1,721,240 research outputs found
Editorial: Potassium channels: A big family, many different targets, great pharmacological opportunities
No full textVascular Effects of p-Carboxyphenyl-Isothiocyanate, a novel H2S-donor
No full textHydrogen sulfide (H2S), is a pivotal mediator in cardiovascular physiology. This gasotransmitter evokes vasorelaxing effects through different mechanisms of action, such as the inhibition of phosphodiesterases and activation of vascular KATP and Kv7 potassium channels. Indeed, impaired production of H2S contributes to the pathogenesis of important cardiovascular disorders [1]. Therefore, exogenous compounds, acting as H2S-releasing agents, are viewed as promising therapeutic agents for cardiovascular diseases.
This work aimed at evaluating the H2S-releasing properties of the p-Carboxyphenyl-Isothiocyanate (PhNCS-COOH) derivative and its vascular effects.
H2S release was first determined by the amperometric approach, and unequivocally confirmed by gas chromatography/mass spectrometry. Unlike NaHS, a fast H2S-donor widely used in the laboratory but unsuitable for clinical use, PhNCS-COOH exhibited a slow H2S-releasing profile, similar to the slow-releasing reference drugs diallyldisulfide (DADS) and GYY4137. H2S release from PhNCS-COOH occurred only in the presence of an excess of L-Cysteine: this thiol-dependency has been viewed as a particularly advantageous property, because it allows this compound to release H2S only in a biological environment.
The vascular activity of PhNCS-COOH was tested in rat aorta and coronary arteries. Like NaHS, PhNCS-COOH displayed concentration-dependent vasorelaxing effects on endothelium-denuded rat aortic rings. These effects were significantly antagonized by the Kv7 blocker XE991. PhNCS-COOH also inhibited the vasoconstricting effect of noradrenaline (NA), with greater potency than NaHS.
In addition, the isothiocyanate derivative increased basal coronary flow similarly to NaHS. Furthermore PhNCS-COOH was more effective than NaHS in counteracting the coronary vasoconstriction induced by angiotensin II.
Since H2S is known to hyperpolarize vascular smooth muscle by activating KATP and Kv7 channels [1,2], we evaluated its effects on the membrane potential of human aortic smooth muscle cells (HASMC) using a membrane potential sensitive fluorescent dye. Like the reference Kv7 activator Retigabine, PhNCS-COOH evoked a marked hyperpolarization, largely due to the activation of Kv7 channels [3].
In conclusion, PhNCS-COOH can be viewed as a new suitable slow H2S-releasing drug, endowed with vasorelaxing effects, typical of the endogenous gasotransmitter. PhNCS-COOH might be employed as a novel chemical tool in basic studies and in the development of original drugs in cardiovascular diseases
Pharmacodynamic hybrids coupling established cardiovascular mechanisms of action with additional nitric oxide releasing properties
No full textThe pharmacotherapy of complex pathological states at the cardiovascular level often requires different and complementary pharmacodynamic properties. This is frequently achieved through the administration of "cocktails", composed by several drugs possessing different mechanisms of action. In the last years, a revision of the "one-compound-one-target" paradigm led to a wide development of new classes of molecules, possessing more pharmacological targets. Among them, this innovative strategy produced interesting hybrid drugs, with a dual mechanism of action: a) a fundamental and well-established pharmacodynamic profile and b) the release of nitric oxide (NO), playing a pivotal role in the modulation of the function of cardiovascular system, where it induces vasorelaxing and antiplatelet responses. These new pharmacodynamic hybrids present the advantage of adding to a main mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE-inhibition) also a slow release of NO, useful either to reduce the adverse side effects and/or to improve the effectiveness of the drug. This review presents the chemical features of many examples of NO-releasing hybrids of cardiovascular drugs and explains the pharmacological improvements conferred by the addition of such NO-donor properties
NO-releasing hybrids of cardiovascular drugs
No full textNitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system. where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties
Organic Isothiocyanates as Hydrogen Sulfide Donors
No full textSignificance: Hydrogen sulfide (H2S), the "new entry" in the series of endogenous gasotransmitters, plays a fundamental role in regulating the biological functions of various organs and systems. Consequently, the lack of adequate levels of H2S may represent the etiopathogenetic factor of multiple pathological alterations. In these diseases, the use of H2S donors represents a precious and innovative opportunity. Recent Advances: Natural isothiocyanates (ITCs), sulfur compounds typical of some botanical species, have long been investigated because of their intriguing pharmacological profile. Recently, the ITC moiety has been proposed as a new H2S-donor chemotype (with a l-cysteine-mediated reaction). Based on this recent discovery, we can clearly observe that almost all the effects of natural ITCs can be explained by the H2S release. Consistently, the ITC function was also used as an original H2S-releasing moiety for the design of synthetic H2S donors and original "pharmacological hybrids." Very recently, the chemical mechanism of H2S release, resulting from the reaction between l-cysteine and some ITCs, has been elucidated. Critical Issues: Available literature gives convincing demonstration that H2S is the real player in ITC pharmacology. Further, countless studies have been carried out on natural ITCs, but this versatile moiety has been used only rarely for the design of synthetic H2S donors with optimal drug-like properties. Future Directions: The development of more ITC-based synthetic H2S donors with optimal drug-like properties and selectivity toward specific tissues/pathologies seem to represent a stimulating and indispensable prospect of future experimental activities
Role of mitochondrial KATP channels in the reduced cardiac tolerance to ischemic injury in the ageing
No full textCardioprotective effects of naringenin in elderly rats submitted to ischemia-reperfusion.
No full textUnderstanding physician prescription behaviors: a systematic review and meta-analysis of macro, meso, and micro-level influences
Full text linkBackground: Prescription is a complex act that reflects the physician’s expertise and authority. While some factors affecting prescription decisions have been studied, empirical findings often conflict, leaving our understanding of prescription behaviors limited and fragmented. Objective: To assess the factors influencing physicians’ drug prescribing habits by applying Strong Structuration Theory. Factors are categorized at: physician, practice, patient, industry, and system level. Methods: Pubmed, Scopus, and ISI Web of Science were searched from inception to June 2025. Peer-reviewed studies were included if they were published in English, empirical, and assessed at least one factor influencing physicians’ prescribing behaviors. Studies reporting the effect of covariates on prescriptions using Odds Ratios were included in the meta-analysis. Results: 146 studies were selected for the review. At the macro-level, physicians were more likely to prescribe after being exposed to marketing activities by pharmaceutical industries, and for privately insured patients. Meso-level factors, such as practice ownership and setting, showed conflicting results, with no significant effect observed in the meta-analysis. Micro-level influences were the most prevalent in literature. Patient requests had a significant positive effect on prescriptions. Physician-level influences were inconsistent across most variables, except gender, where male physicians were more likely to prescribe. This effect was not confirmed by the meta- analysis, which showed heterogeneity across studies. Conclusion: This study highlights the complexity of prescribing behaviors and the challenges in designing effective micro-level policies. Policymakers should therefore consider the multiple influences on prescribing to design targeted interventions that promote high-quality prescribing practices
Inhibitors of the renal outer medullary potassium channel: A patent review
Full text linkINTRODUCTION:
Hypertension represents a substantial cardiovascular risk factor. Among anti-hypertensive drugs, diuretics play an important role. Nevertheless, they present adverse effects such as hypokalemia or hyperkalemia. In this panorama, inhibitors of the renal outer medullary potassium (ROMK) channels are emerging because they are predicted to give a diuretic/natriuretic activity higher than that provided by loop diuretics, without hypokaliemic and hyperkaliemic side effects.
AREAS COVERED:
This article reviews the current literature, including all the patents published in the field of inhibitors of the ROMK channels for the treatment of hypertension, heart failure and correlated diseases. The patent examination has been carried out using electronic databases Espacenet.
EXPERT OPINION:
Although anti-hypertensive drugs armamentarium enumerates a plethora of therapeutic classes, including diuretics, the novel class of ROMK inhibitors may find a place in this crowded market, because of the diuretic/natriuretic effects, devoid of worrying influence on potassium balance. The patent examination highlights, as a strength, the individuation of a successful template: almost all the compounds show noteworthy potency. However, only few selected compounds underwent an in vivo investigation of diuretic and anti-hypertensive activities, and no data on the hERG channel are given in these patents
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