25 results on '"Santini AM"'
Search Results
2. Cost of illness in Italian women with LUTS followed at urology centres: The flow study
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Sgarbi, S, Rizzi, Ca, Santini, Am, Prezioso, D, Zattoni, Filiberto, Pesce, F, Scarpa, Rm, Tubaro, A, and Artibani, W.
- Published
- 2006
3. A novel, orally active LPA 1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model
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Swaney, JS, primary, Chapman, C, additional, Correa, LD, additional, Stebbins, KJ, additional, Bundey, RA, additional, Prodanovich, PC, additional, Fagan, P, additional, Baccei, CS, additional, Santini, AM, additional, Hutchinson, JH, additional, Seiders, TJ, additional, Parr, TA, additional, Prasit, P, additional, Evans, JF, additional, and Lorrain, DS, additional
- Published
- 2010
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4. PUK9 COST OF ILLNESS IN ITALIAN WOMEN WITH LUTS FOLLOWED AT UROLOGY CENTRES: THE FLOW STUDY
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Sgarbi, S, primary, Rizzi, CA, additional, Santini, AM, additional, Prezioso, D, additional, Zattoni, F, additional, Pesce, F, additional, Scarpa, RM, additional, Tubaro, A, additional, and Artibani, W, additional
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- 2006
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5. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model.
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Swaney, JS, Chapman, C, Correa, LD, Stebbins, KJ, Bundey, RA, Prodanovich, PC, Fagan, P, Baccei, CS, Santini, AM, Hutchinson, JH, Seiders, TJ, Parr, TA, Prasit, P, Evans, JF, Lorrain, DS, Swaney, J S, Correa, L D, Stebbins, K J, Bundey, R A, and Prodanovich, P C
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PULMONARY fibrosis ,BLEOMYCIN ,PHOSPHATIDIC acids ,PHARMACOLOGY ,CHEMOTAXIS ,LABORATORY mice ,INTRACELLULAR calcium - Abstract
Background and Purpose: The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA(1), in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA(1)-antagonist (4'-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (AM966).Experimental Approach: The potency and selectivity of AM966 for LPA(1) receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model.Key Results: AM966 was a potent antagonist of LPA(1) receptors, with selectivity for this receptor over the other LPA receptors. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC(50)= 17 nM) from Chinese hamster ovary cells stably expressing human LPA(1) receptors and inhibited LPA-induced chemotaxis (IC(50)= 181 nM) of human IMR-90 lung fibroblasts expressing LPA(1) receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor beta1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid.Conclusions and Implications: These findings demonstrate that AM966 is a potent, selective, orally bioavailable LPA(1) receptor antagonist that may be beneficial in treating lung injury and fibrosis, as well as other diseases that are characterized by pathological inflammation, oedema and fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2010
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6. Italian validation of the urogenital distress inventory and its application in LUTS patients
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Domenico Prezioso, Andrea Tubaro, Walter Artibani, Ambra M. Santini, Filiberto Zattoni, C.A. Rizzi, Lucia Simoni, Roberto Mario Scarpa, Francesco Pesce, Prezioso, Domenico, Artibani, W, Pesce, F, Scarpa, Rm, Zattoni, F, Tubaro, A, Rizzi, Ca, Santini, Am, Simoni, L, and THE FLOW STUDY, Group
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medicine.medical_specialty ,Urology ,Urinary incontinence ,bother ,female luts ,quality of life ,validation ,Linguistic validation ,Severity of Illness Index ,Quality of life ,Cronbach's alpha ,Lower urinary tract symptoms ,Surveys and Questionnaires ,Terminology as Topic ,medicine ,Humans ,Retrospective Studies ,Gynecology ,Bed-wetting ,business.industry ,Gold standard ,Middle Aged ,medicine.disease ,humanities ,Distress ,Urodynamics ,Urinary Incontinence ,Italy ,Physical therapy ,Quality of Life ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Objectives The objective of this study was to validate the Italian version of the Urogenital Distress Inventory (UDI) in a sample of women with lower urinary tract symptoms (LUTS). Methods The linguistic validation of the questionnaire was performed through a multistep process: backward and forward translations coordinated by clinical investigators, followed by a pretest. The final version was administered to a larger sample of female patients, aged 18 years or older who had been having LUTS for at least 3 months, numbering 53 subjects. To evaluate test-retest reliability, patients were re-rated after 1 week. To test the questionnaire's capacity to discriminate women with or without LUTS (cases and controls, respectively), a sample of 53 healthy women was enrolled. A 72-h voiding diary was used as a gold standard and compared with the UDI. Results The correlation coefficient between ratings was ≥0.80, and the discriminant power between cases and controls was confirmed. The UDI showed good internal consistency for all domains, except irritative symptoms (total score's Cronbach alpha=0.86). Factor analytic structure revealed urinary incontinence to be opposite to the other urologic symptoms, with bed wetting being loaded separately. The average daily number of urgent micturitions was higher in patients who reported they "experience a strong feeling of urgency to empty bladder" in the UDI than those ones who did not ( p Conclusions The Italian version of the UDI is a valid and robust instrument, which can now be used reliably in daily practice and clinical research.
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- 2006
7. Italian validation of the International Consultation on Incontinence Questionnaires
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Ambra M. Santini, Domenico Prezioso, Andrea Tubaro, Roberto Mario Scarpa, Walter Artibani, C.A. Rizzi, Lucia Simoni, Francesco Pesce, Filiberto Zattoni, Prezioso, Domenico, Tubaro, A, Zattoni, F, Scarpa, Rm, Pesce, F, Rizzi, Ca, Santini, Am, Simoni, L, Artibani, W, and FLOW STUDY, Group
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Adult ,medicine.medical_specialty ,Adolescent ,Psychometrics ,Urology ,Pilot Projects ,Urinary incontinence ,Cohort Studies ,Quality of life ,Cronbach's alpha ,Lower urinary tract symptoms ,Surveys and Questionnaires ,Humans ,Medicine ,Aged ,Gynecology ,Analysis of Variance ,Urinary symptoms ,business.industry ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Test (assessment) ,Urinary Incontinence ,Italy ,Case-Control Studies ,Quality of Life ,Female ,medicine.symptom ,business ,Clinical psychology ,Cohort study - Abstract
OBJECTIVE To validate the Italian version of two questionnaires for lower urinary tract symptoms (LUTS), i.e. the long (LF) and the short form (SF) of the International Consultation on Incontinence Questionnaire (ICIQ). METHODS Two native Italian speakers and a native English speaker collaborated with clinical investigators through a multistep process to obtain a consensus version of the questionnaires. The resulting Italian versions were then pre-tested during a pilot study on 16 women for the LF and 10 for the SF. The final versions of the ICIQ-LF and ICIQ-SF were administered to two samples of consecutive female patients, aged ≥ 18 years, who had been having LUTS for ≥ 3 months, with respectively 82 and 50 women. Internal consistency and test-retest reliability were then assessed; to evaluate the latter, a subset of patients (25 for the ICIQ-LF and 42 for ICIQ-SF) was re-rated. To test the capacity of the questionnaires to discriminate women with or without LUTS (respectively cases and controls), a sample of healthy women was also enrolled and assessed. RESULTS Both scales showed good psychometric properties overall. The correlation coefficient between ratings was > 0.75 in both questionnaires, and the discriminant power between cases and controls was confirmed for both scales. The ICIQ-SF showed good internal consistency for the total score (Cronbach's α 0.90). The sections of the ICIQ-LF ‘impact of incontinence on everyday life’, ‘emotional aspects’, ‘urinary symptoms’ and the degree of bother seemed to be internally consistent (Cronbach's α > 0.70); there was a weak relationship for items related to ‘sexual matters’ (Cronbach's α 0.38). CONCLUSION The Italian version of both questionnaires is a valid and robust instrument which can now be used reliably both in daily practice and in clinical research.
- Published
- 2006
8. Author Correction: JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders.
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Ambrus-Aikelin G, Takeda K, Joetham A, Lazic M, Povero D, Santini AM, Pranadinata R, Johnson CD, McGeough MD, Beasley FC, Stansfield R, McBride C, Trzoss L, Hoffman HM, Feldstein AE, Stafford JA, Veal JM, Bain G, and Gelfand EW
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- 2023
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9. JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders.
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Ambrus-Aikelin G, Takeda K, Joetham A, Lazic M, Povero D, Santini AM, Pranadinata R, Johnson CD, McGeough MD, Beasley FC, Stansfield R, McBride C, Trzoss L, Hoffman HM, Feldstein AE, Stafford JA, Veal JM, Bain G, and Gelfand EW
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- Animals, Mice, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein, Caspase 1, Cardiovascular Diseases, Lupus Nephritis
- Abstract
The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle-Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders., (© 2023. Springer Nature Limited.)
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- 2023
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10. Pharmacology of a Potent and Novel Inhibitor of the NOD-Like Receptor Pyrin Domain-Containing Protein 3 (NLRP3) Inflammasome that Attenuates Development of Nonalcoholic Steatohepatitis and Liver Fibrosis.
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Povero D, Lazic M, McBride C, Ambrus-Aikelin G, Stansfield R, Johnson CD, Santini AM, Pranadinata RF, McGeough MD, Stafford JA, Hoffman HM, Feldstein AE, Veal JM, and Bain G
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- Mice, Animals, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Proteins, Pyrin Domain, Liver Cirrhosis drug therapy, Liver Cirrhosis prevention & control, Caspase 1 metabolism, Inflammation, Choline adverse effects, Interleukin-1beta metabolism, Non-alcoholic Fatty Liver Disease drug therapy, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory cytokines interleukin (IL)-1 β and IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and autoimmune diseases, including cardiovascular disease, neurodegenerative diseases, and nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor, JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays, JT001 potently and selectively inhibited NLRP3 inflammasome assembly, resulting in the inhibition of cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1. Oral administration of JT001 to mice inhibited IL-1 β production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered JT001 was effective in reducing hepatic inflammation in three different murine models, including the Nlrp3
A350V /+ CreT model of Muckle-Wells syndrome (MWS), a diet-induced obesity NASH model, and a choline-deficient diet-induced NASH model. Significant reductions in hepatic fibrosis and cell damage were also observed in the MWS and choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic inflammation and fibrosis and support the use of JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of cryopyrin-associated periodic syndromes associated with severe systemic inflammation. NLRP3 is also upregulated in nonalcoholic steatohepatitis, a metabolic chronic liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2023
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11. Concordance Between Electronic Clinical Documentation and Physicians' Observed Behavior.
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Berdahl CT, Moran GJ, McBride O, Santini AM, Verzhbinsky IA, and Schriger DL
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- Adult, Emergency Medicine education, Emergency Service, Hospital, Female, Humans, Male, Middle Aged, Observation, Physicians, Documentation, Electronic Health Records, Emergency Medicine methods, Medical History Taking, Physical Examination, Practice Patterns, Physicians'
- Abstract
Importance: Following the adoption of electronic health records into a regulatory environment designed for paper records, there has been little investigation into the accuracy of physician documentation., Objective: To quantify the percentage of emergency physician documentation of the review of systems (ROS) and physical examination (PE) that observers can confirm., Design, Setting, and Participants: This case series took place at emergency departments in 2 academic medical centers between 2016 and 2018. Participants' patient encounters were observed to compare real-time performance with clinical documentation., Exposures: Resident physicians were shadowed by trained observers for 20 encounters (10 encounters per physician per site) to obtain real-time observational data; associated electronic health record data were subsequently reviewed., Main Outcomes and Measures: Number of confirmed ROS systems (range, 0-14) divided by the number of documented ROS systems (range, 0-14), and number of confirmed PE systems (range, 0-14) divided by the number of documented PE systems (range, 0-14)., Results: The final study cohort included 9 licensed emergency medicine residents who evaluated a total of 180 patients (mean [SD] age, 48.7 [20.0] years; 91 [50.5%] women). For ROS, physicians documented a median (interquartile range [IQR]) of 14 (8-14) systems, while audio recordings confirmed a median (IQR) of 5 (3-6) systems. Overall, 755 of 1961 documented ROS systems (38.5%) were confirmed by audio recording data. For PE, resident physicians documented a median (IQR) of 8 (7-9) verifiable systems, while observers confirmed a median (IQR) of 5.5 (3-6) systems. Overall, 760 of 1429 verifiable documented PE systems (53.2%) were confirmed by concurrent observation. Interrater reliability for rating of ROS and PE was more than 90% for all measures., Conclusions and Relevance: In this study of 9 licensed year emergency medicine residents, there were inconsistencies between the documentation of ROS and PE findings in the electronic health record and observational reports. These findings raise the possibility that some documentation may not accurately represent physician actions. Further studies should be undertaken to determine whether this occurrence is widespread. However, because such studies are unlikely to be performed owing to institution-level barriers that exist nationwide, payers should consider removing financial incentives to generate lengthy documentation.
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- 2019
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12. Identification of 4-(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2).
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Rowbottom MW, Bain G, Calderon I, Lasof T, Lonergan D, Lai A, Huang F, Darlington J, Prodanovich P, Santini AM, King CD, Goulet L, Shannon KE, Ma GL, Nguyen K, MacKenna DA, Evans JF, and Hutchinson JH
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- Administration, Oral, Amino Acid Oxidoreductases metabolism, Animals, Disease Models, Animal, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors therapeutic use, Fibrosis, Halogenation, Humans, Lung drug effects, Lung enzymology, Lung pathology, Lung Diseases drug therapy, Lung Diseases enzymology, Lung Diseases pathology, Male, Methylation, Mice, Inbred C57BL, Models, Molecular, Pyridines administration & dosage, Pyridines therapeutic use, Structure-Activity Relationship, Amino Acid Oxidoreductases antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Pyridines chemistry, Pyridines pharmacology
- Abstract
LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-molecule LOXL2 inhibitor to enter clinical development.
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- 2017
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13. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
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Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, Ma GL, Santini AM, Stein AJ, Lonergan D, King CD, Calderon I, Lai A, Hutchinson JH, and Evans JF
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- Animals, Disease Models, Animal, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, Female, Humans, Male, Mice, Piperazines pharmacokinetics, Piperazines therapeutic use, Enzyme Inhibitors pharmacology, Liver Cirrhosis drug therapy, Liver Cirrhosis enzymology, Phosphoric Diester Hydrolases metabolism, Piperazines pharmacology
- Abstract
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
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- 2017
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14. Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.
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Stein AJ, Bain G, Prodanovich P, Santini AM, Darlington J, Stelzer NM, Sidhu RS, Schaub J, Goulet L, Lonergan D, Calderon I, Evans JF, and Hutchinson JH
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- Animals, Cell Line, Tumor, Crystallization, HEK293 Cells, Humans, Mice, Protein Binding physiology, Protein Structure, Secondary, Protein Structure, Tertiary, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Phosphoric Diester Hydrolases chemistry, Phosphoric Diester Hydrolases metabolism
- Abstract
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
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- 2015
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15. Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor.
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Bain G, King CD, Schaab K, Rewolinski M, Norris V, Ambery C, Bentley J, Yamada M, Santini AM, van de Wetering de Rooij J, Stock N, Zunic J, Hutchinson JH, and Evans JF
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- Administration, Oral, Adolescent, Adult, Aged, Area Under Curve, Asian People, Biomarkers blood, Biomarkers urine, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Leukotriene B4 blood, Leukotriene B4 urine, Leukotriene E4 urine, Male, Middle Aged, White People, Young Adult, 5-Lipoxygenase-Activating Protein Inhibitors adverse effects, 5-Lipoxygenase-Activating Protein Inhibitors pharmacokinetics, 5-Lipoxygenase-Activating Protein Inhibitors pharmacology, Indoles adverse effects, Indoles pharmacokinetics, Indoles pharmacology, Leukotriene E4 blood, Pentanoic Acids adverse effects, Pentanoic Acids pharmacokinetics, Pentanoic Acids pharmacology
- Abstract
Aim: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations., Method: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity., Results: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nM and 89 nM in the Western European and Japanese studies, respectively., Conclusion: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄., (© 2012 GlaxoSmithKline. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)
- Published
- 2013
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16. Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for severe depression: a double-blind randomized trial.
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Brecht S, Desaiah D, Marechal ES, Santini AM, Podhorna J, and Guelfi JD
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- Adult, Antidepressive Agents adverse effects, Depressive Disorder, Major diagnosis, Depressive Disorder, Major psychology, Dose-Response Relationship, Drug, Double-Blind Method, Duloxetine Hydrochloride, Female, Humans, Male, Middle Aged, Personality Inventory statistics & numerical data, Psychometrics, Suicidal Ideation, Thiophenes adverse effects, Antidepressive Agents administration & dosage, Depressive Disorder, Major drug therapy, Hospitalization, Thiophenes administration & dosage
- Abstract
Objective: To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily., Method: Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥ 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores ≥ 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) ≥ 4 and hospitalized ≥ 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008., Results: There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea., Conclusions: Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies., Trial Registration: clinicaltrials.gov Identifier: NCT00422162., (© Copyright 2011 Physicians Postgraduate Press, Inc.)
- Published
- 2011
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17. Pharmacology of AM211, a potent and selective prostaglandin D2 receptor type 2 antagonist that is active in animal models of allergic inflammation.
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Bain G, Lorrain DS, Stebbins KJ, Broadhead AR, Santini AM, Prodanovich P, Darlington J, King CD, Lee C, Baccei C, Stearns B, Troung Y, Hutchinson JH, Prasit P, and Evans JF
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- Adult, Animals, Dogs, Female, Guinea Pigs, HEK293 Cells, Humans, Hypersensitivity drug therapy, Hypersensitivity immunology, Hypersensitivity metabolism, Male, Methylurea Compounds chemistry, Methylurea Compounds pharmacology, Mice, Mice, Inbred BALB C, Phenylacetates chemistry, Phenylacetates pharmacology, Pneumonia drug therapy, Pneumonia immunology, Pneumonia metabolism, Prostaglandin Antagonists chemistry, Prostaglandin Antagonists pharmacology, Protein Binding physiology, Random Allocation, Rats, Rats, Sprague-Dawley, Receptors, Immunologic immunology, Receptors, Immunologic metabolism, Receptors, Prostaglandin immunology, Receptors, Prostaglandin metabolism, Rhinitis, Allergic, Perennial immunology, Rhinitis, Allergic, Perennial metabolism, Disease Models, Animal, Methylurea Compounds therapeutic use, Phenylacetates therapeutic use, Prostaglandin Antagonists therapeutic use, Receptors, Immunologic antagonists & inhibitors, Receptors, Prostaglandin antagonists & inhibitors, Rhinitis, Allergic, Perennial drug therapy
- Abstract
The prostaglandin D(2) (PGD(2)) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the small-molecule DP2 antagonist [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD(2)-stimulated guanosine 5'-O-[γ-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD(2)-stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD(2)-induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases.
- Published
- 2011
- Full Text
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18. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist.
- Author
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Swaney JS, Chapman C, Correa LD, Stebbins KJ, Broadhead AR, Bain G, Santini AM, Darlington J, King CD, Baccei CS, Lee C, Parr TA, Roppe JR, Seiders TJ, Ziff J, Prasit P, Hutchinson JH, Evans JF, and Lorrain DS
- Subjects
- Administration, Oral, Animals, Antifibrinolytic Agents chemistry, CHO Cells, Cell Line, Tumor, Cricetinae, Cricetulus, Dogs, Humans, Male, Mice, Protein Binding physiology, Rats, Rats, Sprague-Dawley, Receptors, Lysophosphatidic Acid metabolism, Antifibrinolytic Agents administration & dosage, Antifibrinolytic Agents pharmacokinetics, Receptors, Lysophosphatidic Acid antagonists & inhibitors
- Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA₁₋₆. LPA type 1 receptor (LPA₁) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA₁-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA₁ receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA₁ with IC₅₀ values of 0.98 and 0.73 μM, respectively, and exhibited no LPA₁ agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA₁ (IC₅₀= 778 nM) and human A2058 melanoma cells (IC₅₀ = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA₁ receptor antagonist with good oral exposure and antifibrotic activity in rodent models.
- Published
- 2011
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19. Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation.
- Author
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Lorrain DS, Bain G, Correa LD, Chapman C, Broadhead AR, Santini AM, Prodanovich PP, Darlington JV, Stock NS, Zunic J, King CD, Lee C, Baccei CS, Stearns B, Roppe J, Hutchinson JH, Prasit P, and Evans JF
- Subjects
- 5-Lipoxygenase-Activating Proteins, Animals, Chronic Disease, Cysteine biosynthesis, Disease Models, Animal, Female, Humans, Indoles pharmacokinetics, Indoles therapeutic use, Inflammation drug therapy, Leukotriene B4 biosynthesis, Leukotrienes biosynthesis, Lung drug effects, Lung metabolism, Male, Mice, Pentanoic Acids pharmacokinetics, Pentanoic Acids therapeutic use, Platelet Activating Factor pharmacology, Propionates pharmacokinetics, Propionates therapeutic use, Rats, Substrate Specificity, Zymosan pharmacology, Carrier Proteins antagonists & inhibitors, Indoles pharmacology, Inflammation metabolism, Membrane Proteins antagonists & inhibitors, Pentanoic Acids pharmacology, Propionates pharmacology
- Abstract
We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12 mg/kg and 0.37 mg/kg, respectively. The inhibition measured 16 h following a single oral dose of 3 mg/kg was 86% and 41% for LTB4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB4, CysLTs, plasma protein extravasation and neutrophil influx induced by peritoneal zymosan injection. Finally, AM803 increased survival time in mice exposed to a lethal intravenous injection of platelet activating factor (PAF). The magnitude of effect was similar to that of an inhibitor of five-lipoxygenase (5-LO) and LTA4 hydrolase but superior to a leukotriene CysLT1 receptor antagonist. In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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20. Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).
- Author
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Bain G, King CD, Rewolinski M, Schaab K, Santini AM, Shapiro D, Moran M, van de Wetering de Rooij S, Roffel AF, Schuilenga-Hut P, Milne GL, Lorrain DS, Li Y, Arruda JM, Hutchinson JH, Prasit P, and Evans JF
- Subjects
- 5-Lipoxygenase-Activating Proteins, Adolescent, Adult, Aged, Area Under Curve, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Indoles adverse effects, Indoles pharmacokinetics, Male, Middle Aged, Propionates adverse effects, Propionates pharmacokinetics, Young Adult, Carrier Proteins antagonists & inhibitors, Indoles pharmacology, Leukotriene B4 biosynthesis, Leukotriene E4 urine, Membrane Proteins antagonists & inhibitors, Propionates pharmacology
- Abstract
The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.
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- 2010
- Full Text
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21. Pharmacological blockade of the DP2 receptor inhibits cigarette smoke-induced inflammation, mucus cell metaplasia, and epithelial hyperplasia in the mouse lung.
- Author
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Stebbins KJ, Broadhead AR, Baccei CS, Scott JM, Truong YP, Coate H, Stock NS, Santini AM, Fagan P, Prodanovich P, Bain G, Stearns BA, King CD, Hutchinson JH, Prasit P, Evans JF, and Lorrain DS
- Subjects
- Animals, Benzylamines pharmacokinetics, Benzylamines pharmacology, Cell Line, Cell Movement, Female, Guinea Pigs, Humans, In Vitro Techniques, Inflammation immunology, Inflammation metabolism, Inflammation prevention & control, Lung immunology, Lung pathology, Lymphocytes drug effects, Lymphocytes immunology, Male, Metaplasia, Mice, Mice, Inbred BALB C, Neutrophils drug effects, Neutrophils immunology, Niacin analogs & derivatives, Niacin pharmacokinetics, Niacin pharmacology, Pulmonary Disease, Chronic Obstructive etiology, Pulmonary Disease, Chronic Obstructive immunology, Pulmonary Disease, Chronic Obstructive pathology, Respiratory Mucosa pathology, Lung drug effects, Mucus metabolism, Pulmonary Disease, Chronic Obstructive prevention & control, Receptors, Immunologic antagonists & inhibitors, Receptors, Prostaglandin antagonists & inhibitors, Respiratory Mucosa drug effects, Smoking adverse effects
- Abstract
Prostaglandin D(2) (PGD(2)) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD(2) is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD(2) and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4'-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.
- Published
- 2010
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- View/download PDF
22. Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.
- Author
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Lorrain DS, Bain G, Correa LD, Chapman C, Broadhead AR, Santini AM, Prodanovich P, Darlington JV, Hutchinson JH, King C, Lee C, Baccei C, Li Y, Arruda JM, and Evans JF
- Subjects
- 5-Lipoxygenase-Activating Proteins, Acute Disease, Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Asthma drug therapy, Asthma enzymology, Asthma metabolism, Chronic Disease, Disease Models, Animal, Dose-Response Relationship, Drug, Extravasation of Diagnostic and Therapeutic Materials drug therapy, Extravasation of Diagnostic and Therapeutic Materials enzymology, Extravasation of Diagnostic and Therapeutic Materials metabolism, Female, Humans, Indoles therapeutic use, Inflammation enzymology, Inflammation metabolism, Leukotriene B4 biosynthesis, Leukotriene B4 blood, Male, Mice, Mice, Inbred BALB C, Pneumonia drug therapy, Pneumonia enzymology, Pneumonia metabolism, Propionates therapeutic use, Rats, Rats, Sprague-Dawley, Zymosan, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Carrier Proteins antagonists & inhibitors, Indoles pharmacology, Inflammation drug therapy, Membrane Proteins antagonists & inhibitors, Propionates pharmacology
- Abstract
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
- Published
- 2009
- Full Text
- View/download PDF
23. Italian validation of the urogenital distress inventory and its application in LUTS patients.
- Author
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Artibani W, Pesce F, Prezioso D, Scarpa RM, Zattoni F, Tubaro A, Rizzi CA, Santini AM, and Simoni L
- Subjects
- Female, Follow-Up Studies, Humans, Italy, Middle Aged, Quality of Life, Retrospective Studies, Severity of Illness Index, Surveys and Questionnaires, Urinary Incontinence physiopathology, Urinary Incontinence psychology, Urodynamics physiology, Terminology as Topic, Urinary Incontinence classification
- Abstract
Objectives: The objective of this study was to validate the Italian version of the Urogenital Distress Inventory (UDI) in a sample of women with lower urinary tract symptoms (LUTS)., Methods: The linguistic validation of the questionnaire was performed through a multistep process: backward and forward translations coordinated by clinical investigators, followed by a pretest. The final version was administered to a larger sample of female patients, aged 18 years or older who had been having LUTS for at least 3 months, numbering 53 subjects. To evaluate test-retest reliability, patients were re-rated after 1 week. To test the questionnaire's capacity to discriminate women with or without LUTS (cases and controls, respectively), a sample of 53 healthy women was enrolled. A 72-h voiding diary was used as a gold standard and compared with the UDI., Results: The correlation coefficient between ratings was >or=0.80, and the discriminant power between cases and controls was confirmed. The UDI showed good internal consistency for all domains, except irritative symptoms (total score's Cronbach alpha=0.86). Factor analytic structure revealed urinary incontinence to be opposite to the other urologic symptoms, with bed wetting being loaded separately. The average daily number of urgent micturitions was higher in patients who reported they "experience a strong feeling of urgency to empty bladder" in the UDI than those ones who did not (p<0.01)., Conclusions: The Italian version of the UDI is a valid and robust instrument, which can now be used reliably in daily practice and clinical research.
- Published
- 2006
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- View/download PDF
24. Italian validation of the International Consultation on Incontinence Questionnaires.
- Author
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Tubaro A, Zattoni F, Prezioso D, Scarpa RM, Pesce F, Rizzi CA, Santini AM, Simoni L, and Artibani W
- Subjects
- Adolescent, Adult, Aged, Analysis of Variance, Case-Control Studies, Cohort Studies, Female, Humans, Italy, Middle Aged, Pilot Projects, Quality of Life, Reproducibility of Results, Surveys and Questionnaires standards, Urinary Incontinence diagnosis
- Abstract
Objective: To validate the Italian version of two questionnaires for lower urinary tract symptoms (LUTS), i.e. the long (LF) and the short form (SF) of the International Consultation on Incontinence Questionnaire (ICIQ)., Methods: Two native Italian speakers and a native English speaker collaborated with clinical investigators through a multistep process to obtain a consensus version of the questionnaires. The resulting Italian versions were then pre-tested during a pilot study on 16 women for the LF and 10 for the SF. The final versions of the ICIQ-LF and ICIQ-SF were administered to two samples of consecutive female patients, aged > or = 18 years, who had been having LUTS for > or = 3 months, with respectively 82 and 50 women. Internal consistency and test-retest reliability were then assessed; to evaluate the latter, a subset of patients (25 for the ICIQ-LF and 42 for ICIQ-SF) was re-rated. To test the capacity of the questionnaires to discriminate women with or without LUTS (respectively cases and controls), a sample of healthy women was also enrolled and assessed., Results: Both scales showed good psychometric properties overall. The correlation coefficient between ratings was > 0.75 in both questionnaires, and the discriminant power between cases and controls was confirmed for both scales. The ICIQ-SF showed good internal consistency for the total score (Cronbach's alpha 0.90). The sections of the ICIQ-LF 'impact of incontinence on everyday life', 'emotional aspects', 'urinary symptoms' and the degree of bother seemed to be internally consistent (Cronbach's alpha > 0.70); there was a weak relationship for items related to 'sexual matters' (Cronbach's alpha 0.38)., Conclusion: The Italian version of both questionnaires is a valid and robust instrument which can now be used reliably both in daily practice and in clinical research.
- Published
- 2006
- Full Text
- View/download PDF
25. N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels.
- Author
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Lim J, Stock N, Pracitto R, Boueres JK, Munoz B, Chaudhary A, Santini AM, Orr K, Schaffhauser H, Bezverkov RE, Aiyar J, and Venkatraman S
- Subjects
- Acetates pharmacology, Binding, Competitive drug effects, Calcium Channels drug effects, Diamines chemical synthesis, Gabapentin, Ligands, Molecular Structure, Protein Binding drug effects, Protein Binding physiology, Protein Subunits drug effects, Structure-Activity Relationship, Amines, Calcium Channels physiology, Cyclohexanecarboxylic Acids, Diamines chemistry, Diamines pharmacology, Protein Subunits physiology, gamma-Aminobutyric Acid
- Abstract
A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the alpha(2)delta subunit of voltage gated calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC(50)=9 nM), which is more potent than gabapentin (IC(50)=27 nM). Partial saturation of the acridine ring was also pursued and provided a compound with higher binding affinity than 1.
- Published
- 2004
- Full Text
- View/download PDF
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