Pharmacological treatment for familial amyloid polyneuropathy.

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.

Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis.

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.

The Diflunisal Trial: study accrual and drug tolerance.

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.

Non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters) in bone and periodontal regeneration.

Bioresorbable polymers offer the potential to deliver biologically active agents that selectively modulate wound healing in bone and periodontal regeneration. This preliminary study characterizes early wound healing in calvarial defects grafted with demineralized bone matrix (DBM) overlaid with membranes made from a novel class of non-steroidal anti-inflammatory drug (NSAID)-derived poly(anhydride-esters). These polymers chemically incorporate either salicylic acid (SA) or 5-(2',4'-difluorophenyl)salicylic acid (diflunisal) into the polymeric backbone and release the NSAIDs upon hydrolysis. Inflammatory cell infiltrate in response to the novel NSAID-derived polymers was compared to defects grafted with DBM alone at 10 days and to defects grafted with DBM and overlaid with poly(lactic acid) (PLA; Atrisorb) at 21 days in 8 Wistar rats (350-450 g). Histological analysis of the calvarial sites at 10 days revealed that the NSAID-derived polymers were associated with moderate levels of inflammation similar to defects grafted without polymer (2.3 +/- 0.96 versus 2.0 +/- 0.82, respectively), consistent with the therapeutic activity of salicylic acid and diflunisal. Defects grafted with DBM and overlaid with NSAID-derived polymers at 21 days exhibited mild inflammation; whereas, defects treated with PLA were consistently associated with moderate to severe inflammatory cell infiltrate (1.8 +/- 0.50 versus 2.7 +/- 0.58, respectively). Histopathological findings, such as foreign body giant cells or fibrous encapsulation, were not observed in any defects with NSAID-derived polymers. Cellular features consistent with bone formation were found in all grafted defects. This novel class of non-steroidal anti-inflammatory drug-derived poly(anhydride-esters) were well tolerated and elicited no demonstrable increase in inflammation, as shown with PLA, during osseous wound healing in a regenerative application.

Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration.

STUDY OBJECTIVE: To validate or refute a widely accepted epidemiologic phenomenon known as the Weber effect by replicating Weber's original observation by using drugs that were marketed in the United States and using reports from a U.S. database. DESIGN: Retrospective analysis of adverse event databases. SETTING: University research center. DRUGS: The original nonsteroidal antiinflammatory drugs studied by Weber that were approved by the U.S. Food and Drug Administration (FDA) and marketed in the United States: diclofenac sodium, diclofenac potassium, diflunisal, sulindac, flurbiprofen, and piroxicam. INTERVENTION: Reports of adverse events submitted to the FDAs Spontaneous Reporting System and the Adverse Event Reporting System from January 1969-December 2000 for these drugs were analyzed according to the number of adverse events reported for each drug per year from the time the drug was approved until December 2000. MEASUREMENTS AND MAIN RESULTS: Reporting patterns were considered to demonstrate the Weber effect if the highest peak in reports during the first 5 years after product approval occurred during year 2. All five drugs analyzed in this study demonstrated the Weber effect. CONCLUSION: The Weber effect was replicable by using drugs marketed in the United States and using reports that were submitted to a U.S. database. Various other factors affected spontaneous reporting of adverse events, as peaks in the number of reports were seen numerous times for each drug after the initial 5-year marketing period.

A study of the comparative efficacy of three common analgesics in the control of pain after third molar surgery under local anaesthesia.

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.

Seudoporfiria inducida por diclofenaco / Pseudoporphyria induced by diclofenac

La seudoporfiria es una dermatosis ampollosa clínica e histológicamente similar a la porfiria cutánea tarda, pero con niveles normales de porfirinas. La mayor parte de la bibliografía referida a la seudoporfiria medicamentosa ha implicado la utilización de los AINE. Presentamos el primer caso de seudoporfiria relacionada con diclofenaco en una mujer de 57 años con poliartritis reumática seronegativa que a los 3 meses de comenzar tratamiento con diclofenaco presentó vesículas y ampollas en el dorso de ambas manos. La retirada del fármaco mejoró el cuadro y la reintroducción desencadenó un nuevo brote que cesó al suprimirlo (AU)

A hydrogel based on a polyaspartamide: characterization and evaluation of in-vivo biocompatibility and drug release in the rat.

This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of alpha, beta-poly[N-(2-hydroxyethyl)-DL-aspartamide] (PHEA). When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and alpha-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHEA microparticles significantly improved the gastric tolerance and oral bioavailability of the drug in comparison with free diflunisal. These results suggest the potential application of PHEA hydrogel as a new delivery system for the oral administration of anti-inflammatory drugs.

A case of eosinophilic pneumonia and vasculitis induced by diflunisal.

Drug-induced pneumonitis is an uncommon complication of nonsteroidal anti-inflammatory drug administration. Herein is the first reported case of pneumonitis resulting from diflunisal therapy. The patient demonstrated clinical and biopsy evidence of systemic vasculitis. She responded dramatically to administration of systemic glucocorticoids.

Clinical effects of diflunisal and paracetamol in impacted mandibular third molar surgery.

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).

'Relapse' of chronic active hepatitis--not always what it seems.

Immune chronic active hepatitis is a disease notorious for its unpredictability. In a patient with chronic hepatitis who has already suffered relapses a search for a second cause of jaundice is not usually necessary. This report emphasises the essential role of liver biopsy.

Comparing reporting rates of adverse events between drugs with adjustment for year of marketing and secular trends in total reporting.

The Food and Drug Administration has collected spontaneous reports on adverse events (AE) from manufacturers and individuals. These data provide useful information on the safety of marketed drugs. Due to many unique characteristics of this reporting system, the information is difficult to evaluate. Incidence rates for specific adverse events and drug combinations cannot be estimated. However, reporting rates (number of reports per market share) based on prescriptions can be computed. These reporting rates provide signals of serious adverse experience that may deserve attention. When the ratio of reporting rates is used for the comparison of two drugs of the same drug class, adjustments are needed for the marketing year and secular trends of all-drug-all-AE reporting. The Mantel-Haenszel procedure is used to combine the multiyear data into one summary statistic. Application of this analysis is illustrated on reports of upper gastrointestinal bleeding, perforation, and ulcer associated with nonsteroidal anti-inflammatory drugs, as given in Rossi et al. (12).

Selective adverse reactions to diflunisal.

BACKGROUND AND OBJECTIVE: Diflunisal is a difluorophenyl derivative of salicylic acid. We report two patients who presented immediate adverse reactions to diflunisal (Dolobid) that consisted of generalized urticaria and chest tightness. METHODS: Diflunisal was conjugated to human serum albumin in order to perform in vivo and in vitro tests (skin prick and intradermal tests, leukocyte histamine release, and RAST). The patients were challenged following a single-blind, placebo-controlled oral procedure with diflunisal and other nonsteroidal antiinflammatory drugs. RESULTS: Skin tests with diflunisal were negative as were leukocyte histamine release tests and RAST in both patients. They tolerated therapeutic doses of aspirin, salsalate, salicylamide, lysine acetylsalicylate, acetaminophen, dipyrone, and propyfenazone. The oral provocation with diflunisal elicited an immediate response at the cumulative dose of 400 mg in both patients. CONCLUSION: These are two exceptional cases of selective adverse reactions to diflunisal with good tolerance to other salicylates and nonsteroidal antiinflammatory drugs. Thus, the inhibition of cyclooxygenase does not seem to be the mechanism involved. The pathogenic mechanism implicated in the reaction remains unclear, both idiosyncratic and immunologic mechanisms could explain our patients' adverse responses.

Development and use of a gastropathy index for ranking the safety of non-steroidal anti-inflammatory drugs in the elderly.

This study, conducted at the Royal Devon & Exeter Hospital, Department of Geriatric Medicine, was carried out using 2987 sets of admission data. The number of patients taking non-steroidal anti-inflammatory drugs was identified together with a suite of clinical factors used to indicate the presence of gastrointestinal pathology. From this a gastropathy index was developed to establish a rank order for the individual drugs. Ketoprofen, piroxicam and fenbufen were all significantly associated with factors suggestive of gastropathy, whereas indomethacin, diclofenac and ibuprofen appeared relatively free of such association. Naproxen, azapropazone and mefenamic acid ranked in an intermediate category. This noninvasive analysis of routinely acquired data provides a potentially useful discriminator between individual non-steroidal anti-inflammatory drugs for this age group.

Acute renal failure due to acute rhabdomyolysis precipitated by MAST trousers and diflunisal.

This report describes a patient who developed acute rhabdomyolysis and acute renal failure following the application of MAST trousers associated with an overdose of diflunisal. This association has not previously been reported.

Comparative multiple-dose study of ketorolac tromethamine and diflunisal for pain following orthopaedic surgery.

A total of 100 patients were enrolled after orthopaedic surgery in a multiple-dose, randomized, double-blind, parallel-group study to compare the analgesic efficacy and safety of 10 mg ketorolac tromethamine given orally four times daily for 3 days with 500 mg diflunisal given orally twice daily plus placebo twice daily for 3 days. Ketorolac was significantly (P = 0.04) superior to diflunisal in reducing the pain severity during the first 9 h of treatment; a difference possibly related to the more flexible dosage regimen of ketorolac. Patients and the investigator, however, rated ketorolac and diflunisal as being equally effective in terms of the overall drop in severity of pain and pain relief at the end of days 1, 2 and 3. Ketorolac-treated patients reported a total of nine adverse events and diflunisal-treated patients reported 13. It is concluded that in the treatment of acute post-operative pain a drug with a more flexible dosage regimen may provide superior pain relief.