Antirheumatic Arthritis Leflunomide Immunosuppressant Cas 75706-12-6

Polyvinylpyrrolidone Definition

A vinyl polymer composed of repeating -CH2-CR- units where R is a 2-oxopyrrolidin-1-yl group.

Polyvinylpyrrolidone Description

Leflunomide is an orally-available disease-modifying antirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need.
Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation.
In vitro, Leflunomide's active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornide showed efficacy both prophylactically and therapeutically.

Immunosuppressant leflunomide, also known as Alovar, leflomide and Donvar, is a kind of isooxazole immunosuppressant with anti-proliferative activity. Modern pharmacology categorize this product as antipyretic, analgesic and anti-inflammatory drug. This product by the liver and intestinal wall and microsomal rapidly into the cytoplasm of active metabolite and play a role, the main mechanism for the inhibition of DNA synthesis in the process of a key enzyme - dihydro orotic acid dehydrogenase activity (DHODH), so that the consumption as the nucleotides of B lymphocyte in termination of the biosynthesis of DNA and RNA, unable to enter the cell S period, Finally can not proliferate, thus produces the anti-rheumatism effect, is suitable for the treatment of adult active rheumatoid arthritis, ankylosing spondylitis, can slow down the destruction of bone, reduce the symptoms and signs. In addition, lefluride inhibits the activity of tyrosine kinases, which inhibit the proliferation of T cells, B cells and non-immune cells. It also inhibits the biosynthesis of COX2, which inhibits the synthesis of prostaglandin and exerts anti-inflammatory Chemicalbook, and inhibits the release of histamine from mast cells and basophils. Due to the difficulty in dose adjustment for organ transplant patients, this product is mainly used for the treatment of rheumatoid arthritis and other autoimmune diseases. After oral administration, the product is rapidly transformed into active metabolites in the intestinal wall and liver, F is 80%, and absorption is not affected by eating. Tmax is 6-12h, if the first dose is given load dose 100mg, the steady-state blood concentration will be reached in 3 days, otherwise it will take several months to reach steady-state blood concentration. The active metabolite PPB was 99.3%, mainly distributed in liver, kidney and skin, but less in brain tissue. After further metabolism of active metabolites, 43% of the markers were excreted by urine and 48% by feces, and the enterohepatic circulation was the main factor leading to the long half-life of active metabolites. A high fat diet does not have a significant effect on drug plasma concentration. Activated carbon or cholestyramine may inhibit drug absorption. The major adverse reactions of leflunomide were anorexia, vomiting, abdominal pain, diarrhea, gastritis and gastroenteritis, rash, reversible alopecia and elevated aminotransferase.