Selective intracellular receptor antagonists are used clinically to ameliorate hormone-dependent disease states. Patients with Cushing's syndrome have high levels of the glucocorticoid, cortisol, and suffer significant consequences from this overexposure. High levels of this hormone are also implicated in exacerbating diabetes and the stress response. Selectively inhibiting this hormone may have clinical benefit in these disease states. To this end, we have identified the first selective, nonsteroidal glucocorticoid receptor (GR) antagonist. This compound is characterized by a tri-aryl methane core chemical structure. This GR-specific antagonist binds with nanomolar affinity to the GR and has no detectable binding affinity for the highly related receptors for mineralocorticoids, androgens, estrogens, and progestins. We demonstrate that this antagonist inhibits glucocorticoid-mediated transcriptional regulation. This compound binds competitively with steroids, likely occupying a similar site within the ligand-binding domain. Once bound, however, the compound fails to induce critical conformational changes in the receptor necessary for agonist activity.
NSAIDS have antipyretic activity and can be used to treat fever.   Fever is caused by elevated levels of prostaglandin E2 , which alters the firing rate of neurons within the hypothalamus that control thermoregulation.   Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis ( PGE2 ) within the hypothalamus .   PGE2 signals to the hypothalamus to increase the body's thermal set point.   Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen).   Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.
Limited evidence supported the use of NSAIDs in the treatment of acute gout. One placebo-controlled trial provided evidence of benefit at 24 hours and little or no harm. We downgraded the evidence due to potential selection and reporting biases, and imprecision. While these data were insufficient to draw firm conclusions, they did not conflict with clinical guideline recommendations based upon evidence from observational studies, other inflammatory arthritis and expert consensus, which support the use of NSAIDs in acute -quality evidence suggested that selective COX-2 inhibitors and non-selective NSAIDs are probably equally beneficial although COX-2 inhibitors are likely to be associated with significantly fewer total and gastrointestinal adverse events. We downgraded the evidence due to an unclear risk of selection and reporting biases. Moderate-quality evidence indicated that systemic glucocorticoids and NSAIDs were also equally beneficial in terms of pain relief. There were no withdrawals due to adverse events and total adverse events were similar between groups. We downgraded the evidence due to unclear risk of selection and reporting bias. There was low-quality evidence that there was no difference in function. We downgraded the quality due to unclear risk of selection bias and imprecision.