in unadjusted analysis (HR 0.13, 95% CI 0.05 - 0.36, < 0.001) that persisted after adjustment for age, baseline BNP, eGFR, troponin I, interventricular septal thickness, and left ventricular ejection fraction (HR 0.18, 95% CI 0.06 - 0.51, = 0.0006). Over the observation period, no significant changes in BNP, troponin I, interventricular septal thickness or left ventricular ejection fraction were observed with diflunisal treatment. A total of 14 patients (40%) discontinued diflunisal in this study, but only 3 within the first year. Mean eGFR in treated patients was 59 ml/min/1.73m at 1 year (change from baseline = 0.03).
CONCLUSION
Diflunisal administration in ATTRwt-CM was associated with improved survival and overall stability in clinical and echocardiographic markers of disease with decrement renal function.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Diflunisal; Humans; Prealbumin; Retrospective Studies; Stroke Volume; Troponin I; Universities; Ventricular Function, Left
PubMed: 35083944
DOI: 10.1080/13506129.2021.2000388 -
Health Science Reports Mar 2022Our primary aim was to evaluate the healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy. Second, we aim to assess the...
OBJECTIVES
Our primary aim was to evaluate the healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy. Second, we aim to assess the effect of the number of diagnostic tests and clinical contact points on the total time and costs between symptom onset and diagnosis defining a quantitative hypothetical optimized diagnostic pathway.
SETTING
Clinical and cost data were collected from patients presenting between 2010 and 2018 in a tertiary referral institution in South London involving two participating hospitals.
PARTICIPANTS
Thirty-eight adult patients with a definite diagnosis of transthyretin amyloidosis cardiomyopathy were included, mostly male (n = 28, 74%) and of African-Caribbean descent (n = 23, 64%). We excluded patients without a confirmed transthyretin amyloidosis cardiomyopathy or those on inotersen, patisiran, or diflunisal at point of referral.
PRIMARY AND SECONDARY OUTCOME MEASURES
The average time between first presentation and final diagnosis, and the cost per patient per month. By comparing to a more optimal clinical pathway towards diagnosis, we considered what could be the theoretical gain in terms of time to diagnosis and financial savings.
RESULTS
The average time between first presentation and final diagnosis was 2.74 years. The average cost per patient per month was higher with progressive heart failure symptoms. A hypothetical optimal pathway reduces time to diagnosis of 1.65 to 1.74 years per patient. The potential financial savings are estimated within the range of £3000 to £4800 per patient.
CONCLUSIONS
Patients diagnosed with transthyretin amyloidosis cardiomyopathy have substantial healthcare resource utilization and costs starting from symptom onset. Higher costs were observed with progression in symptoms and appear linked to a delayed diagnosis. The number of additional diagnostic tests and clinical contact points may contribute to this and could represent a path to explore further for important health and cost savings, with more efficient pathways for these patients to be managed.
PubMed: 35024457
DOI: 10.1002/hsr2.466 -
Materials (Basel, Switzerland) Nov 2021Diflunisal is a well-known drug for the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, and colon cancer. This molecule belongs to the group of... (Review)
Review
Diflunisal is a well-known drug for the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, and colon cancer. This molecule belongs to the group of nonsteroidal anti-inflammatory drugs (NSAID) and thus possesses serious side effects such as cardiovascular diseases risk development, renal injury, and hepatic reactions. The last clinical data demonstrated that diflunisal is one of the recognized drugs for the treatment of cardiac amyloidosis and possesses a survival benefit similar to that of clinically approved tafamidis. Diflunisal stabilizes the transthyretin (TTR) tetramer and prevents the misfolding of monomers and dimers from forming amyloid deposits in the heart. To avoid serious side effects of diflunisal, the various delivery systems have been developed. In the present review, attention is given to the recent development of diflunisal-loaded delivery systems, its technology, release profiles, and effectiveness.
PubMed: 34772213
DOI: 10.3390/ma14216687 -
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 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2021We report the anti-osteosarcoma stem cell (OSC) properties of a series of gallium(III)-polypyridyl complexes (5-7) containing diflunisal, a non-steroidal...
We report the anti-osteosarcoma stem cell (OSC) properties of a series of gallium(III)-polypyridyl complexes (5-7) containing diflunisal, a non-steroidal anti-inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8-tetramethyl-1,10-phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase-2 (COX-2) and kills osteosarcoma cells in a COX-2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase-dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX-2 and damaging nuclear DNA.
Topics: Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Diflunisal; Gallium; Humans; Neoplastic Stem Cells; Osteosarcoma
PubMed: 34269487
DOI: 10.1002/chem.202102207 -
Crystal Growth & Design Jun 2021Needle crystals can cause filtering and handling problems in industrial settings, and the factors leading to a needle crystal morphology have been investigated. The...
Needle crystals can cause filtering and handling problems in industrial settings, and the factors leading to a needle crystal morphology have been investigated. The crystal growth of the amide and methyl, ethyl, isopropyl, and t-butyl esters of diflunisal have been examined, and needle growth has been observed for all except the t-butyl ester. Their crystal structures show that the t-butyl ester is the only structure that does not contain molecular stacking. A second polymorph of a persistent needle forming phenylsulfonamide with a block like habit has been isolated. The structure analysis has been extended to known needle forming systems from the literature. The intermolecular interactions in needle forming structures have been analyzed using the PIXEL program, and the properties driving needle crystal growth were found to include a 1D motif with interaction energy greater than -30 kJ/mol, at least 50% vdW contact between the motif neighbors, and a filled unit cell which is a monolayer. Crystal structures are classified into persistent and controllable needle formers. Needle growth in the latter class can be controlled by choice of solvent. The factors shown here to be drivers of needle growth will help in the design of processes for the production of less problematic crystal products.
PubMed: 34267600
DOI: 10.1021/acs.cgd.1c00217 -
Cancers May 2021Cyclin D1 () and cyclin-dependent kinase 4 () both play significant roles in regulating cell cycle progression, while polo-like kinase 1 () regulates cell...
Cyclin D1 () and cyclin-dependent kinase 4 () both play significant roles in regulating cell cycle progression, while polo-like kinase 1 () regulates cell differentiation and tumor progression, and activates cancer stem cells (CSCs), with the cluster of differentiation 44 () surface marker mostly being expressed. These oncogenes have emerged as promoters of metastasis in a variety of cancer types. In this study, we employed comprehensive computational and bioinformatics analyses to predict drug targets of our novel small molecules, NSC765600 and NSC765691, respectively derived from diflunisal and fostamatinib. The target prediction tools identified as target genes for NSC765600 and NSC765691 compounds. Additionally, the results of our in silico molecular docking analysis showed unique ligand-protein interactions with putative binding affinities of NSC765600 and NSC765691 with oncogenic signaling pathways. Moreover, we used drug-likeness precepts as our guidelines for drug design and development, and found that both compounds passed the drug-likeness criteria of molecular weight, polarity, solubility, saturation, flexibility, and lipophilicity, and also exhibited acceptable pharmacokinetic properties. Furthermore, we used development therapeutics program (DTP) algorithms and identified similar fingerprints and mechanisms of NSC765600 and NSC765691 with synthetic compounds and standard anticancer agents in the NCI database. We found that NSC765600 and NSC765691 displayed antiproliferative and cytotoxic effects against a panel of NCI-60 cancer cell lines. Based on these finding, NSC765600 and NSC765691 exhibited satisfactory levels of safety with regard to toxicity, and met all of the required criteria for drug-likeness precepts. Currently, further in vitro and in vivo investigations in tumor-bearing mice are in progress to study the potential treatment efficacies of the novel NSC765600 and NSC765691 small molecules.
PubMed: 34063946
DOI: 10.3390/cancers13112523 -
Brain Sciences Apr 2021Over the past decade, three new drugs have been approved for the treatment of hereditary amyloid transthyretin (ATTRv) polyneuropathy. The aim of this work was to...
BACKGROUND
Over the past decade, three new drugs have been approved for the treatment of hereditary amyloid transthyretin (ATTRv) polyneuropathy. The aim of this work was to analyze whether current therapies prolong survival for patients affected by ATTRv amyloidosis.
METHODS
The study was conducted retrospectively, analyzing the medical records of 105 patients with genetic diagnoses of familial amyloidotic polyneuropathy followed at the two referral centers for the disease in Sicily, Italy. Of these, 71 received disease-modifying therapy, while 34 received only symptomatic treatment or no therapy.
RESULTS
The most used treatment in our patient cohort was tafamidis, followed by liver transplantation, patisiran, inotersen, and diflunisal. The median survival was significantly longer for treated vs. untreated patients (12 years vs. 8 years). In the 71 patients who received disease-modifying treatment, the presence of cardiac involvement, weight loss, or autonomic dysfunction at diagnosis was not related to survival. Conversely, patients diagnosed in the early stage of the disease (PND 1) had significantly longer survival than those diagnosed in the late stage (PND 2-4).
PubMed: 33925301
DOI: 10.3390/brainsci11050545 -
Cell May 2021Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation...
Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
Topics: Acetylation; Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Brain Injuries, Traumatic; Cell Line; Diflunisal; Female; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotection; Salicylates; Sirtuin 1; p300-CBP Transcription Factors; tau Proteins
PubMed: 33852912
DOI: 10.1016/j.cell.2021.03.032