Chemiluminescence and LC–MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers

Carini, Marina; Aldini, Giancarlo; Orioli, Marica; Piccoli, Angela; Tocchetti, Paola; Facino, Roberto Maffei

doi:10.1016/s0731-7085(03)00531-4

Cited by 26 publications

(28 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As mentioned earlier, NO-ASA traverses the stomach intact [17,18], thus ruling out such a mechanism. Therefore, the only remaining possibility, that could link gastric cytoprotection to the NO that is released from NO-NSAIDs, is that NO reaches the mucosa via the circulation.…”

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 81%

“…First, NO levels (measured as NOx) are increased in the circulation following NO-NSAID administration [17,42]. Second, no intact NO-NSAID has been identified in the circulation or target tissues [17,18] and our own unpublished data], suggesting that the breakdown of the NO-NSAID molecule occurs either prior to or rapidly after it reaches the circulation. Third, S-nitrosylation, an unambiguous marker of NO action, following exposure to NO-NSAIDs has been repeatedly identified [43].…”

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

“…The strongest evidence against this mechanism comes form the pharmacokinetic studies of NO-aspirin (NO-ASA). Carini et al have shown that NO-ASA traverses the stomach intact, thus ruling out this mechanism, at least in the case of NO-ASA [17,18]. The alternative explanation that NO, released beyond the upper GI tract, can reach the gastric mucosa via the circulation remains unproven; elevated NO levels in the circulation following the administration of NO-NSAIDs have been repeatedly demonstrated (e.g., [18]).…”

Section: No-nsaids: Rationale and Structurementioning

confidence: 99%

“…Therefore, the only remaining possibility, that could link gastric cytoprotection to the NO that is released from NO-NSAIDs, is that NO reaches the mucosa via the circulation. This is entirely possible as elevated circulating NO levels have been documented following NO-NSAID administration [18,42]. Whether, however, such a mechanism is operative alone or as part of a complex series of events remains uncertain; NO is indeed an important mediator of mucosal defense in the stomach [47].…”

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

See 3 more Smart Citations

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

View full text Add to dashboard Cite

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

show abstract

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 81%

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

Section: No-nsaids: Rationale and Structurementioning

confidence: 99%

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

See 2 more Smart Citations

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

View full text Add to dashboard Cite

show abstract

“…One of these compounds, 2-acetoxybenzoate 2-(2-nitroxymethyl)phenyl ester (NO-aspirin), has been shown to be easily hydrolyzed by ubiquitous esterases in vivo into acetylsalicylic acid and an unchanged NO-donating moiety in the circulatory system (6), and NO release has been shown at a constant rate from NO-aspirin metabolite in the same cell compartments as the endogenous NO derived from L-arginine at the cellular level (11). NO can inhibit platelet aggregation (34), thus counteracting the inhibition of PGI 2 by the aspirin moiety.…”

mentioning

confidence: 99%

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

Fu¹,

Wang²,

Chen³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. Am J Physiol Heart Circ Physiol 293: H1545-H1552, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00064.2007.-In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), and NO-aspirin (56 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n ϭ 23), aspirin (n ϭ 22), and NO-aspirin groups (n ϭ 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 Ϯ 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin-and NOaspirin-pretreated groups, 36.7 Ϯ 1.8 and 22.9 Ϯ 4.3%, respectively (both P Ͻ 0.05 compared with vehicle group; P Ͻ 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P Ͻ 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P Ͻ 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N G -nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion. nitroaspirin; aspirin; cardioprotection; ischemia-reperfusion; infarct size ISCHEMIC MYOCARDIAL TISSUE will inevitably induce necrosis if blood flow is not restored immediately. Early reperfusion after coronary obstruction is well established to recover injured myocardium; nevertheless, reperfusion itself is believed to bring about additional cellular injury (25,30). During the last two decades, numerous studies have been done that focus on the roles of nitric oxide (NO) in the pathogenesis progress and pharmacological intervention of myocardial ischemia and reperfusion. Of them, exogenous NO donors may provide therapeutic benefit and are also a recent conceptual advance in the management of reperfusion damage (1,17,19,39). However, conventional NO donors (e.g., organic nitrates) frequently result in unwanted hemodynamic effects due to the ...

show abstract

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

Szabó

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Nitric oxide ( NO ), carbon monoxide ( CO ), and hydrogen sulfide ( H 2 S ) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H 2 S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) and S ‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H 2 S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H 2 S donor molecules have also been identified, which are used in preclinical studies.

show abstract

Chemiluminescence and LC–MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers

Cited by 26 publications

References 16 publications

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

Contact Info

Product

Resources

About

Chemiluminescence and LC–MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers

Cited by 26 publications

References 16 publications

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

Contact Info

Product

Resources

About

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs