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Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
In addition to symptomatic management of ATTR-CM with salt restriction, diuretics, and aldosterone antagonism, there have been advances in disease-specific interventions (Table 35.6). The rate-limiting step in amyloid fibril formation is the dissociation of the transthyretin tetramer, and stabilization of the tetramer has been a target for therapies. Diflunisal is a nonsteroidal anti-inflammatory agent (NSAID) that also binds and stabilizes TTR. Diflunisal was evaluated in patients with hereditary ATTR polyneuropathy, and improved quality of life and reduced neurologic impairment.50 The true efficacy of diflunisal in ATTR-CM is not clear, but one study of 13 patients, including wtATTR and hATTR cardiac amyloidosis, demonstrated no significant change in left ventricular (LV) mass or function, a finding consistent with stabilization of the disease.51 However, caution must be utilized with the administration of diflunisal given its potential for renal dysfunction, gastrointestinal bleeding, and heart failure exacerbations.
Drugs Affecting the Musculoskeletal System
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: It is better to be avoided during the 1st and 3rd Trimesters because the pregnancy experience in humans suggests a risk of pulmonary hypertension of the newborn, SABs, and congenital malformations linked to the use of Diflunisal.
Pharmacokinetic-Pharmacodynamic Correlations of Analgesics
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Subsequently, Walker and Levy145 compared the pharmacodynamics of diflunisal in normal rats after multiple doses and found no statistically significant differences between the area under the total or free (unbound) drug concentration vs. time curves of the first and last dose, but the average analgesic effect after the last dose was 28% that of the first dose. This change in pharmacologic response with time indicates tolerance to the analgesic effects of diflunisal.145
Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis
Published in Expert Review of Clinical Pharmacology, 2019
Morie A. Gertz, Morton Scheinberg, Márcia Waddington-Cruz, Stephen B. Heitner, Chafic Karam, Brian Drachman, Sami Khella, Carol Whelan, Laura Obici
An alternative strategy for the treatment of ATTRv is to stabilize the TTR protein tetramer, preventing the dissociation of misfolded TTR into monomers and thus the formation of amyloid fibrils [5]. Diflunisal, a nonsteroidal anti-inflammatory drug, prevents the formation of TTR amyloid fibrils [1]. A randomized, double-blind, placebo-controlled phase 3 study demonstrated that twice-daily diflunisal 250 mg over 2 years significantly reduced the rate of progression of neurologic impairment and preserved quality of life (QoL) in patients with ATTRv [23]. Although diflunisal is not FDA approved for the treatment of ATTRv, it is available as an off-label option in the United States and in some European countries [5]. However, long-term use of nonsteroidal anti-inflammatory drugs is associated with an increased risk of gastrointestinal, renal, and cardiac toxicity; as a result, caution should be taken when considering the use of diflunisal in ATTRv patients with cardiac involvement [8].
Treatment of hereditary and acquired forms of transthyretin amyloidosis in the era of personalized medicine: the role of randomized controlled trials
Published in Amyloid, 2019
The study design was very similar to that of the tafamidis trial with few major differences [2]. Only half the subjects were TTR V30M, the remainder having 21 other amyloidogenic TTR mutations (Table 1). Rather than including only early stage patients, almost two thirds were stage II or later. Although the age range in both studies was similar (18–75), the mean age of the participants was 60, compared to 39 in the tafamidis study. Again the patients were recruited from eight centres in five countries. The duration of the study was 2 years rather than 18 months. Similar to the tafamidis trial, 130 patients were randomized. All had positive biopsies and genotyping. The primary outcome measure was the NIS + 7 evaluation of peripheral nerve function. The NIS-LL metric used in the tafamidis analysis was also performed as was a generalized quality of life questionnaire (SF36) as measures of secondary endpoints. The dose of diflunisal was 250 mg twice daily.
Effect of diflunisal on clusterin levels in ATTRwt amyloidosis
Published in Amyloid, 2019
Celia Torres-Arancivia, Lawreen H. Connors
Serum samples from patients with biopsy-proven ATTRwt amyloidosis featuring cardiac involvement were obtained from the Boston University Amyloidosis Center IRB-approved repository; healthy control sera were purchased from Bioreclamation (Westbury, NY). All sera (patients and controls) were collected from Caucasian males ≥60 years of age. ATTRwt patients were assessed at baseline and 1-year follow-up evaluations. In the study group receiving drug, treatment with diflunisal was initiated post-baseline visit; untreated patients did not receive diflunisal. Serum clusterin concentrations were measured by sandwich ELISA on a 96-well plate format using a commercially available human clusterin ELISA kit (R&D Systems, Minneapolis, MN). GraphPad Prism software (GraphPad Software, La Jolla, CA) was used for data calculations and generation of plots. CLU levels are presented as mean ± SD. Deviations from normal distribution were assessed using the Shapiro–Wilk test. p Values comparing groups were determined by unpaired, two-sided t-test. Spearman’s or Person’s correlation coefficients were used to assess associations between CLU levels and baseline values for ∼30 routinely measured laboratory and echocardiographic parameters. p Values comparing linear associations were obtained by linear regression analysis.