A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches

Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg−1), naproxen (30 mg kg−1) and ibuprofen (30 mg kg−1) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua

Cyclooxygenases and the cardiovascular system.

Cyclooxygenase (COX)-1 and COX-2 are centrally important enzymes within the cardiovascular system with a range of diverse, sometimes opposing, functions. Through the production of thromboxane, COX in platelets is a pro-thrombotic enzyme. By contrast, through the production of prostacyclin, COX in endothelial cells is antithrombotic and in the kidney regulates renal function and blood pressure. Drug inhibition of COX within the cardiovascular system is important for both therapeutic intervention with low dose aspirin and for the manifestation of side effects caused by nonsteroidal anti-inflammatory drugs. This review focuses on the role that COX enzymes and drugs that act on COX pathways have within the cardiovascular system and provides an in-depth resource covering COX biology and pharmacology. The review goes on to consider the role of COX in both discrete cardiovascular locations and in associated organs that contribute to cardiovascular health. We discuss the importance of, and strategies to manipulate the thromboxane: prostacyclin balance. Finally within this review the authors discuss testable COX-2-hypotheses intended to stimulate debate and facilitate future research and therapeutic opportunities within the field

Role of site-specific binding to plasma albumin in drug availability to

ABSTRACT Many studies have reported greater drug uptake into brain than that predicted based upon existing models using the free fraction (f u ) of drug in arterial serum. To explain this difference, circulating plasma proteins have been suggested to interact with capillary membrane in vivo to produce a conformational change that favors net drug dissociation and elevation of f u . Albumin, the principal binding protein in plasma, has two main drug binding sites, Sudlow I and II. We tested this hypothesis using drugs that bind selectively to either site I (warfarin) or site II (ibuprofen), as well as mixed ligands that have affinity for both sites (tolbutamide and valproate). Brain uptake was determined in the presence and absence of albumin using the in situ rat brain perfusion technique. Unidirectional brain uptake transfer constants (K in ) were measured and compared with those predicted using the modified Kety-Crone-Renkin model: Ϫfu ϫ PSu/F ), where F is perfusion flow and PS u is the permeability-surface area product to free drug of brain capillaries. The results demonstrated good agreement between measured and predicted K in over a 100-fold range in perfusion fluid albumin concentration using albumin from three different species (i.e., human, bovine, and rat), as well as whole-rat serum. K in decreased in the presence of albumin in direct proportion to perfusion fluid f u with constant PS u . The results show that brain uptake of selected Sudlow site I and II ligands matches that predicted by the modified Kety-Crone-Renkin model with no evidence for enhanced dissociation