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2,10 This may be due to an increase in free-radical burden associated with the metabolite valproate-4-ene

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Several methods are introduced to increase the half-life of GLP-1 including: (i) modifying peptides to make them resistant to cleavage by DPP-4, such as exenatide twice daily and lixisenatide, (ii) attaching free fatty acid side chains to liraglutide and semaglutide, which enhances their binding to plasma albumin thereby preventing renal filtration of GLP-1 and prolonging their action in vivo [36, 37], (iii) conjugation of albumin or the Fc fragment of IgG to GLP-1 molecule is used in albiglutide and dulaglutide [37, 38], (iv) development of modified nanoparticles for the controlled release of exenatide-LAR (long-acting release) that provide prolonged release of the peptide [39], and finally, (v) chemical permeation enhancers such as sodium salcaprozate (SNAC) could be utilized to overcome the low permeability and high enzymatic degradation of the gastrointestinal tract of GLP-1 analog that is administrated orally such as semaglutide [40]