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NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

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PURPOSE. The prostaglandin F2alpha (PGF2a) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470, a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal.METHODS. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits.RESULTS. NCX 470 (0.14%, 30 lL) lowered IOP in tOHT-rabbits with an E max of À7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, À5.4 6 0.7 and À3.4 6 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, À7.7 6 1.4 and À4.8 6 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing.CONCLUSIONS. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.

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Background and purpose:We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)-releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro-inflammatory mediators through NO-mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and neuropathic pain, and characterized its effects on cyclooxygenase (COX)-1 and COX-2. ]. NCX 2057 reversed carrageenan-induced hyperalgesic responses in mice and inhibited prostaglandin E2 formation in paw exudates. Finally, NCX 2057 competitively inhibited COX-1 and COX-2 activities in whole RAW macophages (IC50 = 14.7 Ϯ 7.4 and 21.6 Ϯ 7.5 mM, respectively). None of these properties were exhibited by equivalent treatments with FA or standard NO donor compounds. Conclusions and implications:These studies indicate that NCX 2057 is effective in chronic inflammatory and neuropathic pain models, probably because of its particular combination of anti-COX, antioxidant and NO-releasing properties.

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Involvement of the alpha1-adrenoceptor subtypes in early and late phases of formalin pain was investigated by quantitative in vitro autoradiography in the spinal cord and brain structures of CD-1 mice. Total alpha1-adrenoceptors binding (including all alpha1-adrenoceptor subtypes) was assessed with [3H]prazosin; alpha(1B)-adrenoceptor was assessed with [3H]prazosin in the presence of 10 nM WB4101 to mask remaining alpha1-adrenoceptor subtypes. Early after formalin injection the alpha1-adrenoceptors (mainly alpha1B receptor) binding was reduced in the contralateral hind limb area of the somatosensory cortex and in the secondary motor cortex. A reduction occurred also in the ipsilateral laminae I-III of the spinal cord (both alpha1B- and non-alpha1B-adrenoceptors). Lately an increase of alpha1-adrenoceptors binding (mostly subtypes other than alpha1B) appeared in discrete amygdaloid and thalamic nuclei. These results provide the first description of changes at the level of central alpha1-adrenoceptors' binding during the formalin-induced pain in mice. Their distribution suggests that they may have a functional meaning.