2004 - 05

J Pharmacol Exp Ther. 2004 May;309(2):626-33. Epub 2004 Jan 30.

Gastric tolerability and prolonged prostaglandin inhibition in the brain with a nitric oxide-releasing flurbiprofen derivative, NCX-2216 [3-[4-(2-fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3 methoxyphenyl]-2-prop enoic acid 4-nitrooxy butyl ester].

Wallace JL, Muscara MN, de Nucci G, Zamuner S, Cirino G, del Soldato P, Ongini E. Department of Pharmacology and Therapeutics, University of Calgary, Alberta,

NCX-2216
[3-[4-(2-fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester] is an NO-releasing flurbiprofen derivative that also contains a ferulic acid (antioxidant) moiety. NCX-2216 has been shown to be effective in reducing beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. The tolerability of this compound in the stomach and its ability to suppress prostaglandin synthesis in the brain are not known. The purpose of this study was to assess the contribution of nitric oxide (NO) and ferulic acid to the pharmacological properties of NCX-2216 versus flurbiprofen;thus, we compared their gastric tolerability and suppression of prostaglandin synthesis, peripherally and centrally. Oral flurbiprofen produced extensive gastric damage and suppressed gastric prostaglandin synthesis. In contrast, while suppressing prostaglandin production, equimolar doses of NCX-2216 did not cause detectable gastric injury. The NO-releasing moiety of NCX-2216 (but not the ferulic acid moiety) was crucial for the gastric safety of this compound. NCX-2216 substantially inhibited prostanoid synthesis despite not being detectable in plasma and despite producing only low amounts of flurbiprofen in plasma and in the brain. Inhibition of brain prostaglandin synthesis by NCX-2216 (22 mg/kg) persisted for a much longer period of time (up to 48 h) than was seen with flurbiprofen (inf. or=12 h). These results demonstrate that a single administration of NCX-2216 can produce prolonged suppression of brain prostaglandin synthesis without causing gastric injury. It is likely that an active metabolite of NCX-2216 contributes to the suppression of cyclooxygenase activity. NCX-2216 may represent an attractive alternative to conventional nonsteroidal anti-inflammatory drugs for long-term treatment of a variety of inflammatory disorders, especially those occurring in the central nervous system.



Curr Opin Investig Drugs. 2004 May;5(5):551-6.

Nitroflurbiprofen (NicOx).

Scatena R. Istituto di Biochimica e Biochimica Clinica, Faculty of Medicine, Universita' Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.

Nitroflurbiprofen is a nitrosylated flurbiprofen analog under development by NicOx for the potential treatment of urinary incontinence, Alzheimer's disease (AD) and the prevention and treatment of accelerated bone resorption associated with disorders such as osteoporosis, inflammatory joint disease and Paget's disease. In addition, a topical formulation of nitroflurbiprofen is under development for the potential treatment of dermatological disorders, including contact urticaria. By 1999, nitroflurbiprofen was in phase IIa trials for urinary incontinence, Paget's disease and osteoporosis, and phase II trials of the topical formulation were underway in contact urticaria by March 2002. Phase I trials for AD had commenced by May 2003, and in September 2003, NicOx was intending to conduct further phase II trials for micturition disorders in 2003.



J Neuroimmunol. 2004 May;150(1-2):10-9.

A nitric oxide releasing derivative of flurbiprofen inhibits experimental autoimmune encephalomyelitis.

Furlan R, Kurne A, Bergami A, Brambilla E, Maucci R, Gasparini L, Butti E, Comi G, Ongini E, Martino G. Neuroimmunology Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have a safer profile and additional anti-inflammatory and immuno-modulatory properties compared to parent compounds. Preventive treatment of experimental autoimmune encephalomyelitis (EAE)-induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55-with the NO-releasing derivative of flurbiprofen HCT1026 delayed disease onset and significantly decreased disease severity. HCT1026 treatment was associated to (i) decreased mRNA levels of pro-inflammatory cytokines, caspase-1, and iNOS in blood cells; (ii) decreased ability of encephalitogenic T cells to proliferate; (iii) reduced number of central nervous system (CNS)-infiltrating T cells; (iv) decreased axonal loss and demyelination; (v) increased CD4(+) CD69(-) CD25(+) regulatory T cells in the spleen.



Am J Physiol Renal Physiol. 2004 May;286(5):F945-54. Epub 2003 Dec 16.

Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory.

Gonzalves AR, Fujihara CK, Mattar AL, Malheiros DM, Noronha Ide L, de Nucci G, Zatz R. Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, Brazil.

Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with (5/6) renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT(1) receptor (AT(1)R); 2) the renoprotective and antiinflammatory effects of an association between the AT(1)R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nx(pre)). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: Nx(V) (vehicle), Nx(Los) (Los), Nx(NOF) (NOF), and Nx(Los/NOF) (Los/NOF). Nx(pre) rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT(1)R distribution shifted from mostly tubular in S to predominantly interstitial in Nx(pre). All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT(1)R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT(1)R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.