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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., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate., Areas of Uncertainty: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data., Data Sources: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal.", Therapeutic Advances: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72)., Conclusion: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 μ M ±   143.7 μ M (mean ± standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400  μM diflunisal concentrations, all observed in patients after 250 mg BID oral dosing. A 250 μ M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.

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, p  = 0.034), with lower B-type natriuretic peptide (BNP, 335 +/- 67 vs. 520 +/- 296 pg/mL, p  = 0.006), similar troponin I (0.1 +/- 0.1 vs 0.2 +/- 0.3 ng/mL, p  = 0.09), and better renal function (eGFR 67 +/- 17 vs 53 +/- 18 mL/min/1.73m2, p  = 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, p  < 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, p  = 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 2 at 1 year (change from baseline p  = 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.

Objectives: To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Methods: 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. Results: 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 ( p = 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. Conclusion: 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nedkova-Hristova, Baliellas, González-Costello, Lladó, González-Vilatarsana, Vélez-Santamaría and Casasnovas.)

Transthyretin cardiac amyloidosis (ATTR-CM) is caused by the accumulation of misfolded transthyretin (TTR) protein in the myocardium. Diflunisal, an agent that stabilizes TTR, has been used as an off-label therapeutic for ATTR-CM. Given limited data surrounding the use of diflunisal, a systematic review of the literature is warranted. We searched the PubMed, MEDLINE, and Embase databases for studies that reported on the use of diflunisal therapy for patients with ATTR-CM. We included English language studies which assessed the effect of diflunisal in adult patients with ATTR-CM who received diflunisal as primary treatment and reported clinical outcomes with emphasis on studies that noted the safety and efficacy of diflunisal in cardiac manifestations of ATTR amyloidosis. We excluded studies which did not use diflunisal therapy or used diflunisal therapy for non-cardiac manifestations of TTR amyloidosis. We also excluded case reports, abstracts, oral presentations, and studies with fewer than 10 subjects. Our search yielded 316 records, and we included 6 studies reporting on 400 patients. Non-comparative single-arm small non-randomized trials for diflunisal comprised 4 of the included studies. The 2 studies that compared diflunisal versus no treatment found improvements in TTR concentration, left atrial volume index, cardiac troponin I, and global longitudinal strain. Overall, diflunisal use was associated with decreased mortality and number of orthotopic heart transplant in ATTR-CM patients. Although a smaller number of patients had to stop treatment due to gastrointestinal side effects and transient renal dysfunction, there were no severe reactions reported in the studies included in our review. This systematic review supports the use of diflunisal for ATTR-CM. Additional long-term analyses and randomized clinical trials are needed to confirm these results., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This clinical practice guideline for treating transthyretin amyloid (ATTR) cardiomyopathy is based on the best available evidence of clinical effectiveness. The PICO format was used to generate a list of questions focused on the effectiveness and safety of the specific treatment of patients with ATTR cardiomyopathy. The search was conducted in PubMed, Cochrane and Epistemokus, between July-August 2020, and selected articles between 2000-2020, in English and Spanish. The level of evidence and recommendations were analyzed and classified by the GRADE system. The following drugs were included in the analysis: tafamidis, diflunisal, inotersen, patisiran y doxycycline and ursodeoxycholic acid. The expert panel had an agreement that tafamidis 80mg/daily is the only available drug with moderate evidence and weak recommendation for the reduction of total mortality, cardiovascular morbidity, heart failure hospitalization and progression of the disease in patients with ATTR cardiomyopathy and NYHA class = 3. In contrast, tafamidis 20 mg/daily had low-quality evidence in this group of patients. The expert panel did not recommend inotersen, patisiran and diflunisal in patients with ATTR cardiomyopathy due to the lack of supporting evidence, local drug availability, and the potential risk of toxicity. When patients did not have access to tafamidis, the expert panel stated a weak recommendation to use doxycycline and ursodeoxycholic acid in patients with ATTR cardiomyopathy.

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., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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.

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., Competing Interests: Declaration of interests A.A.P. is an inventor on patents related to P7C3. L.G. is a founder of Aeton Therapeutics. No other authors declare competing interests., (Published by Elsevier Inc.)

Abstract: Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors report that they have no conflicts of interest for this work., (© 2021 Bashir et al.)

Aim: Examine safety and pharmacodynamics of patisiran alone or with concomitant transthyretin stabilizers from the Phase II open-label extension study and safety and efficacy of patisiran in patients with prior transthyretin stabilizer use from the Phase III APOLLO study. Patients & methods: Post hoc analyses in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Results: Patisiran safety was consistent regardless of concomitant or prior transthyretin stabilizers. In the Phase II open-label extension (n = 27), transthyretin reduction was similar over 24 months, regardless of concomitant transthyretin stabilizers. In APOLLO (n = 225), patisiran-treated groups showed stabilization or improvements in neurological function (modified Neuropathy Impairment Score +7) and quality of life (Norfolk Quality of Life-Diabetic Neuropathy questionnaire) at 18 months, regardless of prior transthyretin stabilizers. Conclusion: Patients benefit from patisiran regardless of transthyretin stabilizer use.

Objective: To carry out a systematic review of the literature to analyse the efficacy and safety of treatments available or under investigation for amyloidosis due to mutations in the transthyretin gene (ATTR)., Methods: A bibliographic search was carried out in the following electronic databases up to September 2017: PubMed, Cochrane Library and EMBASE. The inclusion criteria were: efficacy and/or safety studies conducted in humans, studies that included treatments, including treatments in the research phase, and studies that included 10 or more patients., Results: A total of 21 articles were included; 16 were clinical trials, eight of them (50%) phase III trials, and five were observational studies. Of the total number of studies selected, 11 were on tafamidis, four on diflunisal, two on liver transplantation, two on patisiran and two on other therapeutic alternatives. Of the 11 studies related to the drug, the pivotal trial, the results of its two extension studies and an additional post hoc analysis were selected. In addition, two phase III trials were included in specific populations, two phase II studies, one safety study and two observational studies. Regarding the four included studies related to the drug, one was the pivotal trial that gave the indication to diflunisal, another a safety summary of the pivotal trial, and the other two trials were carried out in specific populations, one in a Japanese population and another phase I trial in cardiac amyloidosis in the USA. As far as other alternatives are concerned, of the six studies included in this section, two were related to liver transplantation, two to patisiran and two to different therapeutic alternatives., Conclusions: Sufficient evidence has not been found that demonstrates superiority among the available oral alternatives, diflunisal or tafamidis, in the treatment of ATTR. Direct comparisons between both drugs and pharmacoeconomic studies would be necessary to select the most efficient treatment., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors., Objectives: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs)., Search Methods: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites., Selection Criteria: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial., Data Collection and Analysis: We followed standard Cochrane methodology., Main Results: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP., Authors' Conclusions: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.

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 2 . 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.

Transthyretin (TTR) is a globular tetrameric transport protein in plasma. Nearly 140 single amino acid substitutions in TTR cause life-threatening amyloid disease. We report a one-of-a-kind pathological variant featuring a Glu51, Ser52 duplication mutation (Glu51&#95;Ser52dup). The proband, heterozygous for the mutation, exhibited an unusually aggressive amyloidosis that was refractory to treatment with the small-molecule drug diflunisal. To understand the poor treatment response and expand therapeutic options, we explored the structure and stability of recombinant Glu51&#95;Ser52dup. The duplication did not alter the protein secondary or tertiary structure but decreased the stability of the TTR monomer and tetramer. Diflunisal, which bound with near-micromolar affinity, partially restored tetramer stability. The duplication had no significant effect on the free energy and enthalpy of diflunisal binding, and hence on the drug-protein interactions. However, the duplication induced tryptic digestion of TTR at near-physiological conditions, releasing a C-terminal fragment 49-129 that formed amyloid fibrils under conditions in which the full-length protein did not. Such C-terminal fragments, along with the full-length TTR, comprise amyloid deposits in vivo. Bioinformatics and structural analyses suggested that increased disorder in the surface loop, which contains the Glu51&#95;Ser52dup duplication, not only helped generate amyloid-forming fragments but also decreased structural protection in the amyloidogenic residue segment 25-34, promoting misfolding of the full-length protein. Our studies of a unique duplication mutation explain its diflunisal-resistant nature, identify misfolding pathways for amyloidogenic TTR variants, and provide therapeutic targets to inhibit amyloid fibril formation by variant TTR., Competing Interests: The authors declare no conflict of interest.

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.

Purpose of Review: Cardiomyopathies due to genetic mutations are a heterogeneous group of disorders that comprise diseases of contractility, myocardial relaxation, and arrhythmias. Our goal here is to discuss a limited list of genetically inherited cardiomyopathies and the specific therapeutic strategies used to treat them., Recent Findings: Research into the molecular pathophysiology of the development of these cardiomyopathies is leading to the development of novel treatment approaches. Therapies targeting these specific mutations with gene therapy vectors are on the horizon, while other therapies which indirectly affect the physiologic derangements of the mutations are currently being studied and used clinically. Many of these therapies are older medications being given new roles such as mexiletine for Brugada syndrome and diflunisal for transthyretin amyloid cardiomyopathy. A newer targeted therapy, the inhibitor of myosin ATPase MYK-461, has been shown to suppress the development of ventricular hypertrophy, fibrosis, and myocyte disarray and is being studied as a potential therapy in patients with hypertrophic cardiomyopathy. While this field is too large to be completely contained in a single review, we present a large cross section of recent developments in the field of therapeutics for inherited cardiomyopathies. New therapies are on the horizon, and their development will likely result in improved outcomes for patients inflicted by these conditions.

We report here the case of a 67-year-old man who was initially diagnosed with myocardial hypertrophy with progressive hypertensive heart disease. After 6 years a cardiac biopsy was conducted because of changes in the electrocardiogram and transthoracic echocardiogram results, revealing amyloid deposition. Additional genetic studies revealed no TTR gene mutations, leading to a definitive diagnosis of wild-type transthyretin-related amyloidosis (ATTR). The patient started taking diflunisal as a stabilizer which is one of the advanced therapies for ATTR, and then the heart failure symptoms and brain natriuretic peptide (BNP) level improved in short-term follow-up. We present an elderly patient with ATTR, which is believed to be rare. We also discuss the apparent efficacy of novel therapeutic agents that increase the incentive to diagnose ATTR at an early stage. Therefore, we should always consider the existence of cardiac amyloidosis when we initiate the management of an elderly patient with cardiac wall thickening.

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.

Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.

Two series of iododiflunisal and diflunisal analogues have been obtained by using a two step sequential reaction solution-phase parallel synthesis. The synthesis combined an aqueous Suzuki-Miyaura cross-coupling and a mild electrophilic aromatic iodination step using a new polymer-supported iodonium version of Barluenga's reagent. From a selected set of 77 noniodinated and 77 iodinated diflunisal analogues, a subset of good transthyretin amyloid inhibitors has been obtained with improved turbidimetry inhibition constants, high binding affinity to transthyretin, and good selectivity for TTR compared to other thyroxine binding proteins.

Background: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis., Methods: Diflunisal was administered orally at 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 months)., Results: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (p = 0.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment., Conclusions: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.

Objective: To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area., Methods: Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and (123)iodine-metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy., Results: One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3-5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on (123)I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated., Conclusion: Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Familial amyloid polyneuropathy (FAP) is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils, and is characterized by progressive sensory, motor, and autonomic polyneuropathy. FAP was considered a rare endemic disease; however, its worldwide incidence is much higher than previously recognized. Until recently, liver transplantation was the only effective treatment for FAP. However, liver transplantation has a number of limitations, including a shortage of donors and a requirement for surgery for both the recipient and living donor. Furthermore, a large number of the patients are not good transplant candidates because of their age and/or advanced disease status. Recently, the clinical effects of two transthyretin tetramer stabilizers, diflunisal and tafamidis, were demonstrated in randomized clinical trials, and tafamidis was approved for the treatment of FAP in European countries in 2011 and Japan in 2013.

What Is Known and Objective: Transthyretin (TTR) is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant familial amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) presenting as sporadic amyloid disease in the elderly. The objective of this review is to summarize recent progress in our understanding and treatment of TTR amyloidosis., Methods: Literature searches were conducted on the topics of transthyretin, familial amyloid polyneuropathy and clinical trials, using PubMed, the United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected, evaluated for relevance and quality, critically assessed and summarized., Results and Discussion: The current standard first-line treatment of familial TTR amyloidosis is liver transplantation. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of FAP in European countries and Japan. In addition, gene therapies with antisense oligonucleotides and small interfering RNAs are promising strategies to ameliorate TTR amyloidoses and are currently in clinical trials., What Is New and Conclusions: Liver transplantation to treat the familial TTR amyloidosis will likely be replaced by other less invasive therapies, such as TTR tetramer stabilizers and possibly gene therapy approaches. These newly developed therapies are expected to be effective for not only familial TTR amyloidosis but also SSA, based on their mechanisms of action., (© 2014 John Wiley & Sons Ltd.)

Hereditary amyloid neuropathy includes hereditary ATTR, hereditary AGel, hereditary AApoAI, and hereditary Aβ2M amyloidosis. Among these diseases, hereditary ATTR is the most common type of amyloidosis caused by mutation in the transthyretin (TTR) gene. Hereditary ATTR amyloidosis is a life-threatening, multi-symptom, gain-of-toxic-function disease that may present with peripheral neuropathy, autonomic neuropathy, cardiomyopathy, ophthalmopathy, and/or leptomeningeal amyloidosis. In addition to the clinical symptoms described above, proven amyloid deposition in biopsy specimens and identification of disease-causing mutations in the TTR gene are necessary to establish the diagnosis. Deposition of amyloid in tissue can be demonstrated by Congo red staining of biopsy materials. Liver transplantation has been shown to be an effective therapeutic strategy for ameliorating hereditary ATTR amyloidosis, however, large numbers of patients are not suitable transplant candidates because of their age and/or advanced disease status. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomised clinical trials, and tafamidis has been approved for the treatment of hereditary ATTR amyloidosis in European countries and in Japan. With the availability of disease-modifying therapies, early diagnosis and therapy become increasingly important in ATTR amyloidosis.

Importance: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro., Objective: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy., Design, Setting, and Participants: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012., Intervention: Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years., Main Outcomes and Measures: The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data., Results: By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007)., Conclusions and Relevance: Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy., Trial Registration: clinicaltrials.gov Identifier: NCT00294671.

Transthyretin (TTR) cardiac amyloidosis is an important, often under-recognized and potentially modifiable cause of heart failure with a preserved ejection fraction. The only proven treatment is liver or combined heart/liver transplantation, which, although effective, is not suitable for the vast majority of older adults with this condition. Diflunisal, a nonsteroidal anti-inflammatory drug, can stabilize the TTR tetramer in vitro and may prevent misfolding monomers and dimers from forming amyloid deposits in the heart. It is one of two small molecules assessed in animal safety studies and human clinical trials of TTR polyneuropathy. The authors conducted a single-arm, open-label investigation with a mean follow-up of 0.9 ± 0.3 years to determine the safety and efficacy of diflunisal administration in a cohort of 13 patients with confirmed wild-type or mutant TTR cardiac amyloidosis. Diflunisal was well tolerated from a hematologic standpoint, although a 6% decline in estimated glomerular filtration rate was noted. Therapy was discontinued in one patient who rapidly developed volume overload. There was no significant mean change in cardiac structure (left ventricular mass: -53 g/m(2) change, P=.36), function (ejection fraction: -2% change, P=.61), or biomarkers (Troponin I: +0.03 ng/mL, P=.08; BNP: +93 pg/mL change, P=.52) during the course of therapy. These data suggest that at low dosages and with careful monitoring, diflunisal can be safely administered to compensated patients with cardiac TTR amyloidosis. Further study in a randomized placebo-controlled trial is warranted., (© 2012 Wiley Periodicals, Inc.)

Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner.

Familial amyloidotic polyneuropathy (FAP) is a protein folding disorder that induces neuropathy and cardiomyopathy, leading to death within 7-15 years after onset of clinical disease. In vitro, small ligands binding the thyroid hormone docking site stabilize tetrameric transthyretin, inhibiting amyloid fibril formation. We undertook a randomized, placebo-controlled clinical trial to determine whether diflunisal, a well-known non-steroidal anti-inflammatory drug (NSAID) alters neurologic disease progression in FAP. We enrolled 130 subjects with wide age and FAP mutation representation. To date, few recognized complications of NSAIDs have occurred in the study cohort. Data collection will be completed by November 2012.

Objective: To investigate oral nonsteroidal anti-inflammatory drug (NSAID) therapy in the prevention of recurrences of uveitis in patients with recurrent nongranulomatous, idiopathic, or HLA-B27-associated acute anterior uveitis (AAU)., Methods: Retrospective case series of 59 patients with recurrent AAU treated with celecoxib or diflunisal., Results: The average duration of NSAID therapy was 21.2 +/- 5.7 months. The average number of relapses for all patients prior to systemic NSAID therapy was 2.84 per person-year follow-up. These relapses declined to 0.53 per person-year follow-up with NSAID therapy (p < .001). The relapse rates prior to and after treatment in the HLA-B27-positive group (n = 21) were compared with the relapse rates prior to and after treatment in the HLA-B27-negative group (n = 38) and were also statistically significant (p < .001)., Conclusion: Morbid attacks and the cumulative exposure to corticosteroids can be prevented with systemic NSAID therapy in patients with recurrent AAU.

Diflunisal and lornoxicam are currently available non-steroidal anti-inflammatory drugs (NSAIDs) that have been shown to be effective to various degrees in pain relief when administered either pre-emptively or postoperatively. The pre-emptive analgesic efficacy of diflunisal 1000 mg was compared with that of lornoxicam 16 mg in 40 ASA I patients undergoing surgical removal of bilateral impacted third molars. The impacted third molar teeth on one side were removed at the first surgical appointment using one of the two drug regimens being assessed and the teeth on the contralateral side were removed at a second appointment using the alternate drug regimen; all operations were performed by the same surgeon. Acetaminophen up to 2000 mg daily was provided as rescue medication. The postoperative rescue analgesic consumption was recorded and pain scores were evaluated with a visual analogue scale at 2, 4, 6, 12 and 24h postoperatively. No statistically significant differences were found between groups with respect to rescue analgesic consumption and postoperative pain scores. Pre-emptive administration of both NSAIDs proved to be effective in the management of pain following the surgical removal of impacted third molar teeth.

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble, abnormal fibrils that impair organ function. More than 20 unrelated proteins can form amyloid fibrils in vivo. All fibrils share cross-beta core structure and pathognomonic red-green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloidosis can be acquired or hereditary, localized or systemic, and is classified according to the fibril precursor protein. Local amyloid deposition occurs in the brain in Alzheimer's disease and in the pancreas in maturity-onset diabetes, but a direct role in the pathogenesis of these diseases remains unproven. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls and connective tissues, is usually fatal and is the cause of about one death per thousand in developed countries. Recent elucidation of fundamental aspects of the pathogenesis of amyloidosis, and developments in diagnosis and monitoring of this disorder have greatly improved outcome for patients. Several exciting novel therapeutic strategies, reviewed in this article, are in development. These include interference with different stages of fibrillogenesis and enhancement of clearance of amyloid deposits.

Background: The aim of this study was to evaluate the comparative efficacy of three commonly used analgesics (Panadeine, Diflunisal and Etodolac) in the control of pain after third molar surgery under local anaesthesia., Methods: A randomized control study. Outcome of primary efficacy was judged by overall assessment of the area under the curve of graphs for pain intensity, measured from serial visual analogue scales over a 24-hour period. Other measures of efficacy included the number (per cent) of patients who took 'additional' analgesics and the incidence of adverse effects occurring in each treatment group over the study period., Results: The three drugs were effective in the control of post-operative pain (p<0.01). Variations in pain intensity and the use of additional medication between the treatment groups were observed over the study period. The Diflunisal group experienced less pain than the Panadeine or Etodolac group (p<0.01). Furthermore, a lesser number of those in the Diflunisal group used additional medication compared to the other two groups (p<0.01). The incidence of side effects from all three drugs was low., Conclusion: Diflunisal is superior in the control of pain following third molar surgery under local anaesthesia than either Panadeine or Etodolac, and has few side effects.

The incidence of interappointment emergencies in symptomatic and asymptomatic teeth with necrotic pulps was evaluated, and severity of flare-ups was determined by a quantitative method using a flare-up index. There were no significant differences in the incidence of flare-ups attributable to gender, age, diameter of lesion, taking analgesics, placebos, or no medication, or preoperative symptomatic or asymptomatic tooth diagnoses (p > 0.05). There were significantly more painful flare-ups in mandibular teeth than in maxillary (p < 0.05).

The efficacy of diflunisal in cancer pain was evaluated and compared with dipyrone. Diflunisal was given at the dosage of 500 mg perorally twice a day, and dipyrone was given at the dosage of 500 mg perorally three times a day. Duration of each treatment was 7 days; after a 12-hour wash-out period, patients were given the other drug for another 7 days. A total of 50 patients were enrolled in the study. Pain intensity was assessed by 10-point visual analog scale (VAS). Patients who had a VAS score higher than 5 were included. A total of 47 patients were evaluable. Initial VAS score was a mean of 8.57+/-1.33. Diflunisal reduced the pain score by a mean of 4.65+/-3.10, whereas dipyrone reduced the pain score by a mean of 3.25 < or = 2.85 (p < 0.001). Patients were also analyzed in three subgroups according to the presence of nonmetastatic, metastatic, and bone metastatic diseases. In each of these subgroups, diflunisal reduced the pain score more than dipyrone; however, the difference was statistically significant only in patients who had bone metastasis. Adverse reactions were rare and acceptable with both drugs. Diflusinal is superior to dipyrone at this dosage and schedule in the treatment of moderate to severe cancer pain.

A double-blind, randomized, cross-over study to compare diflunisal and paracetamol for postoperative pain, swelling and trismus relief following impacted mandibular third molar surgery was designed. 25 patients received one of the drugs at one visit and the alternative at the other visit. First doses were given two hours preoperatively and continued twice daily for five days. The study was carried out to determine the effect of preoperatively used diflunisal on postoperative pain after surgical removal of the third molars as compared to paracetamol used in a similar manner. The degree of impaction, pain, swelling and mouth opening were assessed by standardized methods and possible adverse effects were also recorded separately. Statistical analysis was carried out by "Student's t test". (p < 0.01 statistically significant).

The search for new effective analgesics without unwanted effects on the coagulation mechanism and a longer duration of activity has been intensified. One such development is diflunisal and the aim of this study was to compare the analgesic effect of diflunisal with that of paracetamol. A combined single dose (500-mg tablets), double-blind, randomized, controlled design in out-patients (n = 104) with moderate or severe pain caused by the surgical removal of impacted mandibular third molars was used in this study. Pain intensity and relief were assessed postoperatively for 8h using category-rating scales. The results showed a statistically significant difference in favour of diflunisal in each and every parameter used in determining the efficacy of the treatment.