生物活性

• 描述Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. 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^[3]. Diflunisal exhibits activity after oral administration with potency about 25 times greater than that of aspirin, about 3 times that of glafenine and twice that of zomepirac. Repeated administration of large doses produced neither tolerance nor sensitization to the analgesic action of diflunisal^[4]. Administration of increasing doses of diflunisal to rats shows that the effect of the dose on the pharmacokinetics of diflunisal is quite complicated. The CLp is reduced considerably when the dose increases from 3 to 10 mg/kg and then remains relatively constant over the dose range of 10 to 60 mg/kg. Diflunisal has been shown to be highly bound to rat plasma protein and dependent on concentration. The fraction of unbound diflunisal is increased about 10-fold over the concentration range of 5 to 300 μg/mL^[5]. Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID), specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex^[6].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03190577	Familial Amyloid Neuropathy ... more >> Transthyretin Amyloidosis Collapse <<	Not Applicable	Recruiting	January 30, 2021	France ... more >> Chu Angers Not yet recruiting Angers, France, 49000 Contact: julien Chassereau, MD          Sub-Investigator: Vivien PAUTOT, MD          Chru Brest Not yet recruiting Brest, France, 29609 Contact: STEEVE GENESTET, MD          Chd La Roche Sur Yon Active, not recruiting La Roche-sur-Yon, France, 85000 Ch La Rochelle Recruiting La Rochelle, France, 17019 Contact: KARINE BOYER, MD          Ch Le Mans Active, not recruiting Le Mans, France, 72033 Chu Nantes Recruiting Nantes, France Contact: ARMELLE MAGOT          Chu Poitiers Active, not recruiting Poitiers, France, 86021 Ch Quimper Recruiting Quimper, France, 29107 Contact: Maud LEPETIT, MD          Chu Rennes Active, not recruiting Rennes, France, 35033 Ch Saint Brieuc Recruiting Saint-Brieuc, France, 22000 Contact: BENOIT PEGAT, MD          Ch Saint Nazaire Recruiting Saint-Nazaire, France, 44606 Contact: Lucie METZGER, MD          Chru Tours Active, not recruiting Tours, France, 37044 Collapse <<
  NCT00294671	Familial Amyloid Polyneuropath... more >>y Familial Amyloidosis Collapse <<	Phase 2 Phase 3	Completed	-	United States, Massachusetts ... more >> Amyloidosis Center, Boston Medical Center Boston, Massachusetts, United States, 02118 United States, Minnesota Mayo Clinic Rochester Rochester, Minnesota, United States, 55905 United States, New York Mount Sinai School of Medicine, Department of Medicine New York, New York, United States, 10029-6574 Italy IRCCS Policlinico San Matteo Pavia, Italy, 27100 Japan Kumamoto University Kumamoto, Japan, 860-0811 Shinshu University Matsumoto, Japan, 390-8621 Sweden Umea University Hospital Umea, Sweden, SE-901 86 United Kingdom King's College Hospital London, United Kingdom, SE5 9RS Collapse <<
  NCT01432587	-	-	Completed	-	Sweden ... more >> Dept of Clinical Medicin, Ptieå Hospital Piteå, Sweden, SE-941 28 Dept of clinical medicin, Skellefteå Hospital Skellefteå, Sweden, SE-931 86 Dept of Clinical Medicine, Umeå University Hospital Umeå, Sweden, SE-90185 Collapse <<

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• 参考文献

• [1] Shirakawa K, Wang L, Man N, et al. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife. 2016 May 31;5. pii: e11156.

  [2] Cappon GD, Cook JC, Hurtt ME. Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol. 2003 Feb;68(1):47-56.

  [3] Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-2667

  [4] Winter CA, Kling PJ, Tocco DJ, Tanabe K. Analgesic activity of diflunisal [MK-647; 5-(2,4-difluorophenyl)salicylic acid] in rats with hyperalgesia induced by Freund's adjuvant. J Pharmacol Exp Ther. 1979;211(3):678-685

  [5] Lin JH, Hooke KF, Yeh KC, Duggan DE. Dose-dependent pharmacokinetics of diflunisal in rats: dual effects of protein binding and metabolism. J Pharmacol Exp Ther. 1985;235(2):402-406

  [6] De Leo F, Quilici G, Tirone M, et al. Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment. EMBO Rep. 2019;20(10):e47788

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