Leflunomide (Arava), an isoxazole prodrug, is an orally active DMARD marketed in 1998 for the treatment of RA. It is well absorbed and extensively metabolized in vivo to its active metabolite, 2-cyano-3-hydroxy-2-buteneamide (teri-flunomide), resulting from a reductive ring opening of the isoxazole ring (see Fig. 24.24). Unlike MTX, teriflunomide blocks T-cell proliferation by inhibiting dihydroorotate de-hydrogenase, the rate-limiting enzyme in the de novo biosynthesis of pyrimidine that is believed to be responsible for the immunosuppressive properties of leflunomide.235,236 For this reason, it is not surprising that leflunomide has a very comparable therapeutic efficacy to the first-line DMARD, MTX as shown in several extended open clinical trials.237 However, even though leflunomide is well tolerated like MTX, several cases of toxic neuropathy have been observed during its use, thus careful monitoring of the patient's neurological status during treatment is mandatory.237 Like MTX, leflunomide is contraindicated in pregnancy or in women considering pregnancy.
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A Guide to Natural Sleep Remedies. Many of us experience the occasional night of sleeplessness without any consequences. It is when the occasional night here and there becomes a pattern of several nights in arow that you are faced with a sleeping problem. Repeated loss of sleep affects all areas of your life The physical, the mental, and theemotional. Sleep deprivation can affect your overall daily performance and may even havean effecton your personality.