Tafamidis

Tafamidis(Fx1006A) is a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Target: Others Tafamidis is a drug for the amelioration of transthyretin-related hereditary amyloidosis.Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis [1].

References:
[1]. Bulawa, C.E., et al., Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A, 2012. 109(24): p. 9629-34.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the assay of tafamidis in rat plasma: Application to a pharmacokinetic study in rats.[Pubmed:28107689]

J Pharm Biomed Anal. 2017 Apr 15;137:90-95.

Tafamidis is a first-in-class inhibitor of transthyretin amyloid fibril formation. It has been available in Argentina, Japan, and Mexico for the treatment of transthyretin amyloidosis in adult patients with early-stage symptomatic polyneuropathy. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the assay of Tafamidis in rat plasma. The method was also assessed for its applicability to pharmacokinetic studies in rats. Tafamidis was extracted from rat plasma by the liquid-liquid extraction method using hydrochloric acid and ethyl acetate. A reversed-phase C18 column and a mobile phase consisting of 10mM ammonium formate and acetonitrile were used to achieve chromatographic separation. The flow rate for the mobile phase was set at 0.3mL/min. Tafamidis and 2-CBC, which was used as the internal standard (IS), were analyzed by multiple reaction monitoring in negative ESI mode at m/z transitions of 305.4-->261.4 for Tafamidis and 271.7-->227.8 for the IS. The lower limit of quantification of Tafamidis was obtained as 3ng/mL, and the calibration curve was linear over a concentration range of 3-3000ng/mL (R(2)>0.99). The validation parameters investigated, which were specificity, precision, accuracy, matrix effect, recovery, and stability, were well within acceptable limits. The method was successfully used for the evaluation of the pharmacokinetics of Tafamidis in rats.

Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report.[Pubmed:28152524]

Cardiology. 2017;137(2):74-77.

Tafamidis meglumine is a novel medicine that has been shown to slow the progression of peripheral neurological impairment in patients with hereditary transthyretin amyloidosis (ATTR). However, the efficacy of Tafamidis against ATTR-related cardiac amyloidosis remains unclear. A 72-year-old woman had cardiac hypertrophy and axonopathy in her lower legs. Endomyocardial biopsy revealed an infiltrative cardiomyopathy consistent with amyloidosis. Immunostaining and genetic studies confirmed the diagnosis of ATTR, and Tafamidis was started subsequently. Two years after the initiation of Tafamidis treatment, electromyography demonstrated no change in the axonopathy in her lower legs; however, electrocardiography displayed QRS prolongation, and echocardiography disclosed an increase in interventricular septal thickness. Endomyocardial biopsy indicated that transthyretin amyloid infiltration of the myocardium was not reduced. In this case, there was no apparent progression of axonopathy, although there were signs of worsening amyloid cardiomyopathy during the treatment with Tafamidis.

Treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a case report.[Pubmed:28202889]

Nihon Ronen Igakkai Zasshi. 2017;54(1):75-80.

INTRODUCTION: Familial amyloid polyneuropathy (FAP) is a rare hereditary disorder caused by mutations in the transthyretin (TTR) gene. Tafamidis is a TTR stabilizer able to prevent TTR tetramer dissociation, and several studies have demonstrated its safety and efficacy at slowing the progression of neuropathy in FAP caused by the TTR Val30Met mutation. However, nerve conduction study (NCS) and electromyography (EMG) results have yet to be reported in relation to FAP progression during Tafamidis therapy. CASE PRESENTATION: A 71-year-old man was admitted to the hospital because of severe numbness and walking difficulties. He did not complain of any autonomic dysfunction or visual disturbance, and he had no family history of neuromuscular disorders. A NCS and EMG indicated length-dependent axonal sensorimotor polyneuropathy. A sural nerve biopsy revealed amyloid deposits, and genetic testing demonstrated a TTR Val30Met mutation. We diagnosed the patient with FAP and treated him using Tafamidis therapy. One year later, the patient is still on Tafamidis therapy, and his symptoms have shown no significant change. The NCS showed no changes in the compound muscle action potential amplitudes of the left ulnar nerve, while EMG showed the fibrillation/positive sharp wave to have disappeared from the patient's upper limb. We conclude from these findings a slowing of the neurologic progression. CONCLUSIONS: Tafamidis was effective in slowing the neurologic progression over one year in a FAP patient with the TTR Val30Met mutation, and NCS and EMG were useful for assessing this therapeutic effect.

Tafamidis is a potent and selective transthyretin (TTR) stabilizer, shows comparable potency and efficacy to the mutumant homotetramers V30M-TTR, V122I-TTR and wild type WT-TTR, with EC50s of 2.7-3.2 μM. Tafamidis inhibits amyloidogenesis.

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