An investigation into the side effects of NSAIDs: do NSAIDs interact with oestrogen and progesterone receptors?

1. Introduce NSAIDS and side effects, think mostly about cardiovascular side effects. Cover what the direct effects of NSAIDs are ie COX inhibitors. There is a big debate about whether NSAIDs are deleterious due to COX2 effects in the arteries. Paper attached indicates that the model is being rewritten. – Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents for analgesic, anti- pyretic and anti-inflammatory purposes, with many of the drugs being readily available over-the-counter. – They include such various substances as salicylates (aspirin), aryl propi- onic derivatives like ibuprofen, aryl acetic derivatives like diclofenac, indole derivatives like indometacin, oxicams like piroxicam, nimesulide, phenylbutazone, etc. – As initially pro- posed by Vane[1], these structurally diverse chemicals have in common the fact that they inhibit cyclooxygenase (COX) enzymes, which catalyse the conversion of arachidonic acid to prostaglandin (PG) G2 and eventually to PGH2, a precursor of thromboxane A2 and other effector prostaglandins. At least two distinct isoforms of COX are known to exist: the constitutive COX-1 found in platelets, kidneys, gut and other tissues, and the inducible COX-2 produced locally in response to inflammatory signals, growth factors, cytokines, oncogenes and other stress signals.[4,5] The existence of different COX isoforms has stimulated the development of new isoform-selective NSAIDs. However, most of the drugs commonly used in the therapy are COX nonselective (i.e. they inhibit both COX-1 and COX-2). – William B. White study does not support the hypothesis that COX-2 specific inhibition is associated with an increased risk of CV thromboembolic events. – However, the idea that NSAIDs and COX-2-selective drugs inherently cause different cardiovascular side- effects is fundamentally flawed, since it relies on the incorrect premise that at standard doses traditional NSAIDs inhibit COX-2 less than COX-2 selective drugs do. Figure 1 is also therapeutically misleading because it implies that, irrespective of dose, traditional NSAIDs pose less cardiovascular risk than do COX-2-selective drugs. Approved by the results of VIGOR. 2. What are the off target effects of NSAIDs? Could they have side effects due to non-COX mediated events? We started investigating via computational chemistry (previous paper sent) cover this 3. Choice of nuclear receptors based on this paper (Zloh et al) other nuclear receptors to investigate We investigated the indirect side effects of celecoxib and diclofenac using computational chemistry methods. In silico modelling indicated a potential for both drugs to associate with thyroid hormone receptor ? (TR?), and further analysis using in vitro methods indicate that both celecoxib and diclofenac possess TR? antagonistic properties. This nuclear receptor is of great interest, with clear relationships between hypothyroidism. – From table 1 in Zloh et al paper 4. Describe how antagonism of your nuclear receptor could be linked to CVD (estrogen and progesterone) Estrogen -Endogenous estrogens may attenuate CVD. Age-associ- ated CVD lags by 10 years in premenopausal women compared with men (Fig. 1). – Early loss of endogenous estradiol is associated with CVD. – Cross-sectional and prospective studies demonstrate significant reductions in CVD in women taking conjugated equine estrogens (CEEs) [5], suggesting that exogenous estrogens prevent CVD. (Raghvendra K. Dubey et al ) – Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation – Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. NONGENOMIC EFFECTS OF SEX HORMONES The interaction of sex hormones with plasmalemmal receptors in the endothelium and VSM may initiate additional nongenomic vascular effects. For example, estrogen may induce acute inhibition of vascular contraction (24, 129). Also, progestins may have direct vascular effects or modify the effects of estrogen on vascular contraction (24). Interestingly, direct vascular effects of testosterone have also been described (142, 145). For example, testosterone induces pulmonary and coronary artery dilation (24, 145). The acute nongenomic vasodilator effects of sex hormones appear to have both endo- thelium-dependent as well as endothelium-independent mech- anisms involving direct effects on VSM. – Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculature. NONGENOMIC EFFECTS Progesterone 5. Provide evidence that your nuclear receptor agonist can induce vasodilation look up journal articles that cover Non genomic activity you are incubating for a short period of time to induce dilation, so your expt covers short term non-genomic activity. Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. NONGENOMIC EFFECTS OF SEX HORMONES The interaction of sex hormones with plasmalemmal receptors in the endothelium and VSM may initiate additional nongenomic vascular effects. For example, estrogen may induce acute inhibition of vascular contraction (24, 129). Also, progestins may have direct vascular effects or modify the effects of estrogen on vascular contraction (24). – It”s not clear if the risk of heart attack and stroke is the same for all NSAIDs.