Pharmacology
Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with familial amyloid polyneuropathy, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.The maximum plasma concentration is achieved around two hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine. Chemistry
The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecule has two crystalline forms and one amorphous form; it is manufactured in one of the possible crystalline forms. It is marketed as a meglumine salt. It is slightly soluble in water. History
The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit transthyretin fibril formation in the 1990s. : 210   Tafamidis was eventually discovered by Kellys team using a structure-based drug design strategy; the chemical structure was first published in 2003. In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of the Massachusetts Institute of Technology and the Whitehead Institute, and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010. FoldRx was acquired by Pfizer later that year.Tafamidis was approved by the European Medicines Agency in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis.
This involves no radiation, no needles and no contrast agents that may cause allergic reactions. This test has good sensitivity and specificity.Typically duplex ultrasound scan is the only investigation required for decision making in carotid stenosis as it is widely available and rapidly performed. However, further imaging can be required if the stenosis is not near the bifurcation of the carotid artery.One of several different imaging modalities, such as a computed tomography angiogram (CTA) or magnetic resonance angiogram (MRA) may be useful. Each imaging modality has its advantages and disadvantages - Magnetic resonance angiography and CT angiography with contrast is contraindicated in patients with chronic kidney disease, catheter angiography has a 0.5% to 1.0% risk of stroke, MI, arterial injury or retroperitoneal bleeding. The investigation chosen will depend on the clinical question and the imaging expertise, experience and equipment available.For purpose of treatment, the degree of carotid stenosis is defined as:
percent stenosis = ( 1 − ( minimum diameter within stenosis) / ( poststenotic diameter ) ) × 100%. Screening
The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening for carotid artery stenosis in those without symptoms as of 2021.While routine population screening is not advised, the American Heart Association and the Society for Vascular Surgery recommend screening in those diagnosed with related medical conditions or have risk factors for carotid artery disease.