naproxen-n-butyl-nitrate and Inflammation

This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cystic Fibrosis; Humans; Inflammation; Molecular Structure; Nitric Oxide

There are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents; Aspirin; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Inflammation; Naproxen; Nitrates; Nitric Oxide

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective we have synthesized a NO-donating prodrug of naproxen named NMI-1182. We evaluated two cyclo-oxygenase (COX)-inhibiting nitric oxide donors (CINODs), NMI-1182 and AZD3582, for their ability to be gastro-protective compared to naproxen and for their anti-inflammatory activity. NMI-1182 and AZD3582 were found to produce similar inhibition of COX activity to that produced by naproxen. Both NMI-1182 and AZD3582 produced significantly less gastric lesions after oral administration than naproxen. All three compounds effectively inhibited paw swelling in the rat carrageenan paw edema model. In the carrageenan air pouch model all three compounds significantly reduced PGE2 levels in the pouch exudate but only NMI-1182 and naproxen inhibited leukocyte influx. These data demonstrate that NMI-1182 has comparable anti-inflammatory activity to naproxen but with a much reduced likelihood to cause gastric damage.

Topics: Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Edema; Gastric Mucosa; Humans; In Vitro Techniques; Inflammation; Male; Molecular Structure; Naphthalenes; Naproxen; Neutrophil Infiltration; Nitric Oxide Donors; Protective Agents; Rats; Rats, Sprague-Dawley; Vasodilation

Selective cyclo-oxygenase (COX)-2 inhibitors and nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX-2 inhibitor (celecoxib), a nitric-oxide releasing derivative of naproxen (HCT-3012) and naproxen in a model of wound collagen deposition in the rat. Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti-inflammatory doses. Naproxen (10 mg kg(-1)) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle-treated control group. In contrast, HCT-3012 (14.5 mg kg(-1)) significantly increased (62%) collagen deposition, while celecoxib (10 mg kg(-1)) had no effect. Naproxen and HCT-3012 suppressed prostaglandin (PG) E(2) levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE(2) levels, but slightly reduced whole blood thromboxane synthesis (by 17%). COX-1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX-2 mRNA, but not protein, was expressed in wound and normal skin. These results demonstrate that HCT-3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide-releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti-inflammatory and analgesic agents by post-surgery patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Celecoxib; Collagen; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Exudates and Transudates; Gastric Mucosa; Inflammation; Isoenzymes; Male; Membrane Proteins; Naproxen; Nitrates; Nitric Oxide Donors; Nitrites; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Thromboxanes; Wound Healing

1. Anti-inflammatory non steroidal drugs releasing NO (NO-NSAIDs) are a new class of anti-inflammatory drugs to which has been added an NO-releasing moiety. These compounds have been shown to retain the anti-inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity. 2. Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 microl of mycobacterium butirricum (6 mg ml(-1)). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg(-1)) and NO-naproxen (1.5, 4.5 and 16 mg kg(-1)) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1 - 21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7 - 21). 3. Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitro proliferation of T cells following stimulation with concanavalin A (0.5 - 5 microg ml(-1)) was measured using a tritiated thymidine incorporation assay. IL-2 receptor expression on T cells was measured by FACS analysis. 4. Naproxen and NO-naproxen showed similar activity in reducing oedema formation in the non-injected (controlateral) hindpaw. Both drugs showed anti-nociceptive effect. NO-naproxen was anti-nociceptive at a dose of 4.5 mg kg(-1) while naproxen showed the same extent of inhibition only at a dose of 10 mg kg(-1). 5. T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitro caused a significant increase in thymidine uptake. NO-naproxen at a dose of 4.5 mg kg(-1) inhibited T cell proliferation to the same extent as 10 mg kg(-1) of naproxen. 6. Inhibition of T cell proliferation was well correlated with reduced IL-2 receptor expression on T cells. In addition, NO-naproxen reduced both IL-1beta and TNFalpha plasma levels whilst naproxen reduced IL-1beta levels only. 7. In conclusion, both naproxen and NO-naproxen reduce inflammation and nociception associated with arthritis. In addition NO-naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structu

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Dose-Response Relationship, Drug; Edema; Flow Cytometry; Hindlimb; Inflammation; Interleukin-1; Male; Naproxen; Nitric Oxide; Nociceptors; Pain; Pain Measurement; Rats; Rats, Inbred Lew; Receptors, Interleukin-2; T-Lymphocytes; Thymidine; Time Factors; Tumor Necrosis Factor-alpha