tak-475 has been researched along with Mevalonate-Kinase-Deficiency* in 2 studies
1 review(s) available for tak-475 and Mevalonate-Kinase-Deficiency
Article | Year |
---|---|
Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.
Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.. MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases. Topics: Acyl Coenzyme A; Cholesterol; Drug Repositioning; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hypercholesterolemia; Mevalonate Kinase Deficiency; Oxazepines; Phosphotransferases (Alcohol Group Acceptor); Piperidines | 2018 |
1 other study(ies) available for tak-475 and Mevalonate-Kinase-Deficiency
Article | Year |
---|---|
Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation.
Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms. Topics: Alendronate; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Biosynthetic Pathways; Cell Death; Cell Shape; Farnesyl-Diphosphate Farnesyltransferase; Inflammation; Interleukin-6; Lipopolysaccharides; Macrophages; Mevalonate Kinase Deficiency; Mevalonic Acid; Mice; Mitochondria; Oxazepines; Piperidines; RAW 264.7 Cells; Tumor Necrosis Factor-alpha | 2021 |