Menarini Ricerche SpA

Firenze, Italy

Menarini Ricerche SpA

Firenze, Italy
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Valenti C.,Menarini Ricerche S.p.A. | Giuliani S.,Menarini Ricerche S.p.A. | Cialdai C.,Menarini Ricerche S.p.A. | Tramontana M.,Menarini Ricerche S.p.A. | Maggi C.A.,Menarini Ricerche S.p.A.
British Journal of Pharmacology | Year: 2012

BACKGROUND AND PURPOSE Bradykinin, through the kinin B 2 receptor, is involved in inflammatory processes related to arthropathies. B 2 receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated. EXPERIMENTAL APPROACH Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h. KEY RESULTS The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg 9-[Leu 8]-bradykinin (B 2 receptor, leukotriene, catecholamine and B 1 receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg 9-[Leu 8]- bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg 9-[Leu 8]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment. CONCLUSIONS AND IMPLICATIONS Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B 2 receptor, or through the indirect effects mediated by release of eicosanoids and cytokines. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Cialdai C.,Menarini Ricerche S.p.A. | Giuliani S.,Menarini Ricerche S.p.A. | Valenti C.,Menarini Ricerche S.p.A. | Tramontana M.,Menarini Ricerche S.p.A. | Maggi C.A.,Menarini Ricerche S.p.A.
European Journal of Pharmacology | Year: 2013

Dexketoprofen and tramadol, alone or in combination, were evaluated after oral or intra-articular administration on knee osteoarthritis nociception induced by intra-articular ( monosodium iodoacetate (MIA, 1 mg/25 ml) in the rat right knee while the left knee received saline (25 ml). Seven days after MIA treatment, dexketoprofen, tramadol, their combination or the vehicle were administered. Nociception was evaluated as alteration in hind limb weight distribution with Incapacitance tester at different time-points after drug administration. Oral dexketoprofen (0.1-1 mg/kg) or tramadol (0.5-5 mg/kg) induced maximal antinociception at 1 and 5 mg/kg, respectively. Their combination dose-dependently increased the intensity and duration of antinociception, that was additive and lasted up to 3 days. Also the intra-articular administration of dexketoprofen or tramadol (10-100 μg/25 μl) inhibited MIA-induced nociception, and the combination of the lower doses (10 μg/25 μl) produced a long lasting more than additive antinociceptive effect indicating a synergistic interaction between the two drugs. This effect was significantly reduced by naloxone (10 μg/25 μl, co-administered with both compounds. The intra-articular administration of both drugs at 10 μg/25 μl in the contralateral control knee joint provoked a marked synergistic antinociceptive effect indicating significant systemic diffusion through synovial membrane. The oral or intra-articular combination of dexketoprofen and tramadol produced additive or synergistic antinociceptive effects, respectively, in the model of MIA-induced osteoarthritis in rats, that might allow to obtain therapeutic advantages with lower side effects. © 2013 Elsevier B.V. All rights reserved.

Altamura M.,Menarini Ricerche S.p.A
Expert Opinion on Therapeutic Patents | Year: 2012

Tachykinins are endogenous peptide neurotransmitters, acting through the NK1, NK2 and NK3 receptors, at central and peripheral level. At peripheral level, they are involved in contraction of smooth muscle, secretion of water and ion from epithelia, as well as modulation of visceral pain sensitivity. Tachykinin NK2 receptor antagonists have the potential to be useful in the treatment of various gastrointestinal, genitourinary and CNS diseases. Areas covered: In this review, an overview of the patenting activity in the last 5 years is provided. Patents from different companies and research groups are discussed for their novelty and evaluated in relation to proposed indications and clinical studies. Relevant biological data are also presented. Patents claiming new therapeutic indications are included in a dedicated section. Expert opinion: Although there is still no tachykinin NK2 receptor antagonist approved for use in human therapy, research in the field is still proposing new compounds and possible uses. A number of candidates are being evaluated in Phase II clinical studies, in indications ranging from gastrointestinal disorders to inflammatory diseases. The results of these studies will indicate the role of tachykinin NK2 receptor antagonists in human therapy. © 2012 Informa UK, Ltd.

Meini S.,Menarini Ricerche S.p.A. | Cucchi P.,Menarini Ricerche S.p.A. | Catalani C.,Menarini Ricerche S.p.A. | Bellucci F.,Menarini Ricerche S.p.A. | And 2 more authors.
British Journal of Pharmacology | Year: 2011

Background and Purpose: In osteoarthritis (OA), bradykinin (BK) is known to contribute to pain and synovitis, but not to cartilage degradation. Here, we investigated effects of BK and its antagonists on chondrocytes, cells involved in cartilage homeostasis. Experimental Approach: BK receptor density and affinities of BK, its analogues and antagonists were measured in cultured human and rat chondrocytes by radioligand binding. Effects of BK were assessed by accumulation of inositol phosphates (IP) and release of interleukin (IL)-6 and IL-8. Key Results: Density of [ 3H]-BK binding sites was higher (13-30-fold) and BK evoked a greater (48-fold) IP production, in human than in rat chondrocytes. The BK B 2 receptor antagonists MEN16132 and icatibant displayed similar binding affinity. MEN16132 was 40-fold more potent than icatibant in the IP assay. In human chondrocytes, BK increased release (over 24 h) of IL-6 and IL-8, effects blocked by MEN16132 but not by the B 1 receptor antagonist Lys-[Leu 8][desArg 9]BK. BK-induced release of IL-6, but not of IL-8, was partially inhibited by indomethacin (10 μM) and nordihydroguaiaretic acid (10 μM). Antagonists for the prostanoid EP receptors (AH6809 10 μM; L-798 196, 200 nM; L-161 982, 1 μM) were ineffective. Dexamethasone (100 nM) partially inhibited release of both IL-6 and IL-8. Inhibitors of intracellular downstream signalling pathways (SB203580 10 μM; PD98059, 30 μM; SP600125, 30 μM; BAY-117085, 5 μM) indicated the involvement of p38 MAPK and the activation of NF-κB. CONCLUSION AND IMPLICATIONS BK mediated inflammatory changes and cartilage degradation and B 2 receptor blockade would, therefore, be a potential treatment for OA. © 2011 The Authors.

Catalioto R.-M.,Menarini Ricerche SpA | Maggi C.A.,Menarini Ricerche SpA | Giuliani S.,Menarini Ricerche SpA
Current Medicinal Chemistry | Year: 2011

The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are. © 2011 Bentham Science Publishers Ltd.

Evangelista S.,Menarini Ricerche SpA
Progress in Drug Research | Year: 2014

Calcitonin gene-related peptide (CGRP), a 37 aminoacid-residue peptide, is a marker of afferent fibers in the upper gastrointestinal tract, being almost completely depleted following treatment with the selective neurotoxin capsaicin that targets these fibers via transient receptor potential vanilloid type-1 (TRPV-1). It is widely distributed in the peripheral nervous system of mammals where it is present as α isoform, while intrinsic neurons of the enteric nervous systems express predominantly CGRP-β. Many gastrointestinal functions involve CGRP-containing afferent fibers of the enteric nervous system such as defense against irritants, intestinal nociception, modulation of gastrointestinal motility and secretion, and healing of gastric ulcers. The main effects on stomach homeostasis rely on local vasodilator actions during increased acid-back diffusion. In humans, release of CGRP through the activation of TRPV-1 has been shown to protect from gastric damage induced by several stimuli and to be involved in gastritis. In both dyspepsia and irritable bowel syndrome the repeated stimulation of TRPV-1 induced an improvement in epigastric pain of these patients. The TRPV-1/CGRP pathway might be a novel target for therapeutics in gastric mucosal injury and visceral sensitivity. © Springer Basel 2014.

Evangelista S.,Menarini Ricerche SpA
Expert Review of Clinical Pharmacology | Year: 2015

Capsaicin, a pharmacologically active agent found in chili peppers, causes burning and itching sensation due to binding at the transient receptor potential vanilloid-1 (TRPV-1) receptor, a polymodal receptor critical to the sensing of a variety of stimuli (e.g., noxious heat, bidirectional pH), and subsequent activation of polymodal C and A-δ nociceptive fibers. Acutely, TRPV-1 activation with peripheral capsaicin produces pronociceptive effects, which extends to the development of hyperalgesia and allodynia. However, capsaicin has been reported to display antinociceptive properties as well, largely through TRPV-1-dependent mechanisms. Local application of high concentration of capsaicin is used for neuropathic pain and repeated stimulation of TRPV-1 induced an improvement of epigastric pain in irritable bowel syndrome and dyspepsia patients by desensitization of nociceptive pathways. New TRPV-1 agonists are currently under preclinical study and TRPV-1 antagonists are in early clinical development as analgesics. The TRPV-1 pathway might be a novel target for therapeutics in pain sensitivity. © 2015 Informa UK, Ltd.

Evangelista S.,Menarini Ricerche SpA
Gastroenterology Research and Practice | Year: 2012

It is known that irritable bowel syndrome (IBS) is a chronic disease of cyclic nature characterized by recurrent symptoms. IBS patients should receive, as initial therapeutic approach a short course of treatment which, if effective, has the additional value of confirming the diagnosis. Long-term treatment should be reserved to diagnosed IBS patients with recurrent symptoms. Clinical trials with stabilized therapies and new active treatments showed an improvement of the symptoms over placebo that is often time-dependent but with high relapse rates (around 40-50 when stopping treatment). Relapse is not always immediate after stopping treatment and the recent data from OBIS trial with otilonium bromide or with psychotherapy, showed that due to different chemico-physical characteristics of the drugs or the psychosomatic impact to the disease not all treatment gave the same relapsing rate if compared to placebo. Results of IBS clinical trials with different therapies tailored to the patient needs indicate that a cyclic treatment therapy is advisable to counteract the nature of the disease. Copyright © 2012 Stefano Evangelista.

Bucci M.,University of Naples Federico II | Vellecco V.,University of Naples Federico II | Cantalupo A.,University of Naples Federico II | Brancaleone V.,University of Basilicata | And 5 more authors.
Cardiovascular Research | Year: 2014

AimsTherapeutic use of sulfhydrylated inhibitor S-zofenopril has raised different hypotheses regarding the role played by its thiol group in the beneficial clinical effects exerted compared with other angiotensin-converting enzyme (ACE) inhibitors. Here, we investigated hydrogen sulfide (H2S) pathway as accountable for extra-beneficial effects in vascular function.Methods and resultsSpontaneously hypertensive rat (SHRs) and control Wistar Kyoto (WKY) rats were treated with either S-zofenopril or enalapril in vivo. Aorta and carotid were harvested and ex vivo vascular reactivity to acetylcholine (Ach) and l-cysteine (l-cys) assessed. Cystathionine-β- synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptosulfur- transferase (3MST) expression, as well as H2S levels, were evaluated in both vascular tissues. The vascular response to Ach in both carotid and aorta was impaired in SHR (∼30%, P < 0.001). S-zofenopril, but not enalapril, restored this response, while l-cys-induced relaxation was enhanced. CSE expression in vessels and tissue/plasma H2S levels were restored to WKY values in SHRs receiving S-zofenopril. In contrast, CBS and 3MST expression were not modified by treatments. S-zofenoprilat, an active metabolite of S-zofenopril, releases H2S in a 'cell-free' assay and it directly relaxed vessels in vitro in a concentration-dependent manner (P < 0.001). In vivo administration of R-zofenoprilat diasteroisomer, which does not inhibit ACE, did not modify blood pressure; nonetheless, it retained the beneficial effect on SHR vascular function as well as restored plasma/tissue H2S levels.ConclusionOur findings establish that S-zofenopril improves vascular function by potentiating the H2S pathway in a model of spontaneous hypertension. This novel mechanism, unrelated to ACE inhibition and based on H2S release, could explain the beneficial effects of sulfhydrylated ACE inhibitors reported in the clinical literature. © 2014 The Author.

Bressan A.,Menarini Ricerche S.p.A | Bozzo F.,Menarini Ricerche S.p.A | Maggi C.A.,Menarini Ricerche S.p.A | Binaschi M.,Menarini Ricerche S.p.A
Disease Markers | Year: 2013

The human cancer antigen 125 (CA125) is over-expressed in epithelial ovarian cancer cells and it plays a role in the pathogenesis of ovarian cancer. This protein presents a repeat region containing up to sixty tandem repeat units. The anti-CA125 monoclonal antibodies have been previously classified into three groups: two major families, the OC125-like antibodies and M11-like antibodies, and a third group, the OV197-like antibodies. A model in which a single repeat unit contains all the epitopes for these antibodies has been also proposed, even if their exact position is still undetermined. In the present work, the affinities of the monoclonal antibodies, representative of the three families, have been investigated for different CA125-recombinant repeats through Western blot analysis. Different patterns of antibody recognition for the recombinant repeats show that CA125 epitopes are not uniformly distributed in the tandem repeat region of the protein. The minimal region for the recognition of these antibodies has been also individuated in the SEA domain through the subcloning of deleted sequences of the highly recognized repeat-25 (R-25), their expression as recombinant fragments in E. coli and Western blot analysis. Obtained data have been further confirmed by ELISA using the entire R-25 as coating antigen. © 2013-IOS Press and the authors. All rights reserved.

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