Thse are relevant to NicOx. Jason
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Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 3, 1677-1682, February 5, 2002
Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis
Mark J. Paul-Clark*, Lucia Mancini*, Piero Del Soldato~, Roderick J. Flower*, and Mauro Perretti*
* William Harvey Research Foundation, Pharmacology Division of St. Bartholomew's and Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England; and ~ NicOx, 06906 Sophia Antipolis Cedex, Nice, France
Here, we describe the improved antiarthritic properties of a nitric oxide-releasing derivative of prednisolone that includes a sparing of the effects on bone. Glucocorticoids are widely used in the treatment of chronic inflammatory pathologies, but their use is often accompanied by side effects, including osteoporosis. Recently, a new steroid able to release low levels of nitric oxide showed potent inhibition of leukocyte trafficking and chemokine generation in models of acute inflammation. The objective of this study was to assess the anti-inflammatory activity of this nitric-oxide releasing glucocorticoid, nitro-prednisolone (NCX-1015), in parallel with the parent compound prednisolone and a control molecule lacking an NO group, (NCX-1016), in a model of rat collagen-induced arthritis. Dosing of rats with NCX-1015 (0.4-4 µmol/kg, i.p.) greatly reduced all parameters of inflammation. A significant but inferior anti-inflammatory effect also was obtained with prednisolone. Collagen-induced arthritic rats had elevated pyridinoline values (>60% over naïve rats), indicating bone and cartilage erosion; this increase was prevented by NCX-1015 but not by prednisolone or NCX-1016 treatment. In vitro, prednisolone (1 nM), but not NCX-1015, elevated bone resorbing activity of rat primary osteoclasts. In conclusion, NCX-1015 is a steroid derivative with a potential for the treatment of chronic inflammatory pathologies and that has milder side effects anticipated on the bone compartment.
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www.pnas.org/cgi/doi/10.1073/pnas.022641099
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Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 3, 1689-1694, February 5, 2002
Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis
Claudio Napoli*,, Giancarlo Aldini, John L. Wallace§, Filomena de Nigris*,, Roberto Maffei, Pasquale Abete*, Domenico Bonaduce*, Gianluigi Condorelli¶, Franco Rengo*,, Vincenzo Sica**, Francesco P. D'Armiento*, Chiara Mignogna*, Gaetano de Rosa*, Mario Condorelli*, Lilach O. Lerman, and Louis J. Ignarro,§§
* Departments of Medicine, Geriatrics, and Human Pathology, Federico II University of Naples, 80131 Naples, Italy; Department of Medicine-0682, University of California, San Diego, CA 92093; Institute of Pharmaceutical Chemistry, University of Milan, 20131 Milan, Italy; § Department of Pharmacology and Therapeutics, University of Calgary, AB, Canada T2N4N1; Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, MN 55905; ¶ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Salvatore Maugeri Foundation, Institute of Care and Scientific Research, Telese 83050, Italy; ** Clinical Pathology, Second University of Naples, Naples 80100, Italy; and Department of Molecular and Medical Pharmacology, Box 951735, University of California, Los Angeles, CA 90095-1735
Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague-Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S-nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA. NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.
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www.pnas.org/cgi/doi/10.1073/pnas.022639399 |
