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JAMA Dec 2013Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability.... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Aged; Amyloid Neuropathies, Familial; Anti-Inflammatory Agents, Non-Steroidal; Body Mass Index; Diflunisal; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Quality of Life; Survival Analysis; Treatment Outcome
PubMed: 24368466
DOI: 10.1001/jama.2013.283815 -
British Journal of Clinical Pharmacology Mar 1979A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition...
A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition kinetics of this drug. Diflunisal and the sum of its ester and ether glucuronides conjugates were measured fluorimetrically. In normals terminal plasma half-lives (β) of diflunisal and its glucuronides were very similar: 10.8 h and 11.8 h respectively. The finding that plasma half-life was shortened with declining diflunisal plasma levels suggests capacity-limited elimination. In subjects with normal renal function 78.6 ± 2.7% of the administered dose was recovered in 72 h urine, mainly as the glucuronide conjugates. With increasing degree of renal function impairment β of diflunisal was progressively prolonged up to ten times normal probably due to slowed biotransformation. This was associated with increasing retention of the conjugated metabolites in plasma due to marked reduction of the urinary excretion of the glucuronide conjugates. The apparent volume of distribution of diflunisal was very small in normals (7.3 ± 0.4 l) and was significantly increased in patients with renal insufficiency (up to 16.2 ± 2.2 l). Diflunisal elimination studies performed during haemodialysis did not reveal any significant change in diflunisal plasma half-time. ultrafiltration studies during haemodialysis have shown that diflunisal is 98-99% plasma protein bound in uraemic patients. The present study indicates that although diflunisal is primarily eliminated by biotransformation, β is prolonged in renal insufficiency and dose adjustment will accordingly be required in patients with renal function impairment.
Topics: Adult; Analgesics; Biotransformation; Biphenyl Compounds; Creatinine; Glucuronates; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Renal Dialysis
PubMed: 427004
DOI: 10.1111/j.1365-2125.1979.tb00932.x -
Otolaryngology--head and Neck Surgery :... Mar 2015To perform a systematic review evaluating the association between sensorineural hearing loss and (1) nonsteroidal anti-inflammatory drugs (NSAIDs) as a class, (2) NSAIDs... (Review)
Review
OBJECTIVE
To perform a systematic review evaluating the association between sensorineural hearing loss and (1) nonsteroidal anti-inflammatory drugs (NSAIDs) as a class, (2) NSAIDs available over the counter, (3) NSAIDs in short intravenous courses, (4) prescription NSAIDs utilized by patients without systemic inflammatory conditions, (5) prescription NSAIDs in patients with arthritides, and (6) acetaminophen with and without concomitant narcotic usage.
DATA SOURCES
Computerized searches of PubMed, EMBASE, and the Cochrane Library were updated through May 2014, along with manual searches and inquiries to topic experts.
REVIEW METHODS
The systematic review was performed according to an a priori protocol. Data extraction was performed by 2 independent investigators, and it focused on relevant audiologic measurements, methodological elements related to risk of bias, and potential confounders.
RESULTS
The 23 criterion-meeting studies included a total of 92,532 participants, with mixed results. Sulindac was the only specific agent to have been studied with formal audiometry in a randomized double-blind placebo-controlled trial in which hearing was the reported primary outcome: Although an effect was seen in the unadjusted analysis (pure tone threshold>15 dB, 9.3% vs 2.9%; relative risk [RR], 3.2; confidence interval [CI], 1.09-9.55; P=.02), the effect dissipated in the adjusted analysis (P=.09). There was a significant effect on self-reported hearing loss from NSAIDs as a class (RR, 1.21; CI, 1.11-1.33), ibuprofen (RR, 1.13; CI, 1.06-1.19), and acetaminophen (RR, 1.21; CI, 1.11-1.33), but no formal audiometric data confirm or refute this suggested effect. Audiometry has demonstrated profound loss in some instances of acetaminophen-narcotic combination ingestions.
CONCLUSIONS
Data are varied regarding the impact of NSAIDs and acetaminophen on population hearing health.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Audiometry; Hearing; Hearing Loss, Sensorineural; Humans; Risk Factors
PubMed: 25560405
DOI: 10.1177/0194599814564533 -
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 -
British Journal of Clinical Pharmacology May 1991Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate...
Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated diflunisal clearance (by overestimation of plasma diflunisal concentrations through unrecognized acidic hydrolysis of diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.
Topics: Adult; Diflunisal; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Middle Aged
PubMed: 1888623
DOI: 10.1111/j.1365-2125.1991.tb05578.x -
European Journal of Hospital Pharmacy :... Jul 2020To 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...
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.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Diflunisal; Humans; Liver Transplantation; RNA, Small Interfering
PubMed: 32587078
DOI: 10.1136/ejhpharm-2018-001823 -
The Cochrane Database of Systematic... Sep 2011Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data.
OBJECTIVES
To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone.
METHODS
We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event.
MAIN RESULTS
The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken.There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions.NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids.Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (≥ 8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg.Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours.
AUTHORS' CONCLUSIONS
There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.
Topics: Administration, Oral; Adult; Analgesics; Humans; Pain, Postoperative; Review Literature as Topic; Tooth Extraction
PubMed: 21901726
DOI: 10.1002/14651858.CD008659.pub2 -
PloS One 2015The hydrolysis of 4-nitrophenyl esters of hexanoate (NphOHe) and decanoate (NphODe) by human serum albumin (HSA) at Tyr411, located at the FA3-FA4 site, has been...
The hydrolysis of 4-nitrophenyl esters of hexanoate (NphOHe) and decanoate (NphODe) by human serum albumin (HSA) at Tyr411, located at the FA3-FA4 site, has been investigated between pH 5.8 and 9.5, at 22.0°C. Values of Ks, k+2, and k+2/Ks obtained at [HSA] ≥ 5×[NphOXx] and [NphOXx] ≥ 5×[HSA] (Xx is NphOHe or NphODe) match very well each other; moreover, the deacylation step turns out to be the rate limiting step in catalysis (i.e., k+3 << k+2). The pH dependence of the kinetic parameters for the hydrolysis of NphOHe and NphODe can be described by the acidic pKa-shift of a single amino acid residue, which varies from 8.9 in the free HSA to 7.6 and 7.0 in the HSA:NphOHe and HSA:NphODe complex, respectively; the pK>a-shift appears to be correlated to the length of the fatty acid tail of the substrate. The inhibition of the HSA-Tyr411-catalyzed hydrolysis of NphOHe, NphODe, and 4-nitrophenyl myristate (NphOMy) by five inhibitors (i.e., diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol) has been investigated at pH 7.5 and 22.0°C, resulting competitive. The affinity of diazepam, diflunisal, ibuprofen, 3-indoxyl-sulfate, and propofol for HSA reflects the selectivity of the FA3-FA4 cleft. Under conditions where Tyr411 is not acylated, the molar fraction of diazepam, diflunisal, ibuprofen, and 3-indoxyl-sulfate bound to HSA is higher than 0.9 whereas the molar fraction of propofol bound to HSA is ca. 0.5.
Topics: Diazepam; Diflunisal; Esterases; Esters; Humans; Hydrogen-Ion Concentration; Hydrolysis; Ibuprofen; Models, Molecular; Propofol; Serum Albumin; Tyrosine
PubMed: 25790235
DOI: 10.1371/journal.pone.0120603 -
British Journal of Clinical Pharmacology Apr 19901. The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2. The plasma... (Comparative Study)
Comparative Study
1. The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2. The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 +/- 1.2 and 4.2 +/- 0.7 ml min-1 for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration 11.4 +/- 3.1 and 9.9 +/- 2.0 ml min-1 for the 250 and 500 mg single doses, respectively). 3. The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (greater than 50%) after multiple dose administration. 4. The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 +/- 2.8 and 9.1 +/- 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 +/- 3.1 and 15.9 +/- 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5. The plasma protein binding of diflunisal was concentration-dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentration-dependent plasma binding.
Topics: Adolescent; Adult; Blood Proteins; Chromatography, High Pressure Liquid; Diflunisal; Glucuronates; Humans; Male; Protein Binding
PubMed: 2328191
DOI: 10.1111/j.1365-2125.1990.tb03654.x -
International Journal of Molecular... Dec 2022The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the...
The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the starting point of this research. This work is an in-depth study of the diflunisal release behaviour from either chitosan or carboxymethylchitosan dispersions. The microstructure is not usually considered when designing this type of products; however, it is essential to understand the process of solvent penetration and subsequent drug release through a polymeric system, as has been evidenced in this study. In accordance with the kinetic data analysed, it is possible to conclude that the porous structure, conditioned by the sample preparation method, can be considered the main factor involved in diflunisal release. The low mean pore size (1-2 μm), low porosity, and high tortuosity of the amorphous kneaded products are responsible for the slow drug release in comparison with the crystalline coevaporated systems, which exhibit larger pore size (8-10 μm) and lower tortuosity. Nevertheless, all diflunisal-carboxymethylchitosan products show similar porous microstructure and overlapping dissolution profiles. The drug release mechanisms obtained can also be related to the porous structure. Fickian diffusion was the main mechanism involved in drug release from chitosan, whereas an important contribution of erosion was detected for carboxymethylchitosan systems, probably due to its high solubility.
Topics: Drug Liberation; Chitosan; Solubility; Diflunisal; Polymers
PubMed: 36499692
DOI: 10.3390/ijms232315367