Pharmacological profile of a novel H2S-releasing aspirin

Sparatore, Anna; Perrino, Elena; Tazzari, Valerio; Giustarini, Daniela; Rossi, Ranieri; Rossoni, Giuseppe; Erdman, Kati; Schröder, H.; Soldato, Piero Del

doi:10.1016/j.freeradbiomed.2008.11.013

Cited by 125 publications

(101 citation statements)

References 32 publications

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“…ACS14 also produces a concentrationdependent increase in HO-1 promoter activity in NIH3T3-HO-1-luc cells. ACS14 does not adversely affect aspirin's ability to inhibit thromboxane synthesis (145). Intraperitoneal injection of ACS14 or ADT-OH (both 0.1 mmol/kg) increases plasma H 2 S from 0.4 to ϳ0.65 M in 15 min with a 2nd peak (0.5 M) at 12-24 h, which is attributed to elevated plasma cysteine and subsequent metabolism to H 2 S. Both ACS14 and ADT-OH decrease plasma homocysteine and malonyldialdehyde (an indicator of oxidative stress) and increase total (reduced plus disulfide) cysteine and GSH.…”

Section: R304 Therapeutic Potential Of H2smentioning

confidence: 99%

The therapeutic potential of hydrogen sulfide: separating hype from hope

Olson

2011

American Journal of Physiology-Regulatory, Integrative and Comp

163

154

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Hydrogen sulfide (H2S) has become the hot new signaling molecule that seemingly affects all organ systems and biological processes in which it has been investigated. It has also been shown to have both proinflammatory and anti-inflammatory actions and proapoptotic and anti-apoptotic effects and has even been reported to induce a hypometabolic state (suspended animation) in a few vertebrates. The exuberance over potential clinical applications of natural and synthetic H2S-“donating” compounds is understandable and a number of these function-targeted drugs have been developed and show clinical promise. However, the concentration of H2S in tissues and blood, as well as the intrinsic factors that affect these levels, has not been resolved, and it is imperative to address these points to distinguish between the physiological, pharmacological, and toxicological effects of this molecule. This review will provide an overview of H2S metabolism, a summary of many of its reported “physiological” actions, and it will discuss the recent development of a number of H2S-donating drugs that show clinical potential. It will also examine some of the misconceptions of H2S chemistry that have appeared in the literature and attempt to realign the definition of “physiological” H2S concentrations upon which much of this exuberance has been established.

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Section: R304 Therapeutic Potential Of H2smentioning

confidence: 99%

The therapeutic potential of hydrogen sulfide: separating hype from hope

Olson

2011

American Journal of Physiology-Regulatory, Integrative and Comp

163

154

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“…Several concepts that have been previously used by medicinal chemistry for improving well-known drugs through the development of 'NO-hybrids' are presently being translated to the design of 'H2S hybrids'. This general concept has been applied also to the design of H2S-releasing non-steroidal anti-inflammatory drugs (NSAIDs), obtained through the conjugation of the 'parent' NSAIDs with a dithiolethione moiety [5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione] (HPDTT), which is currently the most widely used H2S-releasing moiety for synthesizing pharmacological hybrids (Li et al, 2007;Sparatore et al, 2009). Another class of H2S donors is thioamino acids that release H2S upon reaction with bicarbonate at a rate that is faster than GYY4137, yet appreciably slower than Na2S or NaSH (Zhou et al, 2012).…”

Section: Cardioprotection By Exogenous H 2 S Administrationmentioning

confidence: 99%

The role of gasotransmitters NO, H₂S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Andreadou

Iliodromitis

Rassaf

et al. 2014

British J Pharmacology

186

153

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Ischaemic heart disease is one of the leading causes of morbidity and mortality worldwide. The development of cardioprotective therapeutic agents remains a partly unmet need and a challenge for both medicine and industry, with significant financial and social implications. Protection of the myocardium can be achieved by mechanical vascular occlusions such as preconditioning (PC), when brief episodes of ischaemia/reperfusion (I/R) are experienced prior to ischaemia; postconditioning (PostC), when the brief episodes are experienced at the immediate onset of reperfusion; and remote conditioning (RC), when the brief episodes are experienced in another vascular territory. The elucidation of the signalling pathways, which underlie the protective effects of PC, PostC and RC, would be expected to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent reperfusion injury. Gasotransmitters including NO, hydrogen sulphide (H2S) and carbon monoxide (CO) are a growing family of regulatory molecules that affect physiological and pathological functions. NO, H2S and CO share several common properties; they are beneficial at low concentrations but hazardous in higher amounts; they relax smooth muscle cells, inhibit apoptosis and exert anti-inflammatory effects. In the cardiovascular system, NO, H2S and CO induce vasorelaxation and promote cardioprotection. In this review article, we summarize current knowledge on the role of the gasotransmitters NO, H2S and CO in myocardial I/R injury and cardioprotection provided by conditioning strategies and highlight future perspectives in cardioprotection by NO, H2S, CO, as well as their donor molecules. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx. Abbreviations 3MP, 3-mercaptopyruvate; 3-MST, 3-mercaptopyruvate transferase; BCA, cyano-L-alanine; CBS, cystathionine β-synthase; CHD, coronary heart disease; CK, creatinine kinase; CORM, carbon monoxide-releasing molecule; CSE, cystathionine γ-lyase; CyPD, cyclophilin D; HPDTT, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione; eNOS, endothelial nitric oxide synthase; FeTPPS, 5,10,15, porphyrinato iron; GYY4137, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate; HNO, nitroxyl; HO, haem oxygenase; I/R, ischaemia/reperfusion; iNOS, inducible nitric oxide synthase; L-NAME, N-nitro-L-arginine methylester; L-NNA, Nω-nitro-l-arginine; LV, left ventricular; MitoSNO, mitochondria-targeted S-nitrosothiols; mPTP, mitochondria permeability transition pore; nNOS, neuronal nitric oxide synthase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; NSAIDs, non-steroidal antiinflammatory drugs; ONOO − , peroxynitrite; PRG, DL-propargylglycine; PC, preconditioning; PostC, postconditioning; RC, remote conditioning; RISK, reperfusion injury salvage kinase; ROS, reactive oxygen species; SAC, S-allylcysteine; SAFE, survivor activating factor enhancement; SOD, superoxide dismutase; XOR, xanthin...

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“…One key GI safety clinical trial fell just short of showing a significant benefit as compared to naproxen (P = 0.066) [167] . H2S-releasing NSAIDs exhibit enhanced anti-inflammatory activity relative to the parent drugs [37,151,155,168,169] , presumably attributable to the anti-inflammatory and pro-resolution effects of the H2S released from these drugs [149,158,[170][171][172][173][174] . In addition to sparing the gastric mucosa of damage in several circumstances of impaired mucosal defence [38,175] , H2S-releasing NSAIDs have been shown not to cause damage in the small intestine of rats [38,155,175] .…”

Section: Novel Intestinal-sparing Nsaidsmentioning

confidence: 99%

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

Wallace¹

2013

WJG

151

148

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This article reviews the latest developments in understanding the pathogenesis, detection and treatment of small intestinal damage and bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs). With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous. However, there are no proven-effective therapies for NSAIDenteropathy, and detection remains a challenge, particularly because of the poor correlation between tissue injury and symptoms. Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e. , proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine. The pathogenesis of NSAIDenteropathy is complex, but studies in animal models are shedding light on the key factors that contribute to ulceration and bleeding, and are providing clues to the development of effective therapies and prevention strategies. Novel NSAIDs that do not cause small in- FRONTIER

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Pharmacological profile of a novel H2S-releasing aspirin

Cited by 125 publications

References 32 publications

The therapeutic potential of hydrogen sulfide: separating hype from hope

The therapeutic potential of hydrogen sulfide: separating hype from hope

The role of gasotransmitters NO, H₂S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

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Pharmacological profile of a novel H2S-releasing aspirin

Cited by 125 publications

References 32 publications

The therapeutic potential of hydrogen sulfide: separating hype from hope

The therapeutic potential of hydrogen sulfide: separating hype from hope

The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

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The role of gasotransmitters NO, H₂S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning