Mitochondrial Potassium Channels as Pharmacological Target for Cardioprotective Drugs

Brief periods of ischemia are known to confer to the myocardium an increased resistance to the injury due to a later and more prolonged ischemic episode. This phenomenon, known as ischemic preconditioning (IPreC), is ensured by different biological mechanisms. Although an exhaustive comprehension of them has not been reached yet, it is widely accepted that mitochondria are pivotally involved in controlling cell life and death, and thus in IPreC. Among the several signaling pathways involved, as triggers and/or end effectors, in the mitochondrial mechanisms of cardioprotection, an important role is played by the activation of potassium channels located in the mitochondrial inner membrane (mitoK) of cardiomyocytes. Presently, different types of mitoK channels have been recognized in the heart, such as ATP-sensitive (mitoK(ATP)) and calcium-activated (mitoBK(Ca) and mitoSK(Ca)) potassium channels. Consistently, drugs modulating mitoK, on one hand, have been employed as useful experimental tools for early basic studies on IPreC. On the other hand, activators of mitoK are promising and innovative therapeutic agents for limiting the myocardial injury due to ischemic episodes. In this review, we report the experimental evidence supporting the role of mitoK in signaling pathways in the mechanisms of cardioprotection and an overview on the most important molecules acting as modulators of these channels, with their profiles of selectivity. Some innovative pharmaceutical strategies for mitochondriotropic drugs have been also reported. Finally, an appendix describing the main experimental approaches usually employed to study mitoK in isolated mitochondria or in intact cells has been added

Synthesis and evaluation of multi-functional NO-donor/insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications

Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity

A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions

Bisphosphonates (BPs) are the first-line treatment of bone loss resulting from various pathological conditions. Due to their high affinity to bone they have been used to develop conjugates with pro-Anabolic or anti-catabolic drugs. We recently demontrated that hydrogen sulfide (H2S), promotes osteogenesis and inhibits osteoclast differentiation. Here we developed an innovative molecule, named DM-22, obtained from the combination of alendronate (AL) and the H2S-releasing moiety aryl-isothiocyanate. DM-22 and AL were assayed in vitro in the concentration range 1-33 μM for effects on viability and function of human osteoclasts (h-OCs) and mesenchymal stromal cells (h-MSCs) undergoing osteogenic differentiation. Amperometric measures revealed that DM-22 releases H2S at a slow rate with a thiol-dependent mechanism. DM-22 significantly inhibited h-OCs differentiation and function, maintaining a residual h-OCs viability even at the high dose of 33 μM. Contrary to AL, in h-MSCs DM-22 did not induce cytotoxicity as revealed by LDH assay, significantly stimulated mineralization as measured by Alizarin Red staining and increased mRNA expression of Collagen I as compared to control cultures. In conclusion, DM-22 is a new BP which inhibits h-OCs function and stimulate osteogenic differentiation of h-MSCs, without cytotoxicity. DM-22 is an ideal candidate for a novel family of osteoanabolic drugs

LA RELIGIONE COME DIMENSIONE DELL’INTERCULTURALITÁ E COME CONDIZIONE DELL’AGIRE DELLO STATO (a cura di Annamaria Passaseo)

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H2S-BASED THERAPEUTIC AGENTS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

The present invention concerns the field of neurodegenerative diseases, and in particular relates to compounds, pharmaceutical compositions and their uses in the protection of neuronal cells from inflammation and from oxidative stress in the early stage of Parkinson's Disease as well as in Alzheimer's Disease

NO-releasing hybrids of cardiovascular drugs

Nitric 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

New Emerging Prospects in the Pharmacotherapy of Hypertension

One of the main approaches to the treatment of cardiovascular diseases is to block pathways and enzymes within the Renin-Angiotensin System (RAS) involved in the modulation of Angiotensin II. Besides this complex system, many other alternative strategies may represent interesting targets for new and more effective cardiovascular therapies. Many different approaches have led medicinal chemists to develop new molecules with the aim of improving current antihypertensive therapies. The development of these new compounds is based on different strategies which include the synthesis of new hybrid compounds in which two or more pharmacophore groups are combined together to give a new entity with better pharmacodynamic properties and fewer side effects, and the development of new molecules with targets such as renin, angiotensin (1-7) and urotensin-II. The aim of this review is to present various approaches used to improve antihypertensive therapy, developing both original molecules with new mechanisms of action (such as renin inhibitors, or Mas-agonists) and new hybrid cardiovascular drugs targeting multiple factors involved in hypertensive disease (NO-ACE inhibitors, NO-sartans, AT1/ETA antagonists)

NUOVE MOLECOLE PER LA RIGENERAZIONE TISSUTALE OSSEA

La presente invenzione ha per oggetto nuovi composti per il trattamento dell’osteoporosi e in generale delle patologie ossee caratterizzate da una progressiva perdita di massa ossea, ad esempio artrite reumatoide, iperparatiroidismo, metastasi tumorali ossee

PHARMACEUTICAL COMBINATION FOR THE TREATMENT OF TUMORS

The invention concerns a combination comprising at least one 2-oxo-indole derivative of formula (I) in which R1 is selected from the group consisting of thienyl, imidazolyl and pyridyl, optionally substituted by (C1-C3) alkyl, A is a -CH2CO- o -SO2- group; R is selected from the group consisting of 6,7-dimethoxy-1,2,3,4- tetrahydroisoquinolinyl, 3,4-dimethoxy-benzylamino, (C1-C3)alkyl, benzyl or a pharmaceutically acceptable salt thereof and at least one antitumor drug. The combination is for use in the treatment of tumors, in particular glioblastoma multiforme (GBM), breast tumor and pancreatic tumor. The combination is effective in the treatment of resistant tumor forms