Pharmacology and potential therapeutic applications of nitric oxide‐releasing non‐steroidal anti‐inflammatory and related nitric oxide‐donating drugs

Abstract

This review examines the biological signi®cance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-in¯ammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the pro®le of pharmacological activity of the parent, nonsteroidal anti-in¯ammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-in¯ammatory and antinociceptive ecacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic bene®t in a wide variety of disease states including pain and in¯ammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed.

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

“…Along this line of research, particular interest has been focused on the generation of NOdonating nonsteroidal anti-inflammatory drugs (NSAID) that consist of NSAID to which an NO-donating group is covalently attached via an aromatic or aliphatic spacer (6). Although these drugs share some of pharmacologic properties with parental compounds, current data indicate that their structural modification is responsible for enhanced potency and diminished toxicity (7). Preclinical studies have shown that NO-NSAIDs are effective in Alzheimer's disease, cardiovascular, rheumatologic, and lung diseases (7).…”

“…Although these drugs share some of pharmacologic properties with parental compounds, current data indicate that their structural modification is responsible for enhanced potency and diminished toxicity (7). Preclinical studies have shown that NO-NSAIDs are effective in Alzheimer's disease, cardiovascular, rheumatologic, and lung diseases (7). Combination of cyclooxygenase inhibition property of NSAIDs with tumoricidal potential of NO makes these drugs suitable candidates for treatment of malignant diseases (6).…”

New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity

“…In the last decades a lot of hybrid nitrates as in vivo NO-donors have been studied for their potential use in the treatment of a variety of diseases, including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases, cancer, liver disease, impotence, bronchial asthma and osteoporosis (Keeble and Moore, 2002). Since some disagreement about whether nitrates really generate NO at all, some authors prefer to use the term NO-mimetics (Thatcher et al, 2005).…”

“…1), NO-aspirin showed pharmacological effects in cardiovascular, cancer and inflammation models, and when tested in clinical trials showed little or no gastric toxicity (Cena et al, 2003;Keeble and Moore, 2002), due to gastro-protective effects of NO . A new class of cyclooxygenase-inhibiting nitric oxide donors (CINODs) has been developed with the aim of achieving greater safety than the existing non-steroidal anti-inflammatory drug (NSAIDs) (Boschi et al, 2010(Boschi et al, , 2009.…”

“…1), i.e., 4-(ONO2)butyl esters of flurbiprofen and naproxen, respectively. HCT-1026 has been under study for its therapeutic use in a variety of conditions, including neurodegeneration and inflammation (Keeble and Moore, 2002;Scatena et al, 2005;Gasparini et al, 2005;Prosperi et al, 2004;Wenk et al, 2004Wenk et al, , 2002Ronchetti et al, 2009;Idris et al, 2004). HTC-3012, as single (S)-enantiomer, has been tested in clinical trials for the treatment of osteoarthritis (Geusens, 2009;Zhang et al, 2011).…”