PMID- 30040996 OWN - NLM STAT- MEDLINE DCOM- 20190410 LR - 20190410 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 135 DP - 2018 Sep TI - Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs). PG - 60-79 LID - S1043-6618(18)30627-3 [pii] LID - 10.1016/j.phrs.2018.07.016 [doi] AB - The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug-drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Gelosa, Paolo AU - Gelosa P AD - Centro Cardiologico Monzino IRCCS, Via C. Parea, 4, 20138 Milan, Italy. Electronic address: paolo.gelosa@guest.unimi.it. FAU - Castiglioni, Laura AU - Castiglioni L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via G. Balzaretti 9, 20133 Milan, Italy. Electronic address: laura.castiglioni@unimi.it. FAU - Tenconi, Marco AU - Tenconi M AD - EDRA S.p.A., Via G. Spadolini, 7, 20141 Milan, Italy. Electronic address: m.tenconi@lswr.it. FAU - Baldessin, Ludovico AU - Baldessin L AD - EDRA S.p.A., Via G. Spadolini, 7, 20141 Milan, Italy. Electronic address: l.baldessin@lswr.it. FAU - Racagni, Giorgio AU - Racagni G AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via G. Balzaretti 9, 20133 Milan, Italy. Electronic address: giorgio.racagni@unimi.it. FAU - Corsini, Alberto AU - Corsini A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via G. Balzaretti 9, 20133 Milan, Italy; IRCCS MultiMedica, via G. Fantoli 16, 20138 Milan, Italy. Electronic address: alberto.corsini@unimi.it. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via G. Balzaretti 9, 20133 Milan, Italy; IRCCS MultiMedica, via G. Fantoli 16, 20138 Milan, Italy. Electronic address: stefano.bellosta@unimi.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20180721 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Anticoagulants) RN - 0 (Platelet Aggregation Inhibitors) RN - 12001-79-5 (Vitamin K) RN - 5Q7ZVV76EI (Warfarin) SB - IM MH - Administration, Oral MH - Animals MH - Anticoagulants/*pharmacokinetics MH - Drug Interactions MH - Humans MH - Phytotherapy MH - Platelet Aggregation Inhibitors/pharmacokinetics MH - Vitamin K/antagonists & inhibitors MH - Warfarin/pharmacokinetics OTO - NOTNLM OT - *Apixaban OT - *Apixaban (CID: 10182969) OT - *Betrixaban OT - *Betrixaban (CID: 10275777) dabigatran etexilate (CID: 216210) OT - *Dabigatran etexilate OT - *Edoxaban OT - *Edoxaban (CID: 10280735) OT - *Rivaroxaban OT - *Rivaroxaban (CID: 9875401) OT - *Warfarin OT - *Warfarin (CID: 54678486) EDAT- 2018/07/25 06:00 MHDA- 2019/04/11 06:00 CRDT- 2018/07/25 06:00 PHST- 2018/04/29 00:00 [received] PHST- 2018/07/10 00:00 [revised] PHST- 2018/07/16 00:00 [accepted] PHST- 2018/07/25 06:00 [pubmed] PHST- 2019/04/11 06:00 [medline] PHST- 2018/07/25 06:00 [entrez] AID - S1043-6618(18)30627-3 [pii] AID - 10.1016/j.phrs.2018.07.016 [doi] PST - ppublish SO - Pharmacol Res. 2018 Sep;135:60-79. doi: 10.1016/j.phrs.2018.07.016. Epub 2018 Jul 21. PMID- 29428206 OWN - NLM STAT- MEDLINE DCOM- 20190118 LR - 20190118 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 130 DP - 2018 Apr TI - Proprotein Convertase Subtilisin-Kexin type-9 (PCSK9) and triglyceride-rich lipoprotein metabolism: Facts and gaps. PG - 1-11 LID - S1043-6618(17)31656-0 [pii] LID - 10.1016/j.phrs.2018.01.025 [doi] AB - After more than a decade of intense investigation, Pro-protein Convertase Subtilisin-Kexin type 9 (PCSK9) remains a hot topic of research both at experimental and clinical level. Interestingly PCSK9 is expressed in different tissues suggesting the existence of additional function(s) beyond the modulation of the Low-Density Lipoprotein (LDL) receptor in the liver. Emerging data suggest that PCSK9 might play a role in the modulation of triglyceride-rich lipoprotein (TGRL) metabolism, mainly Very Low-Density Lipoproteins (VLDL) and their remnants. In vitro, PCSK9 affects TGRLs production by intestinal cells as well as the catabolism of LDL receptor homologous and non-homologous targets such as VLDL receptor, CD36 and ApoE2R. However, the in vivo relevance of these findings is still debated. This review aims at critically discussing the role of PCSK9 on TGRLs metabolism with a major focus on the impact of its genetic and pharmacological modulation on circulating lipids and lipoproteins beyond LDL. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Baragetti, Andrea AU - Baragetti A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy; S.I.S.A. Center for the Study of Atherosclerosis - Bassini Hospital, Cinisello Balsamo, Milan, Italy. FAU - Grejtakova, Daniela AU - Grejtakova D AD - IRCCS MultiMedica, via Fantoli 16, 20138, Milan, Italy. FAU - Casula, Manuela AU - Casula M AD - Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. FAU - Olmastroni, Elena AU - Olmastroni E AD - Epidemiology and Preventive Pharmacology Centre (SEFAP), Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy. FAU - Jotti, Gloria Saccani AU - Jotti GS AD - Department of Medicine & Surgery, Faculty of Medicine, University of Parma, Via Volturno 39, 43121 Parma, Italy. FAU - Norata, Giuseppe Danilo AU - Norata GD AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Kent St., Bentley Western Australia 6102, Australia. FAU - Catapano, Alberico L AU - Catapano AL AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy; IRCCS MultiMedica, via Fantoli 16, 20138, Milan, Italy. Electronic address: alberico.catapano@unimi.it. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, via Balzaretti 9, 20133, Milan, Italy; IRCCS MultiMedica, via Fantoli 16, 20138, Milan, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20180208 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Lipoproteins) RN - 0 (Receptors, LDL) RN - 0 (Triglycerides) RN - 0 (lipoprotein triglyceride) RN - EC 3.4.21.- (Proprotein Convertase 9) SB - IM MH - Animals MH - Humans MH - Lipoproteins/*metabolism MH - Proprotein Convertase 9/genetics/*metabolism MH - Receptors, LDL/metabolism MH - Triglycerides/*metabolism OTO - NOTNLM OT - *Lipoproteins OT - *Metabolism OT - *Monoclonal antibodies OT - *PCSK9 OT - *Triglycerides EDAT- 2018/02/13 06:00 MHDA- 2019/01/19 06:00 CRDT- 2018/02/12 06:00 PHST- 2017/12/20 00:00 [received] PHST- 2018/01/24 00:00 [revised] PHST- 2018/01/26 00:00 [accepted] PHST- 2018/02/13 06:00 [pubmed] PHST- 2019/01/19 06:00 [medline] PHST- 2018/02/12 06:00 [entrez] AID - S1043-6618(17)31656-0 [pii] AID - 10.1016/j.phrs.2018.01.025 [doi] PST - ppublish SO - Pharmacol Res. 2018 Apr;130:1-11. doi: 10.1016/j.phrs.2018.01.025. Epub 2018 Feb 8. PMID- 29058944 OWN - NLM STAT- MEDLINE DCOM- 20171227 LR - 20190221 IS - 1744-764X (Electronic) IS - 1474-0338 (Linking) VI - 17 IP - 1 DP - 2018 Jan TI - Statin drug interactions and related adverse reactions: an update. PG - 25-37 LID - 10.1080/14740338.2018.1394455 [doi] AB - INTRODUCTION: Statins reduce the risk of cardiovascular morbidity and mortality in patients with or at risk for cardiovascular disease and their use is expanding, especially in elderly. Statins are prescribed on a long-term basis and may undergo drug-drug interactions (DDIs) with other drugs. Statins have different safety and tolerability, and this might affect the possibility of DDIs with other cardiovascular drugs, increasing the risk of statin-associated myopathy and hepatotoxicity. Polypharmacy and pharmacogenetic variability are potential causes of statin DDIs. Thus, the safety and adverse effects of statins, particularly in patients receiving multiple medications at risk of DDIs, are a matter of special concern. AREAS COVERED: The purpose of this manuscript is to give an update on the potential statin DDIs and related adverse drug reactions (myopathy and hepatotoxicity), with special considerations on polypharmacy in elderly population, HIV patients, cardiovascular drugs and liver toxicities. The potential DDIs among statins and monoclonal antibodies including the recently approved PCSK9 inhibitors are also extensively discussed in the present review. EXPERT OPINION: A better understanding of the incidence and clinical significance of statin DDIs will help physicians in fine-tuning the lipid-lowering therapeutic interventions thus providing their patients with an evidence-based, safe and cost-effective clinical support. FAU - Bellosta, Stefano AU - Bellosta S AUID- ORCID: 0000-0001-5344-7824 AD - a Department of Pharmacological and Biomolecular Sciences , Universita degli Studi di Milano , Milan , Italy. AD - b IRCCS MultiMedica , Milan , Italy. FAU - Corsini, Alberto AU - Corsini A AUID- ORCID: 0000-0002-9912-9482 AD - a Department of Pharmacological and Biomolecular Sciences , Universita degli Studi di Milano , Milan , Italy. AD - b IRCCS MultiMedica , Milan , Italy. LA - eng PT - Journal Article PT - Review DEP - 20171030 PL - England TA - Expert Opin Drug Saf JT - Expert opinion on drug safety JID - 101163027 RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) SB - IM MH - Aged MH - Cardiovascular Diseases/prevention & control MH - *Drug Interactions MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*administration & dosage/adverse effects MH - Pharmacogenetics MH - *Polypharmacy MH - Risk Factors OTO - NOTNLM OT - *Dabigatran OT - *HIV patients OT - *PCSK9 inhibitors antibodies OT - *elderly patients OT - *ivabradine OT - *liver toxicity OT - *polypharmacy OT - *sacubitril OT - *ticagrelor OT - *tocilizumab EDAT- 2017/10/24 06:00 MHDA- 2017/12/28 06:00 CRDT- 2017/10/24 06:00 PHST- 2017/10/24 06:00 [pubmed] PHST- 2017/12/28 06:00 [medline] PHST- 2017/10/24 06:00 [entrez] AID - 10.1080/14740338.2018.1394455 [doi] PST - ppublish SO - Expert Opin Drug Saf. 2018 Jan;17(1):25-37. doi: 10.1080/14740338.2018.1394455. Epub 2017 Oct 30. PMID- 29234690 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20181113 IS - 2352-3409 (Print) IS - 2352-3409 (Linking) VI - 16 DP - 2018 Feb TI - The dataset describes: Phenotypic changes induced by cholesterol loading in smooth muscle cells isolated from the aortae of C57BL/6 mice. PG - 334-340 LID - 10.1016/j.dib.2017.11.050 [doi] AB - The data presented in this article is related to the research article entitled "ABCA1 and HDL3 are Required to Modulate Smooth Muscle Cells Phenotypic Switch after Cholesterol Loading" (Castiglioni et al., 2017) [1]. This data describes the characterization of the phenotypic changes induced by cholesterol loading in smooth muscle cells (SMCs) isolated from the aortae of C57BL/6 mice. Upon cholesterol loading, there is a significant and concentration-dependent decrease in the expression of Acta2 and a parallel increase in Mac-2, and ATP binding cassette (ABC) transporters Abca1 and Abcg1. Cholesterol incubation causes the transformation of SMCs into foam cells with a 3-fold increase in cellular total cholesterol content and a 2.5-fold stimulation of the activity of the esterifying enzyme Acyl-CoA:cholesterol acyltransferase (ACAT). The addition of the same amount of cholesterol, either dissolved in ethanol or as lipoprotein cholesterol (AcLDL or native LDL) only slightly induces the activity of the enzyme ACAT, and does not cause the accumulation of lipid droplets into SMCs. We describe also the knock down of ABCA1 expression by siRNA treatment in mouse smooth muscle cells. FAU - Castiglioni, Silvia AU - Castiglioni S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Monti, Matteo AU - Monti M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Buscherini, Giuditta Ainis AU - Buscherini GA AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Arnaboldi, Lorenzo AU - Arnaboldi L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Canavesi, Monica AU - Canavesi M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Corsini, Alberto AU - Corsini A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - IRCCS MultiMedica, Milan, Italy. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. AD - IRCCS MultiMedica, Milan, Italy. LA - eng PT - Journal Article DEP - 20171120 PL - Netherlands TA - Data Brief JT - Data in brief JID - 101654995 PMC - PMC5723262 OTO - NOTNLM OT - ABCA1 OT - Cholesterol OT - HDL3 OT - Phenotypic switch OT - Smooth muscle cells EDAT- 2017/12/14 06:00 MHDA- 2017/12/14 06:01 CRDT- 2017/12/14 06:00 PHST- 2017/09/16 00:00 [received] PHST- 2017/10/25 00:00 [revised] PHST- 2017/11/13 00:00 [accepted] PHST- 2017/12/14 06:00 [entrez] PHST- 2017/12/14 06:00 [pubmed] PHST- 2017/12/14 06:01 [medline] AID - 10.1016/j.dib.2017.11.050 [doi] AID - S2352-3409(17)30646-7 [pii] PST - epublish SO - Data Brief. 2017 Nov 20;16:334-340. doi: 10.1016/j.dib.2017.11.050. eCollection 2018 Feb. PMID- 28946038 OWN - NLM STAT- MEDLINE DCOM- 20180626 LR - 20181202 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 266 DP - 2017 Nov TI - ABCA1 and HDL3 are required to modulate smooth muscle cells phenotypic switch after cholesterol loading. PG - 8-15 LID - S0021-9150(17)31283-2 [pii] LID - 10.1016/j.atherosclerosis.2017.09.012 [doi] AB - BACKGROUND AND AIMS: Cholesterol-loaded smooth muscle cells (SMCs) modify their phenotypic behavior becoming foam cells. To characterize the role of ABCA1 and HDL3 in this process, we evaluated HDL3 effects on cholesterol-induced phenotypic changes in SMCs expressing or not ABCA1. METHODS: SMCs, isolated from the aortae of wild-type (WT) and Abca1 knock-out (KO) mice, were cholesterol-loaded using a "water-soluble cholesterol''. RESULTS: Cholesterol loading downregulates the expression of Acta2 and calponin (SMC markers), and increases the expression of Mac-2, CD11b and MHCII (inflammation-related genes and surface antigens) and Abca1, Abcg1. HDL3 normalizes SMC marker expression and reduces the expression of inflammation-related genes/proteins in WT cells, an effect not observed with free apoA-I. The effect of HDL3 is almost lost in Abca1 KO cells, as well as when Abca1 is silenced in WT SMC. HDL3 does not differently affect cholesterol downloading in WT or KO cells and stimulates phospholipids removal in WT cells. Similarly, the expression of myocardin and its modulators, such as miR-143/145, is reduced by cholesterol loading in WT and Abca1 KO SMCs; HDL3 normalizes their levels in WT cells but not in KO cells. On the contrary, cholesterol loading induces Klf4 expression while HDL3 restores Klf4 to basal levels in WT cells, but again this effect is not observed in KO cells. CONCLUSIONS: Our results indicate that HDL3, by interacting with ABCA1, modulates the miR143/145-myocardin axis and prevents the cholesterol-induced gene expression modification in SMCs regardless of its cholesterol unloading capacity. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Castiglioni, Silvia AU - Castiglioni S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Monti, Matteo AU - Monti M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Arnaboldi, Lorenzo AU - Arnaboldi L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Milan, Italy. FAU - Canavesi, Monica AU - Canavesi M AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Ainis Buscherini, Giuditta AU - Ainis Buscherini G AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Calabresi, Laura AU - Calabresi L AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy. FAU - Corsini, Alberto AU - Corsini A AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Milan, Italy. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological and Biomolecular Sciences, Universita degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Milan, Italy. Electronic address: stefano.bellosta@unimi.it. LA - eng PT - Journal Article DEP - 20170918 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (ABCA1 protein, mouse) RN - 0 (ABCG1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 0 (Biomarkers) RN - 0 (Cholesterol, HDL) RN - 0 (GKLF protein) RN - 0 (Kruppel-Like Transcription Factors) RN - 0 (MIRN145 microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (Mirn143 microRNA, mouse) RN - 0 (Nuclear Proteins) RN - 0 (Trans-Activators) RN - 0 (myocardin) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - ATP Binding Cassette Transporter 1/deficiency/genetics/*metabolism MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics/metabolism MH - Animals MH - Biomarkers/metabolism MH - *Cell Transdifferentiation MH - Cells, Cultured MH - Cholesterol/*metabolism MH - Cholesterol, HDL/*metabolism MH - Female MH - Foam Cells/*metabolism MH - Gene Expression Regulation MH - Genotype MH - Kruppel-Like Transcription Factors/genetics/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - MicroRNAs/genetics/metabolism MH - Muscle, Smooth, Vascular/*metabolism MH - Myocytes, Smooth Muscle/*metabolism MH - Nuclear Proteins/genetics/metabolism MH - Phenotype MH - Signal Transduction MH - Trans-Activators/genetics/metabolism OTO - NOTNLM OT - ABCA1 OT - Cholesterol OT - HDL(3) OT - Myocardin OT - Phenotypic switch OT - SMCs EDAT- 2017/09/26 06:00 MHDA- 2018/06/27 06:00 CRDT- 2017/09/26 06:00 PHST- 2017/04/19 00:00 [received] PHST- 2017/08/29 00:00 [revised] PHST- 2017/09/12 00:00 [accepted] PHST- 2017/09/26 06:00 [pubmed] PHST- 2018/06/27 06:00 [medline] PHST- 2017/09/26 06:00 [entrez] AID - S0021-9150(17)31283-2 [pii] AID - 10.1016/j.atherosclerosis.2017.09.012 [doi] PST - ppublish SO - Atherosclerosis. 2017 Nov;266:8-15. doi: 10.1016/j.atherosclerosis.2017.09.012. Epub 2017 Sep 18. PMID- 27438459 OWN - NLM STAT- MEDLINE DCOM- 20171225 LR - 20180503 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 111 DP - 2016 Sep TI - Pharmacokinetics interactions of monoclonal antibodies. PG - 592-599 LID - S1043-6618(16)30559-X [pii] LID - 10.1016/j.phrs.2016.07.015 [doi] AB - The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction. CI - Copyright (c) 2016 Elsevier Ltd. All rights reserved. FAU - Ferri, Nicola AU - Ferri N AD - Dipartimento di Scienze del Farmaco, Universita degli Studi di Padova, Padua, Italy. Electronic address: nicola.ferri@unipd.it. FAU - Bellosta, Stefano AU - Bellosta S AD - Dipartimento di Oncologia e Emato-Oncologia, Italy. FAU - Baldessin, Ludovico AU - Baldessin L AD - EDRA S.p.A., Milan, Italy. FAU - Boccia, Donatella AU - Boccia D AD - EDRA S.p.A., Milan, Italy. FAU - Racagni, Giorgi AU - Racagni G AD - Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy. FAU - Corsini, Alberto AU - Corsini A AD - Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy. LA - eng PT - Journal Article PT - Review PT - Research Support, Non-U.S. Gov't DEP - 20160718 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Antibodies, Monoclonal) SB - IM MH - Animals MH - Antibodies, Monoclonal/*pharmacokinetics MH - Drug Interactions MH - Humans OTO - NOTNLM OT - *Alirocumab OT - *Evolocumab OT - *IL-6 OT - *Methotrexate OT - *Monoclonal antibodies OT - *PCSK9 OT - *Reticuloendothelial system OT - *Simvastatin OT - *Tocilizumab EDAT- 2016/07/21 06:00 MHDA- 2017/12/26 06:00 CRDT- 2016/07/21 06:00 PHST- 2016/06/08 00:00 [received] PHST- 2016/07/12 00:00 [revised] PHST- 2016/07/13 00:00 [accepted] PHST- 2016/07/21 06:00 [entrez] PHST- 2016/07/21 06:00 [pubmed] PHST- 2017/12/26 06:00 [medline] AID - S1043-6618(16)30559-X [pii] AID - 10.1016/j.phrs.2016.07.015 [doi] PST - ppublish SO - Pharmacol Res. 2016 Sep;111:592-599. doi: 10.1016/j.phrs.2016.07.015. Epub 2016 Jul 18. PMID- 24114622 OWN - NLM STAT- MEDLINE DCOM- 20140606 LR - 20181113 IS - 1179-1950 (Electronic) IS - 0012-6667 (Linking) VI - 73 IP - 15 DP - 2013 Oct TI - Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. PG - 1681-709 LID - 10.1007/s40265-013-0126-z [doi] AB - The P2Y(12) receptor is a key player in platelet activation and represents an effective pharmacological target for the inhibition of platelet aggregation and prevention of atherothrombotic events. Indeed, the clinical use of the P2Y(12) receptor inhibitor clopidogrel is an effective strategy for inhibiting platelet activity in patients with acute coronary syndrome, and for preventing thrombotic events in those undergoing percutaneous coronary intervention with stenting. However, clopidogrel has several drawbacks, which include delayed onset of action, large inter-individual variability in platelet response, genetic polymorphism of the metabolizing enzyme, drug-drug interactions (DDIs), and the two-step activation process catalyzed by a series of cytochrome P450 (CYP) isoenzymes. For these reasons, new P2Y(12) receptor inhibitors have been developed in an attempt to improve on the pharmacological and clinical profile of clopidogrel. Three new P2Y(12) receptor inhibitors--prasugrel, cangrelor, and ticagrelor--have arrived, and more are coming into clinical use. Each of these antagonists has individual properties and, according to their mechanism of inhibition, can be divided into irreversible (prasugrel) and reversible inhibitors (ticagrelor, cangrelor). These agents also have different metabolic pathways: prasugrel is a prodrug that requires metabolic activation through a cytochrome-dependent pathway, while ticagrelor and cangrelor do not require metabolic conversion. However, ticagrelor is a CYP3A4 substrate/inhibitor and thus it can be involved in DDIs. Indeed, ticagrelor significantly increases the plasma levels of CYP3A4 substrates such as statins. Moreover, concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, ritonavir, telithromycin, etc.) is contraindicated, while the co-administration of ticagrelor with potent CYP3A inducers (carbamazepine, rifampicin, phenytoin, phenobarbital) is discouraged. Prasugrel and ticagrelor determine a faster, greater, and more consistent adenosine diphosphate (ADP)-receptor inhibition than clopidogrel, with a near complete inhibition of platelet aggregation between 1-2 h after administration of an oral loading dose, while cangrelor shows a rapid and potent platelet inhibitory effect with intravenous infusion. Thus, the different pharmacokinetic and pharmacodynamic characteristics of the P2Y(12) receptor inhibitors enable clinicians to personalize therapy according to patient-specific medical requirements for better prevention of atherothrombotic events. In the present review, we describe the pharmacological properties, the pharmacokinetic and pharmacodynamic differences, and the clinical efficacy of the currently available P2Y(12) receptor inhibitors. FAU - Ferri, Nicola AU - Ferri N AD - Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy. FAU - Corsini, Alberto AU - Corsini A FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article PT - Review PL - New Zealand TA - Drugs JT - Drugs JID - 7600076 RN - 0 (Fibrinolytic Agents) RN - 0 (P2RY12 protein, human) RN - 0 (Purinergic P2Y Receptor Antagonists) RN - 0 (Receptors, Purinergic P2Y12) SB - IM MH - Animals MH - Drug Interactions MH - *Fibrinolytic Agents/pharmacokinetics/pharmacology/therapeutic use MH - Humans MH - Molecular Targeted Therapy/*methods MH - Platelet Aggregation/drug effects MH - *Purinergic P2Y Receptor Antagonists/pharmacokinetics/pharmacology/therapeutic use MH - Receptors, Purinergic P2Y12/*metabolism EDAT- 2013/10/12 06:00 MHDA- 2014/06/07 06:00 CRDT- 2013/10/12 06:00 PHST- 2013/10/12 06:00 [entrez] PHST- 2013/10/12 06:00 [pubmed] PHST- 2014/06/07 06:00 [medline] AID - 10.1007/s40265-013-0126-z [doi] PST - ppublish SO - Drugs. 2013 Oct;73(15):1681-709. doi: 10.1007/s40265-013-0126-z. PMID- 23400638 OWN - NLM STAT- MEDLINE DCOM- 20131112 LR - 20181202 IS - 1573-7241 (Electronic) IS - 0920-3206 (Linking) VI - 27 IP - 3 DP - 2013 Jun TI - Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol. PG - 211-9 LID - 10.1007/s10557-013-6445-1 [doi] AB - PURPOSE: Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement. METHODS: Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose. Twenty-four hours later carotids were harvested for neutrophil quantification by immunostaining. RESULTS: Treatment with NCX 6560 was associated with a lower neutrophil infiltration (-39.5 %), while atorvastatin did not affect neutrophil content. The result was independent of effects on plasma cholesterol or differences in atorvastatin bioavailability, which suggests an important role of NO-related mechanisms in mediating this effect. Consistent with these in vivo findings, in vitro studies showed that NCX 6560, as compared to atorvastatin, had greater inhibitory activity on processes involved in neutrophil recruitment, such as migration in response to IL-8 and IL-8 release by endothelial cells and by neutrophils themselves. Pretreatment with NCX 6560, but not with atorvastatin, reduced the ability of neutrophil supernatants to promote monocyte chemotaxis, a well-known pro-inflammatory activity of neutrophils. CONCLUSION: Experimental data suggest a potential role of NO-releasing statins in the control of the vascular inflammatory process mediated by polymorphonuclear neutrophils. FAU - Baetta, Roberta AU - Baetta R AD - Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. roberta.baetta@unimi.it FAU - Granata, Agnese AU - Granata A FAU - Miglietta, Daniela AU - Miglietta D FAU - Oliva, Francesca AU - Oliva F FAU - Arnaboldi, Lorenzo AU - Arnaboldi L FAU - Bonomo, Alessandra AU - Bonomo A FAU - Ferri, Nicola AU - Ferri N FAU - Ongini, Ennio AU - Ongini E FAU - Bellosta, Stefano AU - Bellosta S FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cardiovasc Drugs Ther JT - Cardiovascular drugs and therapy JID - 8712220 RN - 0 (Heptanoic Acids) RN - 0 (Interleukin-8) RN - 0 (NCX 6560) RN - 0 (Nitric Oxide Donors) RN - 0 (Pyrroles) RN - 97C5T2UQ7J (Cholesterol) RN - A0JWA85V8F (Atorvastatin) SB - IM CIN - Cardiovasc Drugs Ther. 2013 Jun;27(3):183-5. PMID: 23440356 MH - Acute Disease MH - Animals MH - Atherosclerosis/blood/immunology/pathology/*prevention & control MH - Atorvastatin MH - Carotid Arteries/drug effects/pathology MH - Cell Survival/drug effects MH - Chemotaxis, Leukocyte/drug effects/immunology MH - Cholesterol/*blood MH - Heptanoic Acids/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Interleukin-8/immunology MH - Male MH - Molecular Structure MH - Monocytes/cytology/drug effects MH - Neutrophil Infiltration/*drug effects/immunology MH - Neutrophils/cytology/drug effects MH - Nitric Oxide Donors/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Pyrroles/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Rabbits EDAT- 2013/02/13 06:00 MHDA- 2013/11/13 06:00 CRDT- 2013/02/13 06:00 PHST- 2013/02/13 06:00 [entrez] PHST- 2013/02/13 06:00 [pubmed] PHST- 2013/11/13 06:00 [medline] AID - 10.1007/s10557-013-6445-1 [doi] PST - ppublish SO - Cardiovasc Drugs Ther. 2013 Jun;27(3):211-9. doi: 10.1007/s10557-013-6445-1. PMID- 22866966 OWN - NLM STAT- MEDLINE DCOM- 20130317 LR - 20131106 IS - 1744-764X (Electronic) IS - 1474-0338 (Linking) VI - 11 IP - 6 DP - 2012 Nov TI - Statin drug interactions and related adverse reactions. PG - 933-46 LID - 10.1517/14740338.2012.712959 [doi] AB - INTRODUCTION: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, their possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. AREAS COVERED: This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions and related adverse reactions. EXPERT OPINION: Avoiding drug-drug interactions and consequent adverse drug reactions is essential in order to optimize compliance, and thus improve the treatment of patients at high cardiovascular risk. The different pharmacokinetic profiles among statins should be carefully considered, in order to understand the possible spectrum of drug interactions. The growing trend toward earlier statin treatment for the prevention of cardiovascular disease means that physicians must anticipate future polypharmacy when their patients require additional medications for comorbid conditions. FAU - Bellosta, Stefano AU - Bellosta S AD - Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy. alberto.corsini@unimi.it FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20120807 PL - England TA - Expert Opin Drug Saf JT - Expert opinion on drug safety JID - 101163027 RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) SB - IM MH - Cardiovascular Diseases/etiology/prevention & control MH - Drug Interactions MH - *Food-Drug Interactions MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacokinetics/therapeutic use MH - Medication Adherence MH - *Pharmacogenetics EDAT- 2012/08/08 06:00 MHDA- 2013/03/19 06:00 CRDT- 2012/08/08 06:00 PHST- 2012/08/08 06:00 [entrez] PHST- 2012/08/08 06:00 [pubmed] PHST- 2013/03/19 06:00 [medline] AID - 10.1517/14740338.2012.712959 [doi] PST - ppublish SO - Expert Opin Drug Saf. 2012 Nov;11(6):933-46. doi: 10.1517/14740338.2012.712959. Epub 2012 Aug 7. PMID- 23119149 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20121105 LR - 20181113 IS - 2090-1291 (Electronic) IS - 2090-1283 (Linking) VI - 2012 DP - 2012 TI - Cholesterol: its regulation and role in central nervous system disorders. PG - 292598 LID - 10.1155/2012/292598 [doi] AB - Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer's disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions. FAU - Orth, Matthias AU - Orth M AD - Institut fur Laboratoriumsmedizin, Vinzenz von Paul Kliniken gGmbH, Adlerstra beta e 7, Postfach 103163, 70199 Stuttgart, Germany. FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article DEP - 20121017 PL - United States TA - Cholesterol JT - Cholesterol JID - 101540641 PMC - PMC3483652 EDAT- 2012/11/03 06:00 MHDA- 2012/11/03 06:01 CRDT- 2012/11/03 06:00 PHST- 2012/07/06 00:00 [received] PHST- 2012/09/03 00:00 [revised] PHST- 2012/09/10 00:00 [accepted] PHST- 2012/11/03 06:00 [entrez] PHST- 2012/11/03 06:00 [pubmed] PHST- 2012/11/03 06:01 [medline] AID - 10.1155/2012/292598 [doi] PST - ppublish SO - Cholesterol. 2012;2012:292598. doi: 10.1155/2012/292598. Epub 2012 Oct 17. PMID- 21215399 OWN - NLM STAT- MEDLINE DCOM- 20110627 LR - 20171213 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 215 IP - 1 DP - 2011 Mar TI - Free cholesterol alters macrophage morphology and mobility by an ABCA1 dependent mechanism. PG - 70-6 LID - 10.1016/j.atherosclerosis.2010.12.004 [doi] AB - OBJECTIVE: To investigate whether the morphological and functional changes typical of cell immobilization induced by free cholesterol (FC) accumulation in macrophages is related to the activity of the ATP-binding cassette transporter (ABCA1). METHODS AND RESULTS: FC loading induced actin rearrangement with ruffling and cell spreading in macrophages that normally express ABCA1, but to a significant lesser extent in ABCA1-KO mouse peritoneal macrophages (MPMs) and in normal cells upon pharmacological inhibition of ABCA1 with probucol. In ABCA1-KO MPMs and in probucol-treated J774 cell migration was inhibited to a lower extent by FC as compared to control cells. Similar results were found in stably ABCA1 knocked down J774 (ABCA1-KD-J774) obtained by RNA interference. FC accessible to cholesterol oxidase, a measure of plasma membrane FC content, was significantly higher in FC-loaded WT MPMs and control J774 than in FC-loaded ABCA1-KO MPMs, ABCA1-KD-J774 or probucol-treated J774. In parallel plasma membrane total phospholids and sphingomyelin increased after cholesterol loading in control J774 but not in ABCA1-KD-J774. In addition, apoA-I, that removes FC from ABCA1 specific pool, partially restored chemotactic response in FC-loaded control J774. No effect was observed with HDL(2) that does not interact with ABCA1. Finally, FC-induced Rac activation was more efficient in control J774 than in ABCA1-KD-J774. and was prevented by probucol and apoA-I in control J774. CONCLUSION: In macrophages ABCA1 activity mediates FC ability to alter plasma membrane organization, to inhibit cell migration, and to activate a Rac-mediated signaling pathway. CI - Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved. FAU - Adorni, Maria Pia AU - Adorni MP AD - Department of Pharmacological and Biological Sciences, Parco Area delle Scienze 27/A, 43124 Parma, University of Parma, Italy. FAU - Favari, Elda AU - Favari E FAU - Ronda, Nicoletta AU - Ronda N FAU - Granata, Agnese AU - Granata A FAU - Bellosta, Stefano AU - Bellosta S FAU - Arnaboldi, Lorenzo AU - Arnaboldi L FAU - Corsini, Alberto AU - Corsini A FAU - Gatti, Rita AU - Gatti R FAU - Bernini, Franco AU - Bernini F LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20101215 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (ABCA1 protein, human) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (ATP-Binding Cassette Transporters) RN - 97C5T2UQ7J (Cholesterol) RN - EC 3.6.5.2 (rac GTP-Binding Proteins) SB - IM MH - ATP Binding Cassette Transporter 1 MH - ATP-Binding Cassette Transporters/genetics/*physiology MH - Animals MH - Cell Membrane/drug effects MH - Cell Migration Assays MH - Cholesterol/metabolism/*pharmacology MH - Gene Knockdown Techniques MH - Humans MH - Macrophages, Peritoneal/cytology/*drug effects/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Signal Transduction/drug effects MH - rac GTP-Binding Proteins/physiology EDAT- 2011/01/11 06:00 MHDA- 2011/06/28 06:00 CRDT- 2011/01/11 06:00 PHST- 2010/07/23 00:00 [received] PHST- 2010/11/17 00:00 [revised] PHST- 2010/12/06 00:00 [accepted] PHST- 2011/01/11 06:00 [entrez] PHST- 2011/01/11 06:00 [pubmed] PHST- 2011/06/28 06:00 [medline] AID - S0021-9150(10)01024-5 [pii] AID - 10.1016/j.atherosclerosis.2010.12.004 [doi] PST - ppublish SO - Atherosclerosis. 2011 Mar;215(1):70-6. doi: 10.1016/j.atherosclerosis.2010.12.004. Epub 2010 Dec 15. PMID- 20102205 OWN - NLM STAT- MEDLINE DCOM- 20100528 LR - 20151119 IS - 1520-5118 (Electronic) IS - 0021-8561 (Linking) VI - 58 IP - 4 DP - 2010 Feb 24 TI - Olive oil phenols modulate the expression of metalloproteinase 9 in THP-1 cells by acting on nuclear factor-kappaB signaling. PG - 2246-52 LID - 10.1021/jf9042503 [doi] AB - In vivo studies suggest that the phenolic component contributes to the anti-inflammatory and antiatherosclerotic actions of olive oil; however, the effects in circulating cells are not fully characterized. Monocytes play a key role in inflammation-based diseases by expressing several molecules, including metalloproteinases (MMPs). In the present study, we investigated the effects of olive oil phenolic extract and individual compounds on MMP-9 in THP-1 cells, a human monocyte-like cell line. Olive oil extract prevented the stimulation of MMP-9 expression and secretion in tumor necrosis factor alpha-treated THP-1 cells. Oleuropein aglycone, a typical olive oil phenol, was active at concentrations found in the extract, although other compounds probably contribute to the biological activity. We also found that the effect of the extract and individual compounds on MMP-9 is due to impaired nuclear factor-kappaB signaling. Our findings provide further evidence on the mechanisms by which olive oil reduces the inflammatory burden associated with disorders, such as atherosclerosis. FAU - Dell'Agli, Mario AU - Dell'Agli M AD - Research Centre for the Characterization and Safe Use of Natural Compounds-Giovanni Galli, University of Milano, Via Balzaretti, 9, 20133 Milano, Italy. mario.dellagli@unimi.it FAU - Fagnani, Rossana AU - Fagnani R FAU - Galli, Germana V AU - Galli GV FAU - Maschi, Omar AU - Maschi O FAU - Gilardi, Federica AU - Gilardi F FAU - Bellosta, Stefano AU - Bellosta S FAU - Crestani, Maurizio AU - Crestani M FAU - Bosisio, Enrica AU - Bosisio E FAU - De Fabiani, Emma AU - De Fabiani E FAU - Caruso, Donatella AU - Caruso D LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Agric Food Chem JT - Journal of agricultural and food chemistry JID - 0374755 RN - 0 (DNA Primers) RN - 0 (NF-kappa B) RN - 0 (Olive Oil) RN - 0 (Phenols) RN - 0 (Plant Oils) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Cell Line, Tumor MH - DNA Primers MH - Gene Expression Regulation, Enzymologic/drug effects MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Leukemia, Myeloid MH - Matrix Metalloproteinase 9/*genetics MH - NF-kappa B/*genetics/physiology MH - Olive Oil MH - Phenols/isolation & purification/*pharmacology MH - Plant Oils/*chemistry MH - Promoter Regions, Genetic MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects/*physiology MH - Transcription, Genetic/drug effects MH - Tumor Necrosis Factor-alpha/pharmacology EDAT- 2010/01/28 06:00 MHDA- 2010/05/29 06:00 CRDT- 2010/01/28 06:00 PHST- 2010/01/28 06:00 [entrez] PHST- 2010/01/28 06:00 [pubmed] PHST- 2010/05/29 06:00 [medline] AID - 10.1021/jf9042503 [doi] PST - ppublish SO - J Agric Food Chem. 2010 Feb 24;58(4):2246-52. doi: 10.1021/jf9042503. PMID- 19023042 OWN - NLM STAT- MEDLINE DCOM- 20090223 LR - 20151119 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 328 IP - 2 DP - 2009 Feb TI - Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. PG - 419-25 LID - 10.1124/jpet.108.144147 [doi] AB - Monocytes/macrophages recruited into the arterial wall during atherogenesis are crucial in the initiation and progression of atherosclerosis and play a fundamental role in the destabilization process that is the main causal event of acute coronary syndromes. In the present study, we investigated the effect of the mammalian target of rapamycin inhibitor everolimus on macrophage accumulation within carotid lesions elicited by perivascular collar placement in cholesterol-fed rabbits. Everolimus (1.5 mg/kg given 1 day before collaring followed by 1 mg/kg/day for 14 days, administered by oral gavage) markedly decreased lesion macrophage content as compared with vehicle control (-65%; p < 0.01). This effect was associated with a reduction in intimal thickening and occurred in the absence of changes in plasma cholesterol concentrations. To gain insights on the potential mechanism(s) underlying this effect, we investigated the influence of everolimus on chemoattractant-induced migration of human monocytes in vitro. Pretreatment with therapeutic concentrations of everolimus (10 nM) significantly lowered monocyte chemotaxis in response to various chemotactic factors (i.e., monocyte chemoattractant protein-1/CCL2, fractalkine/CX3CL1, interleukin-8/CXCL8, complement fragment 5a, or N-formyl-Met-Leu-Phe) without inducing monocyte cell death. These results suggest that everolimus may favorably influence the atherosclerotic process by affecting the recruitment of monocytes into early lesions. FAU - Baetta, Roberta AU - Baetta R AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. roberta.baetta@unimi.it FAU - Granata, Agnese AU - Granata A FAU - Canavesi, Monica AU - Canavesi M FAU - Ferri, Nicola AU - Ferri N FAU - Arnaboldi, Lorenzo AU - Arnaboldi L FAU - Bellosta, Stefano AU - Bellosta S FAU - Pfister, Pascal AU - Pfister P FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20081120 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Chemotactic Factors) RN - 0 (Immunosuppressive Agents) RN - 97C5T2UQ7J (Cholesterol) RN - 9HW64Q8G6G (Everolimus) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Carotid Artery Diseases/metabolism/*pathology MH - Cell Movement/*drug effects/physiology MH - Chemotactic Factors/pharmacology MH - Cholesterol/metabolism/*pharmacology MH - Everolimus MH - Humans MH - Immunosuppression MH - Immunosuppressive Agents/pharmacology MH - Macrophages/*drug effects/pathology/physiology MH - Monocytes/*drug effects/physiology MH - Rabbits MH - Sirolimus/*analogs & derivatives/pharmacokinetics/pharmacology EDAT- 2008/11/22 09:00 MHDA- 2009/02/24 09:00 CRDT- 2008/11/22 09:00 PHST- 2008/11/22 09:00 [pubmed] PHST- 2009/02/24 09:00 [medline] PHST- 2008/11/22 09:00 [entrez] AID - jpet.108.144147 [pii] AID - 10.1124/jpet.108.144147 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2009 Feb;328(2):419-25. doi: 10.1124/jpet.108.144147. Epub 2008 Nov 20. PMID- 18646006 OWN - NLM STAT- MEDLINE DCOM- 20090115 LR - 20121115 IS - 1613-4133 (Electronic) IS - 1613-4125 (Linking) VI - 52 IP - 10 DP - 2008 Oct TI - Mediterranean diet and cardioprotection: wild artichoke inhibits metalloproteinase 9. PG - 1147-52 LID - 10.1002/mnfr.200700502 [doi] AB - Metalloproteinases (MMPs) are zinc-dependent endopeptidases responsible for the hydrolysis of various component of extracellular matrix such as gelatin and collagen. MMPs, namely MMP-2 and MMP-9 correlate with cardiovascular events in patients. We sought to determine whether supplementation with polyphenol-rich Cynara cardunculus (wild artichoke, traditional component of the Mediterranean diet) modulates MMP-9 expression and activity in cell cultures. A fully characterized C. cardunculus extract was able to inhibit, in a dose-dependent manner, the gelatinolytic activity of secreted MMP-9 and both secretion and human MMP-9 promoter-driven transcription. Analysis by HPLC of the Cynara extract identified polyphenols such as luteolin, apigenin, and caffeic acid, among others. However, testing a mix of the individual components suggested that the inhibitory effects of C. cardunculus are due to minor constituent fraction(s) as a whole. In promoting the health benefits of the Mediterranean diet, the role of wild plants as important meal components deserves further reappraisal. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological Sciences, University of Milan, Milan, Italy. FAU - Bogani, Paola AU - Bogani P FAU - Canavesi, Monica AU - Canavesi M FAU - Galli, Claudio AU - Galli C FAU - Visioli, Francesco AU - Visioli F LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Germany TA - Mol Nutr Food Res JT - Molecular nutrition & food research JID - 101231818 RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (Phenols) RN - 0 (Polyphenols) SB - IM MH - Animals MH - CHO Cells MH - Cardiovascular Diseases/prevention & control MH - Cricetinae MH - Cricetulus MH - Cynara/*chemistry MH - *Diet, Mediterranean MH - Enzyme Inhibitors/*pharmacology MH - Flavonoids/*pharmacology MH - Fruit/chemistry MH - Humans MH - *Matrix Metalloproteinase Inhibitors MH - Phenols/*pharmacology MH - Polyphenols EDAT- 2008/07/23 09:00 MHDA- 2009/01/16 09:00 CRDT- 2008/07/23 09:00 PHST- 2008/07/23 09:00 [pubmed] PHST- 2009/01/16 09:00 [medline] PHST- 2008/07/23 09:00 [entrez] AID - 10.1002/mnfr.200700502 [doi] PST - ppublish SO - Mol Nutr Food Res. 2008 Oct;52(10):1147-52. doi: 10.1002/mnfr.200700502. PMID- 24410514 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20140114 LR - 20140113 IS - 1751-2433 (Print) IS - 1751-2433 (Linking) VI - 1 IP - 1 DP - 2008 Jan TI - Drug-drug interaction with statins. PG - 105-13 LID - 10.1586/17512433.1.1.105 [doi] AB - 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (the so-called statins: atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin and simvastatin) are a well-established class of drugs in the treatment of hypercholesterolemia. Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Since statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. Moreover, a combination of therapy between statins and other classes of lipid-lowering agents (e.g., ezetimibe, fibrates, resins and nicotinic acid) is recommended for some patients by current guidelines. Therefore, the potential for drug-drug interactions emerges as a relevant factor in determining the safety profile of statins. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions. FAU - Corsini, Alberto AU - Corsini A AD - University of Milan, Department of Pharmacological Sciences, via Balzaretti 9, 20133 Milan, Italy. alberto.corsini@unimi.it. FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article PL - England TA - Expert Rev Clin Pharmacol JT - Expert review of clinical pharmacology JID - 101278296 EDAT- 2008/01/01 00:00 MHDA- 2008/01/01 00:01 CRDT- 2014/01/14 06:00 PHST- 2014/01/14 06:00 [entrez] PHST- 2008/01/01 00:00 [pubmed] PHST- 2008/01/01 00:01 [medline] AID - 10.1586/17512433.1.1.105 [doi] PST - ppublish SO - Expert Rev Clin Pharmacol. 2008 Jan;1(1):105-13. doi: 10.1586/17512433.1.1.105. PMID- 17900531 OWN - NLM STAT- MEDLINE DCOM- 20080211 LR - 20131121 IS - 0006-291X (Print) IS - 0006-291X (Linking) VI - 363 IP - 3 DP - 2007 Nov 23 TI - Thiol supplementation inhibits metalloproteinase activity independent of glutathione status. PG - 651-5 AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes that regulate both integrity and composition of the extracellular matrix (ECM). Excessive ECM breakdown by MMPs is implicated in many physiological and pathological conditions, such as atherosclerosis. Activated macrophages, especially in the atherosclerotic lesion, are a major source of reactive oxygen species (ROS). Antioxidants protect against ROS-induced MMPs activation and inhibit gelatinolytic activity. We sought to determine whether the antioxidants glutathione (GSH), N-acetylcysteine (NAC), or lipoic acid (LA) affect gelatinase production and secretion. The results show that thiol compounds affect MMPs expression and activity in different ways. MMP-2 activity is directly inhibited by NAC and GSH, while LA is ineffective. On the contrary, MMP-9 expression is inhibited by LA at a pretrascriptional level, and MMP-9 activity is stimulated by GSH through a direct interaction with the gelatinase itself. Although all thiols, these compounds have different properties and different cellular uptakes and metabolic characteristics, and this could explain, at least in part, their differential effects on MMPs. FAU - Bogani, Paola AU - Bogani P AD - Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. FAU - Canavesi, Monica AU - Canavesi M FAU - Hagen, Tory M AU - Hagen TM FAU - Visioli, Francesco AU - Visioli F FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070918 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (Antioxidants) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (Sulfhydryl Compounds) RN - 73Y7P0K73Y (Thioctic Acid) RN - EC 3.4.- (Metalloproteases) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - GAN16C9B8O (Glutathione) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/pharmacology MH - Animals MH - Antioxidants/pharmacology MH - CHO Cells MH - Cricetinae MH - Cricetulus MH - Electrophoresis, Polyacrylamide Gel MH - Glutathione/*metabolism/pharmacology MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Matrix Metalloproteinase Inhibitors MH - Metalloproteases/*antagonists & inhibitors/metabolism MH - Sulfhydryl Compounds/*pharmacology MH - Thioctic Acid/pharmacology EDAT- 2007/09/29 09:00 MHDA- 2008/02/12 09:00 CRDT- 2007/09/29 09:00 PHST- 2007/09/06 00:00 [received] PHST- 2007/09/07 00:00 [accepted] PHST- 2007/09/29 09:00 [pubmed] PHST- 2008/02/12 09:00 [medline] PHST- 2007/09/29 09:00 [entrez] AID - S0006-291X(07)01979-1 [pii] AID - 10.1016/j.bbrc.2007.09.018 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2007 Nov 23;363(3):651-5. doi: 10.1016/j.bbrc.2007.09.018. Epub 2007 Sep 18. PMID- 17482195 OWN - NLM STAT- MEDLINE DCOM- 20071207 LR - 20071227 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 195 IP - 1 DP - 2007 Nov TI - Perivascular carotid collar placement induces neointima formation and outward arterial remodeling in mice independent of apolipoprotein E deficiency or Western-type diet feeding. PG - e112-24 AB - We investigated the influence of apolipoprotein E deficiency and Western-type diet feeding on the development and composition of neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in mice. ApoE-/- and wild-type mice were fed a Western-type diet or chow diet for 4 weeks before collar surgery. Diets were continued after collar placement for 6 or 12 weeks. Compared to sham-operated arteries, collared carotids showed significant neointima formation, lumen loss, and outward remodeling in both apoE-/- and wild-type mice. These changes were not affected by either the genotype or the diet. Conversely, significant differences in neointima composition were detected between the two genotypes, with apoE-/- mice showing greater lipid deposition and lower SMC accumulation compared to wild-type mice, independent of the dietetic regimen. Altogether, the results of the present study indicate that although lesion composition may be influenced by genotype, neointima formation and arterial remodeling in the murine perivascular carotid collar model occur independent of the exposure to atherogenic diet or the presence of a sensitized genotype such as apoE-/-. The murine perivascular carotid collar model would thus be suitable for investigating neointima formation, arterial remodeling, and their potential pharmacological modulation in the setting of different genetic and dietary conditions. FAU - Baetta, Roberta AU - Baetta R AD - Department of Pharmacological Sciences, University of Milan, Italy. roberta.baetta@unimi.it FAU - Silva, Francesca AU - Silva F FAU - Comparato, Carmen AU - Comparato C FAU - Uzzo, Marta AU - Uzzo M FAU - Eberini, Ivano AU - Eberini I FAU - Bellosta, Stefano AU - Bellosta S FAU - Donetti, Elena AU - Donetti E FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070504 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (Apolipoproteins E) RN - 0 (Lipids) SB - IM MH - Animal Feed MH - Animals MH - Apolipoproteins E/*deficiency/*genetics MH - Arteries/pathology MH - Carotid Arteries/*pathology MH - Diet MH - Genotype MH - Lipids/chemistry MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Models, Animal MH - Neutrophils/metabolism MH - Tunica Intima/*pathology EDAT- 2007/05/08 09:00 MHDA- 2007/12/08 09:00 CRDT- 2007/05/08 09:00 PHST- 2006/11/08 00:00 [received] PHST- 2007/03/14 00:00 [revised] PHST- 2007/03/23 00:00 [accepted] PHST- 2007/05/08 09:00 [pubmed] PHST- 2007/12/08 09:00 [medline] PHST- 2007/05/08 09:00 [entrez] AID - S0021-9150(07)00207-9 [pii] AID - 10.1016/j.atherosclerosis.2007.03.035 [doi] PST - ppublish SO - Atherosclerosis. 2007 Nov;195(1):e112-24. doi: 10.1016/j.atherosclerosis.2007.03.035. Epub 2007 May 4. PMID- 17582780 OWN - NLM STAT- MEDLINE DCOM- 20071101 LR - 20151119 IS - 1043-6618 (Print) IS - 1043-6618 (Linking) VI - 56 IP - 2 DP - 2007 Aug TI - Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells. PG - 160-7 AB - Secretion of matrix metalloproteinases (MMPs) by macrophages and smooth muscle cells (SMC) may impair atherosclerotic cap integrity leading to atherosclerosis complications. Selective estrogen receptor modulators (SERMs) have favourable impact on plasma lipid levels, but their role in the prevention of atherosclerosis still remains unclear. We investigated the effects of raloxifene, a second generation SERM, on MMP expression and activity in cultured macrophages and SMC, and in rabbit carotid lesions. Human monocyte-derived macrophages were isolated from blood of healthy donors. SMC were isolated from the intima-media layers of collared rabbit carotid arteries. Cells were incubated for 24h with increasing concentrations of raloxifene. Ovariectomized rabbits fed a 1% cholesterol-rich diet were subjected to pericarotid collar placement and treated with or without 10mgkg(-1)d(-1) raloxifene for 2 weeks. In macrophages, raloxifene treatment (0.1-10microM) significantly reduced MMP-9 gelatinolytic potential in a concentration-dependent manner, without affecting MMP-9 activation. This effect was estrogen receptor (ER)-dependent and due to the inhibition of MMP-9 promoter-driven transcription following an interaction with NF-kB pathway. Similarly, in cultured SMC, raloxifene inhibited up to 40% MMP-2 gelatinolytic activity. In vivo, raloxifene decreased the expression of MMP-2, MMP-3, and MMP-9 by intimal cells and the total gelatinolytic activity of collared carotids. These effects were accompanied by reduction of lesion size and inhibition of macrophage accumulation. Overall, results indicate that raloxifene may reduce MMPs expression and activity in macrophages and smooth muscle cells and favourably affect lesion formation. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Stefano.Bellosta@unimi.it FAU - Baetta, Roberta AU - Baetta R FAU - Canavesi, Monica AU - Canavesi M FAU - Comparato, Carmen AU - Comparato C FAU - Granata, Agnese AU - Granata A FAU - Monetti, Mara AU - Monetti M FAU - Cairoli, Fausto AU - Cairoli F FAU - Eberini, Ivano AU - Eberini I FAU - Puglisi, Lina AU - Puglisi L FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20070516 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Cholesterol, Dietary) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (NF-kappa B) RN - 0 (Protease Inhibitors) RN - 0 (Receptors, Estrogen) RN - 0 (Selective Estrogen Receptor Modulators) RN - 4F86W47BR6 (Raloxifene Hydrochloride) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Atherosclerosis/enzymology/etiology/prevention & control MH - CHO Cells MH - Carotid Arteries/drug effects/enzymology MH - Cells, Cultured MH - Cholesterol, Dietary MH - Cricetinae MH - Cricetulus MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Female MH - Gene Expression Regulation, Enzymologic/drug effects MH - Humans MH - Macrophages/*drug effects/enzymology MH - Macrophages, Peritoneal/*drug effects/enzymology MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 3/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - *Matrix Metalloproteinase Inhibitors MH - Matrix Metalloproteinases/genetics/metabolism MH - Mice MH - Muscle, Smooth, Vascular/cytology/*drug effects/enzymology MH - Myocytes, Smooth Muscle/*drug effects/enzymology MH - NF-kappa B/metabolism MH - Ovariectomy MH - Promoter Regions, Genetic/drug effects MH - Protease Inhibitors/*pharmacology/therapeutic use MH - Rabbits MH - Raloxifene Hydrochloride/*pharmacology/therapeutic use MH - Receptors, Estrogen/drug effects/metabolism MH - Selective Estrogen Receptor Modulators/*pharmacology/therapeutic use MH - Transcription, Genetic/drug effects MH - Transfection EDAT- 2007/06/22 09:00 MHDA- 2007/11/02 09:00 CRDT- 2007/06/22 09:00 PHST- 2007/03/12 00:00 [received] PHST- 2007/05/03 00:00 [revised] PHST- 2007/05/07 00:00 [accepted] PHST- 2007/06/22 09:00 [pubmed] PHST- 2007/11/02 09:00 [medline] PHST- 2007/06/22 09:00 [entrez] AID - S1043-6618(07)00102-8 [pii] AID - 10.1016/j.phrs.2007.05.004 [doi] PST - ppublish SO - Pharmacol Res. 2007 Aug;56(2):160-7. doi: 10.1016/j.phrs.2007.05.004. Epub 2007 May 16. PMID- 17392157 OWN - NLM STAT- MEDLINE DCOM- 20070504 LR - 20181113 IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 170 IP - 4 DP - 2007 Apr TI - Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. PG - 1165-77 AB - Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis. FAU - Gianella, Anita AU - Gianella A AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy. luigi.sironi@unimi.it. FAU - Nobili, Elena AU - Nobili E FAU - Abbate, Mauro AU - Abbate M FAU - Zoja, Carla AU - Zoja C FAU - Gelosa, Paolo AU - Gelosa P FAU - Mussoni, Luciana AU - Mussoni L FAU - Bellosta, Stefano AU - Bellosta S FAU - Canavesi, Monica AU - Canavesi M FAU - Rottoli, Daniela AU - Rottoli D FAU - Guerrini, Uliano AU - Guerrini U FAU - Brioschi, Maura AU - Brioschi M FAU - Banfi, Cristina AU - Banfi C FAU - Tremoli, Elena AU - Tremoli E FAU - Remuzzi, Giuseppe AU - Remuzzi G FAU - Sironi, Luigi AU - Sironi L LA - eng PT - Journal Article PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Actins) RN - 0 (Fluorobenzenes) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Plasminogen Activator Inhibitor 1) RN - 0 (Pyrimidines) RN - 0 (Sulfonamides) RN - 83MVU38M7Q (Rosuvastatin Calcium) RN - 9001-32-5 (Fibrinogen) RN - 9007-34-5 (Collagen) RN - AGG2FN16EV (Simvastatin) RN - EC 3.4.21.- (Plasminogen Activators) RN - EC 3.4.21.7 (Fibrinolysin) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - AIM SB - IM MH - Actins/metabolism MH - Animals MH - Blood Pressure/drug effects MH - Blotting, Western MH - Collagen/metabolism MH - Disease Progression MH - Fibrinogen/metabolism MH - Fibrinolysin/metabolism MH - Fibrosis MH - Fluorobenzenes/administration & dosage/*pharmacology MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage/pharmacology MH - Inflammation/metabolism/physiopathology/*prevention & control MH - Kidney/*drug effects/pathology/ultrastructure MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Microscopy, Electron MH - Plasminogen Activator Inhibitor 1/metabolism MH - Plasminogen Activators/metabolism MH - Podocytes/drug effects/metabolism/pathology MH - Proteinuria/prevention & control MH - Pyrimidines/administration & dosage/*pharmacology MH - Rats MH - Rats, Inbred SHR MH - Rosuvastatin Calcium MH - Simvastatin/administration & dosage/pharmacology MH - Stroke/physiopathology MH - Sulfonamides/administration & dosage/*pharmacology PMC - PMC1829451 EDAT- 2007/03/30 09:00 MHDA- 2007/05/05 09:00 CRDT- 2007/03/30 09:00 PHST- 2007/03/30 09:00 [pubmed] PHST- 2007/05/05 09:00 [medline] PHST- 2007/03/30 09:00 [entrez] AID - S0002-9440(10)61332-6 [pii] AID - 10.2353/ajpath.2007.060882 [doi] PST - ppublish SO - Am J Pathol. 2007 Apr;170(4):1165-77. doi: 10.2353/ajpath.2007.060882. PMID- 17052715 OWN - NLM STAT- MEDLINE DCOM- 20061220 LR - 20141120 IS - 0014-5793 (Print) IS - 0014-5793 (Linking) VI - 580 IP - 25 DP - 2006 Oct 30 TI - Inhibition of MMP-2 activation and release as a novel mechanism for HDL-induced cardioprotection. PG - 5974-8 AB - High density lipoproteins (HDL) protect the heart against ischemia/reperfusion (I/R) injury, and matrix metalloproteinase-2 (MMP-2) directly contributes to cardiac contractile dysfunction after I/R. To investigate the possible involvement of MMP-2 inhibition in HDL-mediated cardioprotection, isolated rat hearts underwent 20 min of low-flow ischemia and 30 min of reperfusion. Plasma-derived and synthetic HDL attenuated the I/R-induced cardiac MMP-2 activation and release in a dose-dependent way. The attenuation of I/R-induced MMP-2 activation by HDL correlated with the reduction of post-ischemic contractile dysfunction and cardiomyocyte necrosis. These results indicate prevention of MMP-2 activation as a novel mechanism for HDL-mediated cardioprotection. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological Sciences, University of Milano, Italy. FAU - Gomaraschi, Monica AU - Gomaraschi M FAU - Canavesi, Monica AU - Canavesi M FAU - Rossoni, Giuseppe AU - Rossoni G FAU - Monetti, Mara AU - Monetti M FAU - Franceschini, Guido AU - Franceschini G FAU - Calabresi, Laura AU - Calabresi L LA - eng PT - Journal Article DEP - 20061012 PL - England TA - FEBS Lett JT - FEBS letters JID - 0155157 RN - 0 (DNA, Complementary) RN - 0 (Lipid Peroxides) RN - 0 (Lipoproteins, HDL) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (Reactive Oxygen Species) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) SB - IM MH - Animals MH - Base Sequence MH - DNA, Complementary/genetics MH - Enzyme Activation/drug effects MH - Humans MH - In Vitro Techniques MH - Lipid Peroxides/metabolism MH - Lipoproteins, HDL/*pharmacology MH - Matrix Metalloproteinase 2/genetics MH - *Matrix Metalloproteinase Inhibitors MH - Myocardial Reperfusion Injury/*enzymology/metabolism/*prevention & control MH - Myocardium/metabolism MH - Rats MH - Reactive Oxygen Species/metabolism EDAT- 2006/10/21 09:00 MHDA- 2006/12/21 09:00 CRDT- 2006/10/21 09:00 PHST- 2006/09/18 00:00 [received] PHST- 2006/10/03 00:00 [accepted] PHST- 2006/10/21 09:00 [pubmed] PHST- 2006/12/21 09:00 [medline] PHST- 2006/10/21 09:00 [entrez] AID - S0014-5793(06)01195-1 [pii] AID - 10.1016/j.febslet.2006.10.006 [doi] PST - ppublish SO - FEBS Lett. 2006 Oct 30;580(25):5974-8. doi: 10.1016/j.febslet.2006.10.006. Epub 2006 Oct 12. PMID- 16621589 OWN - NLM STAT- MEDLINE DCOM- 20061026 LR - 20171116 IS - 1043-6618 (Print) IS - 1043-6618 (Linking) VI - 53 IP - 6 DP - 2006 Jun TI - Hypolipidemic therapy for the metabolic syndrome. PG - 492-500 AB - The metabolic syndrome appears to affect a significant proportion of the population and is associated with increased risk for development of cardiovascular disease as well as of type-2 diabetes. No single treatment for the metabolic syndrome as a whole yet exists. While the primary management of patients with the metabolic syndrome involves healthy lifestyle promotion, the atherogenic dyslipidemia is a primary target for cardiovascular disease risk reduction in these patients. Statin therapy provides effective reduction of LDL-cholesterol, which represents the primary therapeutic goal of lipid-lowering therapy in patients at risk for cardiovascular disease. Fibrates in turn are effective in normalizing lipid levels (mainly triglycerides and HDL-cholesterol) in patients with the metabolic syndrome and may improve insulin resistance. Whereas statins remain the drug of choice for patients who need to achieve the LDL-cholesterol goal, fibrate therapy may represent an alternative for those with low HDL-cholesterol and high triglyceride levels. The simultaneous use of fibrates could be indicated in patients whose LDL-cholesterol is controlled by statin therapy but whose HDL-cholesterol and/or triglycerides are still inappropriate. Such a combination, however, needs careful monitoring due to the potential hazard of adverse drug interactions. Nicotinic acid and ezetimibe may be useful agents for therapy, particularly when combined with statins. A number of emerging therapies offer potential as future options for the pharmacological treatment of metabolic syndrome. FAU - Cignarella, Andrea AU - Cignarella A AD - Department of Pharmacological Sciences, University of Milan, via G. Balzaretti 9, I-20133 Milan, Italy. andrea.cignarella@unimi.it FAU - Bellosta, Stefano AU - Bellosta S FAU - Corsini, Alberto AU - Corsini A FAU - Bolego, Chiara AU - Bolego C LA - eng PT - Journal Article PT - Review DEP - 20060327 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Cholesterol, LDL) RN - 0 (Hypolipidemic Agents) RN - 0 (PPAR alpha) SB - IM MH - Cholesterol, LDL/blood MH - Drug Therapy, Combination MH - Humans MH - Hypolipidemic Agents/*therapeutic use MH - Metabolic Syndrome/blood/*drug therapy MH - PPAR alpha/agonists RF - 79 EDAT- 2006/04/20 09:00 MHDA- 2006/10/27 09:00 CRDT- 2006/04/20 09:00 PHST- 2006/03/15 00:00 [received] PHST- 2006/03/17 00:00 [accepted] PHST- 2006/04/20 09:00 [pubmed] PHST- 2006/10/27 09:00 [medline] PHST- 2006/04/20 09:00 [entrez] AID - S1043-6618(06)00051-X [pii] AID - 10.1016/j.phrs.2006.03.012 [doi] PST - ppublish SO - Pharmacol Res. 2006 Jun;53(6):492-500. doi: 10.1016/j.phrs.2006.03.012. Epub 2006 Mar 27. PMID- 16291014 OWN - NLM STAT- MEDLINE DCOM- 20051215 LR - 20131121 IS - 0002-9149 (Print) IS - 0002-9149 (Linking) VI - 96 IP - 9A DP - 2005 Nov 7 TI - Pharmacokinetic interactions between statins and fibrates. PG - 44K-49K; discussion 34K-35K AB - Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug-drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug-drug interactions and combination therapy. FAU - Corsini, Alberto AU - Corsini A AD - Department of Pharmacological Sciences, University of Milan, Milan, Italy. Alberto.corsini@unimi.it FAU - Bellosta, Stefano AU - Bellosta S FAU - Davidson, Michael H AU - Davidson MH LA - eng PT - Journal Article DEP - 20051021 PL - United States TA - Am J Cardiol JT - The American journal of cardiology JID - 0207277 RN - 0 (Drug Combinations) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 53PF01Q249 (Clofibric Acid) SB - AIM SB - IM MH - Area Under Curve MH - Biological Availability MH - Clofibric Acid/administration & dosage/*pharmacokinetics/therapeutic use MH - Drug Combinations MH - Drug Interactions MH - Dyslipidemias/*drug therapy/metabolism MH - Half-Life MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage/therapeutic use MH - Intestinal Absorption MH - Rhabdomyolysis/chemically induced MH - Risk Factors EDAT- 2005/11/18 09:00 MHDA- 2005/12/16 09:00 CRDT- 2005/11/18 09:00 PHST- 2005/11/18 09:00 [pubmed] PHST- 2005/12/16 09:00 [medline] PHST- 2005/11/18 09:00 [entrez] AID - S0002-9149(05)01370-6 [pii] AID - 10.1016/j.amjcard.2005.08.007 [doi] PST - ppublish SO - Am J Cardiol. 2005 Nov 7;96(9A):44K-49K; discussion 34K-35K. doi: 10.1016/j.amjcard.2005.08.007. Epub 2005 Oct 21. PMID- 16239970 OWN - NLM STAT- MEDLINE DCOM- 20060203 LR - 20181113 IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 115 IP - 11 DP - 2005 Nov TI - PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. PG - 3228-38 AB - Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARalpha is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARalpha controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16(INK4a) (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARalpha activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARalpha activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARalpha inhibits SMC proliferation through p16. Thus, the PPARalpha/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis. FAU - Gizard, Florence AU - Gizard F AD - INSERM U545, Departement d'Atherosclerose, Institut Pasteur de Lille et Faculte de Pharmacie, Universite Lille II, Lille, France. FAU - Amant, Carole AU - Amant C FAU - Barbier, Olivier AU - Barbier O FAU - Bellosta, Stefano AU - Bellosta S FAU - Robillard, Romain AU - Robillard R FAU - Percevault, Frederic AU - Percevault F FAU - Sevestre, Henry AU - Sevestre H FAU - Krimpenfort, Paul AU - Krimpenfort P FAU - Corsini, Alberto AU - Corsini A FAU - Rochette, Jacques AU - Rochette J FAU - Glineur, Corine AU - Glineur C FAU - Fruchart, Jean-Charles AU - Fruchart JC FAU - Torpier, Gerard AU - Torpier G FAU - Staels, Bart AU - Staels B LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (Growth Inhibitors) RN - 0 (PPAR alpha) RN - 0 (Retinoblastoma Protein) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 4) SB - AIM SB - IM MH - Animals MH - Carotid Artery Injuries/genetics/metabolism/pathology MH - *Cell Proliferation MH - Cells, Cultured MH - Cyclin-Dependent Kinase 4/physiology MH - Cyclin-Dependent Kinase Inhibitor p16/*biosynthesis/deficiency/genetics/physiology MH - Down-Regulation/genetics MH - G1 Phase/genetics MH - Growth Inhibitors/deficiency/genetics/*physiology MH - HeLa Cells MH - Humans MH - Hyperplasia MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/*pathology MH - Myocytes, Smooth Muscle/metabolism/pathology MH - PPAR alpha/deficiency/genetics/*physiology MH - Phosphorylation MH - Retinoblastoma Protein/metabolism MH - S Phase/genetics MH - Transcription, Genetic/physiology MH - Tunica Intima/cytology/*pathology MH - *Up-Regulation/genetics PMC - PMC1257531 EDAT- 2005/10/22 09:00 MHDA- 2006/02/04 09:00 CRDT- 2005/10/22 09:00 PHST- 2005/10/22 09:00 [pubmed] PHST- 2006/02/04 09:00 [medline] PHST- 2005/10/22 09:00 [entrez] AID - 10.1172/JCI22756 [doi] PST - ppublish SO - J Clin Invest. 2005 Nov;115(11):3228-38. doi: 10.1172/JCI22756. PMID- 15841324 OWN - NLM STAT- MEDLINE DCOM- 20050913 LR - 20111117 IS - 0340-6245 (Print) IS - 0340-6245 (Linking) VI - 93 IP - 4 DP - 2005 Apr TI - Dietary polyphenols and regulation of gelatinase expression and activity. PG - 751-60 AB - The interaction of cells with the extracellular matrix (ECM) is critical for the normal development and function of organisms. The matrix metalloproteinases (MMPs) are a family of Zn(++) and Ca(++) dependent endopeptidases, which are key mediators of ECM remodelling. The turnover and remodelling of ECM must be tightly regulated, since uncontrolled proteolysis would contribute to abnormal development and to the generation of many pathological conditions characterized by either excessive degradation, or lack of degradation of ECM components. In particular, the gelatinases (MMP-2 and -9) are abundantly expressed in various malignant tumors, play an active role in angiogenesis, and may also influence the process of atherosclerotic lesion formation. In recent years, much consideration has been given to the role of diet in preventing degenerative diseases, such as cancer and cardiovascular diseases. Polyphenols are abundant components/micronutrients of the human diet that have been shown in vitro to profoundly affect ECM turnover by regulating gelatinases expression and activity, acting at both the pre- and post-transcriptional level. Therefore, they could have a beneficial effect in many pathological conditions implicated in connective tissue destruction and remodelling associated with degenerative diseases. FAU - Dell'Agli, Mario AU - Dell'Agli M AD - Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milan, Italy. FAU - Canavesi, Monica AU - Canavesi M FAU - Galli, Germana AU - Galli G FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article PT - Review PL - Germany TA - Thromb Haemost JT - Thrombosis and haemostasis JID - 7608063 RN - 0 (Flavonoids) RN - 0 (Phenols) RN - 0 (Polyphenols) RN - EC 3.4.24.- (Gelatinases) SB - IM MH - Diet MH - Extracellular Matrix/metabolism MH - Flavonoids/*pharmacology MH - Gelatinases/*genetics/metabolism MH - Gene Expression Regulation/*drug effects MH - Humans MH - Phenols/*pharmacology MH - Polyphenols RF - 121 EDAT- 2005/04/21 09:00 MHDA- 2005/09/15 09:00 CRDT- 2005/04/21 09:00 PHST- 2005/04/21 09:00 [pubmed] PHST- 2005/09/15 09:00 [medline] PHST- 2005/04/21 09:00 [entrez] AID - 05040751 [pii] AID - 10.1160/TH04-09-0573 [doi] PST - ppublish SO - Thromb Haemost. 2005 Apr;93(4):751-60. doi: 10.1160/TH04-09-0573. PMID- 15861311 OWN - NLM STAT- MEDLINE DCOM- 20050818 LR - 20131121 IS - 1528-9648 (Print) IS - 1528-9648 (Linking) VI - 4 IP - 4 DP - 2004 Nov TI - Statins effect on smooth muscle cell proliferation. PG - 347-56 AB - Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. FAU - Arnaboldi, Lorenzo AU - Arnaboldi L FAU - Gerosa, Lorenzo AU - Gerosa L FAU - Canavesi, Monica AU - Canavesi M FAU - Parente, Rachele AU - Parente R FAU - Baetta, Roberta AU - Baetta R FAU - Paoletti, Rodolfo AU - Paoletti R FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Review PL - United States TA - Semin Vasc Med JT - Seminars in vascular medicine JID - 100940307 RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Animals MH - Arteries/drug effects/pathology MH - Arteriosclerosis/metabolism/pathology/prevention & control MH - Cell Proliferation/*drug effects MH - Cholesterol/biosynthesis MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology MH - Muscle, Smooth, Vascular/drug effects/*pathology RF - 56 EDAT- 2005/04/30 09:00 MHDA- 2005/08/19 09:00 CRDT- 2005/04/30 09:00 PHST- 2005/04/30 09:00 [pubmed] PHST- 2005/08/19 09:00 [medline] PHST- 2005/04/30 09:00 [entrez] AID - 10.1055/s-2004-869591 [doi] PST - ppublish SO - Semin Vasc Med. 2004 Nov;4(4):347-56. doi: 10.1055/s-2004-869591. PMID- 15454849 OWN - NLM STAT- MEDLINE DCOM- 20050614 LR - 20181130 IS - 0160-2446 (Print) IS - 0160-2446 (Linking) VI - 44 IP - 4 DP - 2004 Oct TI - In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix metalloproteinases secretion by macrophages. PG - 416-22 AB - Plaque rupture and thromboembolism play a major role in atherosclerotic acute syndrome. Experimental studies have demonstrated the potential direct anti-atherosclerotic effects of calcium antagonists. We investigated the in vitro effect of lercanidipine (REC 15/2375), a third-generation, highly lipophilic calcium antagonist on cholesterol metabolism and matrix metalloproteinases secretion in macrophages, two functions that predispose plaques to rupture. Lercanidipine (10(-6)-10(-5) M) inhibited cholesterol esterification in macrophages and reduced cellular free and esterified cholesterol accumulation from acetylated LDL (63%, 62% of control P < 0.05, respectively). In addition, lercanidipine inhibited the release of metalloproteinases in the extracellular medium (50% and 95% inhibition at 10(-5) M for MMP-9 and MMP-2, respectively). Experiments performed with lercanidipine enantiomers or other dihydropyridine derivatives, endowed with different lipophilicity and affinity for calcium channels, indicated that the above effects could be related to the lipophilic, but not to the calcium channel blocking properties of these molecules. When cells, after exposure to the drug, were allowed to equilibrate, lercanidipine inhibitory action could be observed at initial concentrations as low as 10(-9) M, which is the actual concentration range observed in plasma in clinical settings. In conclusion, our data indicate that lercanidipine may exert potent anti-atherosclerotic effects by inhibiting macrophage functions involved in plaque stability. FAU - Canavesi, Monica AU - Canavesi M AD - Department of Pharmacological Sciences, University of Milan, Milan 20133, Italy. FAU - Baldini, Novella AU - Baldini N FAU - Leonardi, Amedeo AU - Leonardi A FAU - Sironi, Giorgio AU - Sironi G FAU - Bellosta, Stefano AU - Bellosta S FAU - Bernini, Franco AU - Bernini F LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Cardiovasc Pharmacol JT - Journal of cardiovascular pharmacology JID - 7902492 RN - 0 (Calcium Channel Blockers) RN - 0 (Cholesterol Esters) RN - 0 (Dihydropyridines) RN - 97C5T2UQ7J (Cholesterol) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - V7XTJ4R0BH (lercanidipine) SB - IM MH - Animals MH - Calcium Channel Blockers/*pharmacology MH - Cells, Cultured MH - Cholesterol/*metabolism MH - Cholesterol Esters/metabolism MH - Dihydropyridines/*pharmacology MH - Electrophoresis, Polyacrylamide Gel MH - Humans MH - In Vitro Techniques MH - Macrophages, Peritoneal/*metabolism MH - Matrix Metalloproteinases/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Monocytes/metabolism MH - Species Specificity EDAT- 2004/09/30 05:00 MHDA- 2005/06/15 09:00 CRDT- 2004/09/30 05:00 PHST- 2004/09/30 05:00 [pubmed] PHST- 2005/06/15 09:00 [medline] PHST- 2004/09/30 05:00 [entrez] AID - 00005344-200410000-00002 [pii] PST - ppublish SO - J Cardiovasc Pharmacol. 2004 Oct;44(4):416-22. PMID- 15198967 OWN - NLM STAT- MEDLINE DCOM- 20041018 LR - 20161124 IS - 1524-4539 (Electronic) IS - 0009-7322 (Linking) VI - 109 IP - 23 Suppl 1 DP - 2004 Jun 15 TI - Safety of statins: focus on clinical pharmacokinetics and drug interactions. PG - III50-7 AB - Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions. FAU - Bellosta, Stefano AU - Bellosta S AD - Department of Pharmacological Sciences, University of Milan, Milan, Italy. FAU - Paoletti, Rodolfo AU - Paoletti R FAU - Corsini, Alberto AU - Corsini A LA - eng PT - Journal Article PT - Review PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (Calcium Channel Blockers) RN - 0 (Cytochrome P-450 Enzyme Inhibitors) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (CYP3A protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - EC 1.14.14.1 (Cytochrome P-450 CYP3A) RN - Q8X02027X3 (Gemfibrozil) RN - U202363UOS (Fenofibrate) SB - AIM SB - IM MH - Binding, Competitive MH - Biological Availability MH - Calcium Channel Blockers/pharmacokinetics MH - Chemical and Drug Induced Liver Injury MH - Citrus MH - Cytochrome P-450 CYP2D6/genetics MH - Cytochrome P-450 CYP3A MH - Cytochrome P-450 Enzyme Inhibitors MH - Cytochrome P-450 Enzyme System/physiology MH - Drug Interactions MH - Fenofibrate/pharmacokinetics MH - Gemfibrozil/pharmacokinetics MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacokinetics MH - Liver Function Tests MH - Polymorphism, Genetic MH - Polymyositis/chemically induced MH - Rhabdomyolysis/chemically induced RF - 65 EDAT- 2004/06/17 05:00 MHDA- 2004/10/19 09:00 CRDT- 2004/06/17 05:00 PHST- 2004/06/17 05:00 [pubmed] PHST- 2004/10/19 09:00 [medline] PHST- 2004/06/17 05:00 [entrez] AID - 10.1161/01.CIR.0000131519.15067.1f [doi] AID - 109/23_suppl_1/III-50 [pii] PST - ppublish SO - Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7. doi: 10.1161/01.CIR.0000131519.15067.1f. PMID- 14502637 OWN - NLM STAT- MEDLINE DCOM- 20040226 LR - 20090804 IS - 0947-6539 (Print) IS - 0947-6539 (Linking) VI - 9 IP - 18 DP - 2003 Sep 22 TI - Synthesis, structure and conformation of partially-modified retro- and retro-inverso psi[NHCH(CF3)]Gly peptides. PG - 4510-22 AB - Partially modified retro- (PMR) and retro-inverso (PMRI) psi[NHCH(CF(3))]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF(3))]Gly tripeptides have been studied in solution by (1)H NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH(2)-CH(CF(3))-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF(3) group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl(3) solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF(3))NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF(3))NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF(3))-NH-CH backbone angle close to 120 degrees, C-CF(3) bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O(-))NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF(3) group, tetrahedral backbone carbon). FAU - Volonterio, Alessandro AU - Volonterio A AD - C.N.R.-Dipartimento di Chimica, Materiali ed Ingegneria Chimica "G. Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy. FAU - Bellosta, Stefano AU - Bellosta S FAU - Bravin, Fabio AU - Bravin F FAU - Bellucci, Maria Cristina AU - Bellucci MC FAU - Bruche, Luca AU - Bruche L FAU - Colombo, Giorgio AU - Colombo G FAU - Malpezzi, Luciana AU - Malpezzi L FAU - Mazzini, Stefania AU - Mazzini S FAU - Meille, Stefano V AU - Meille SV FAU - Meli, Massimiliano AU - Meli M FAU - Ramirez De Arellano, Carmen AU - Ramirez De Arellano C FAU - Zanda, Matteo AU - Zanda M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Germany TA - Chemistry JT - Chemistry (Weinheim an der Bergstrasse, Germany) JID - 9513783 RN - 0 (Oligopeptides) RN - 0 (Solutions) SB - IM MH - Biochemistry/methods MH - Crystallography, X-Ray MH - Magnetic Resonance Spectroscopy MH - Models, Chemical MH - Models, Molecular MH - Molecular Structure MH - Oligopeptides/*chemical synthesis/*chemistry MH - *Protein Conformation MH - Protein Structure, Secondary MH - Reproducibility of Results MH - Solutions MH - Temperature EDAT- 2003/09/23 05:00 MHDA- 2004/02/27 05:00 CRDT- 2003/09/23 05:00 PHST- 2003/09/23 05:00 [pubmed] PHST- 2004/02/27 05:00 [medline] PHST- 2003/09/23 05:00 [entrez] AID - 10.1002/chem.200304881 [doi] PST - ppublish SO - Chemistry. 2003 Sep 22;9(18):4510-22. doi: 10.1002/chem.200304881. PMID- 12742636 OWN - NLM STAT- MEDLINE DCOM- 20030722 LR - 20081121 IS - 0006-8993 (Print) IS - 0006-8993 (Linking) VI - 974 IP - 1-2 DP - 2003 Jun 6 TI - Endogenous proteolytic activity in a rat model of spontaneous cerebral stroke. PG - 184-92 AB - We evaluated the expression of two extra-cellular protease systems in a model of spontaneous cerebrovascular pathology: spontaneously hypertensive stroke-prone rats (SHRSP). The appearance of brain damage in individual animals was imaged and followed by means of magnetic resonance imaging (MRI). In situ zymography of brain slices obtained 3 days after the appearance of brain damage showed an increase in plasminogen activator (PA)/plasmin activity that co-localised with the cerebral damage detected by MRI; there was also concomitant accumulation/activation of inflammatory cells in the damaged area. Proteolytic activity was inhibited by the urokinase-specific inhibitor amiloride but not by an antibody against tissue-type plasminogen activator (t-PA). SDS-PAGE zymography of brain extracts revealed the presence of 58 kDa plasminogen-dependent lysis areas in the ischemic and non-ischemic tissues, and a 33 kDa lysis area in ischemic tissue only. An antibody against t-PA inhibited the former, whereas the latter was inhibited by amiloride. The specific induction of urokinase-type plasminogen activator (u-PA) in the damaged tissue was further confirmed by the fact that both u-PA protein mass and mRNA were markedly increased in the damaged cerebral areas. Concomitant metalloproteinase-2 (MMP-2) activation was only observed in the damaged area. These data suggest that u-PA is expressed and selectively catalyses proteolysis in the injured area of spontaneous brain damage in SHRSP. FAU - Sironi, Luigi AU - Sironi L AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Italy. FAU - Maria Calvio, Anna AU - Maria Calvio A FAU - Bellosta, Stefano AU - Bellosta S FAU - Lodetti, Barbara AU - Lodetti B FAU - Guerrini, Uliano AU - Guerrini U FAU - Monetti, Mara AU - Monetti M FAU - Tremoli, Elena AU - Tremoli E FAU - Mussoni, Luciana AU - Mussoni L LA - eng PT - Journal Article PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - EC 3.4.- (Endopeptidases) RN - EC 3.4.21.68 (Tissue Plasminogen Activator) RN - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) SB - IM MH - Animals MH - Blotting, Western MH - Electrophoresis, Polyacrylamide Gel MH - Endopeptidases/analysis/*metabolism MH - Magnetic Resonance Imaging MH - Matrix Metalloproteinase 2/biosynthesis/genetics MH - Rats MH - Rats, Inbred SHR MH - Reverse Transcriptase Polymerase Chain Reaction MH - Stroke/*enzymology/genetics/pathology MH - Tissue Plasminogen Activator/metabolism MH - Urokinase-Type Plasminogen Activator/metabolism EDAT- 2003/05/14 05:00 MHDA- 2003/07/23 05:00 CRDT- 2003/05/14 05:00 PHST- 2003/05/14 05:00 [pubmed] PHST- 2003/07/23 05:00 [medline] PHST- 2003/05/14 05:00 [entrez] AID - S0006899303025782 [pii] PST - ppublish SO - Brain Res. 2003 Jun 6;974(1-2):184-92. PMID- 12615660 OWN - NLM STAT- MEDLINE DCOM- 20040115 LR - 20061115 IS - 1524-4636 (Electronic) IS - 1079-5642 (Linking) VI - 23 IP - 4 DP - 2003 Apr 1 TI - Rupture of the atherosclerotic plaque: does a good animal model exist? PG - 535-42 AB - By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability. FAU - Cullen, Paul AU - Cullen P AD - Institute of Arteriosclerosis Research, Domagkstrasse 3, D-48149 Muenster, Germany. cullen@uni-muenster.de FAU - Baetta, Roberta AU - Baetta R FAU - Bellosta, Stefano AU - Bellosta S FAU - Bernini, Franco AU - Bernini F FAU - Chinetti, Giulia AU - Chinetti G FAU - Cignarella, Andrea AU - Cignarella A FAU - von Eckardstein, Arnold AU - von Eckardstein A FAU - Exley, Andrew AU - Exley A FAU - Goddard, Martin AU - Goddard M FAU - Hofker, Marten AU - Hofker M FAU - Hurt-Camejo, Eva AU - Hurt-Camejo E FAU - Kanters, Edwin AU - Kanters E FAU - Kovanen, Petri AU - Kovanen P FAU - Lorkowski, Stefan AU - Lorkowski S FAU - McPheat, William AU - McPheat W FAU - Pentikainen, Markku AU - Pentikainen M FAU - Rauterberg, Jurgen AU - Rauterberg J FAU - Ritchie, Andrew AU - Ritchie A FAU - Staels, Bart AU - Staels B FAU - Weitkamp, Benedikt AU - Weitkamp B FAU - de Winther, Menno AU - de Winther M CN - MAFAPS Consortium LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20030206 PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 SB - IM MH - Aged MH - Animals MH - Arteriosclerosis/complications/*pathology MH - Columbidae MH - Coronary Thrombosis/etiology MH - Dogs MH - Humans MH - Mice MH - Middle Aged MH - *Models, Animal MH - Rabbits MH - Rats MH - Rupture, Spontaneous MH - Species Specificity MH - Swine MH - Thromboembolism/etiology RF - 91 EDAT- 2003/03/05 04:00 MHDA- 2004/01/16 05:00 CRDT- 2003/03/05 04:00 PHST- 2003/03/05 04:00 [pubmed] PHST- 2004/01/16 05:00 [medline] PHST- 2003/03/05 04:00 [entrez] AID - 10.1161/01.ATV.0000060200.73623.F8 [doi] AID - 01.ATV.0000060200.73623.F8 [pii] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):535-42. doi: 10.1161/01.ATV.0000060200.73623.F8. Epub 2003 Feb 6. PMID- 12441888 OWN - NLM STAT- MEDLINE DCOM- 20030612 LR - 20041117 IS - 0957-9672 (Print) IS - 0957-9672 (Linking) VI - 13 IP - 6 DP - 2002 Dec TI - Safety considerations for statins. PG - 637-44 AB - PURPOSE OF REVIEW: The hydroxymethyl glutaryl coenzyme A reductase inhibitors or statins offer important benefits for the large populations of individuals at high risk for coronary heart disease. These drugs have a good safety profile. Nevertheless, differences in physicochemical and pharmacokinetic properties between statins may translate into significant differences in long-term safety. This review focuses on long-term adverse effects related to statin use, namely hepatotoxicity and myopathy. Moreover, the most common drugs used in combination with statins in long-term therapies are analyzed in terms of possible drug/drug interactions affecting the safety of statins. RECENT FINDINGS: The withdrawal of cerivastatin from the global market in 2001, because of severe cases of rhabdomyolysis, highlighted concerns regarding the safety of the entire class. Afterwards, the role of statins and their interactions with other drugs in precipitating this condition have been carefully reviewed. In approximately 60% of the total number of cases, statin-related rhabdomyolysis was found to be related to drug/drug interactions. Recently, all cases of fatal rhabdomyolysis associated with statin use have been reported to the US Food and Drug Administration. This has shown that fatal rhabdomyolysis among statin users is a rare event, the reporting rates being much less than one death per million prescriptions in the case of all statins except cerivastatin. SUMMARY: The safety and tolerability of the available statins support their use as the first-line treatment of patients at high risk for coronary heart disease, since the clinical benefits greatly outweigh the small risk of myopathy. Nevertheless, clinicians should be aware of the adverse effects possibly related to statin therapy, particularly in patients at high risk for coronary heart disease and requiring long-term multiple-drug therapies. CI - Copyright 2002 Lippincott Williams & Wilkins FAU - Bolego, Chiara AU - Bolego C AD - Department of Pharmacological Sciences, University of Milan, Italy. FAU - Baetta, Roberta AU - Baetta R FAU - Bellosta, Stefano AU - Bellosta S FAU - Corsini, Alberto AU - Corsini A FAU - Paoletti, Rodolfo AU - Paoletti R LA - eng PT - Journal Article PT - Review PL - England TA - Curr Opin Lipidol JT - Current opinion in lipidology JID - 9010000 RN - 0 (Anticholesteremic Agents) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) SB - IM MH - Anticholesteremic Agents/administration & dosage/therapeutic use MH - Drug Interactions MH - Drug Therapy, Combination MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacokinetics/pharmacology MH - Liver/drug effects/enzymology MH - Muscular Diseases/chemically induced MH - Rhabdomyolysis/chemically induced MH - Risk Factors RF - 71 EDAT- 2002/11/21 04:00 MHDA- 2003/06/13 05:00 CRDT- 2002/11/21 04:00 PHST- 2002/11/21 04:00 [pubmed] PHST- 2003/06/13 05:00 [medline] PHST- 2002/11/21 04:00 [entrez] AID - 10.1097/01.mol.0000044007.02154.c3 [doi] PST - ppublish SO - Curr Opin Lipidol. 2002 Dec;13(6):637-44. doi: 10.1097/01.mol.0000044007.02154.c3. PMID- 12402661 OWN - NLM STAT- MEDLINE DCOM- 20021218 LR - 20151119 IS - 0393-9340 (Print) IS - 0393-9340 (Linking) VI - 17 IP - 3 DP - 2002 Jul-Sep TI - [Rhabdomyolysis]. PG - 146-8 FAU - Corsini, Alberto AU - Corsini A FAU - Bellosta, Stefano AU - Bellosta S LA - ita PT - Editorial PT - Review TT - La rabdiomiolisi. PL - Italy TA - Ann Ital Med Int JT - Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna JID - 8806705 RN - 0 (Bicarbonates) RN - 0 (Biomarkers) RN - 0 (Diuretics) RN - 0 (Electrolytes) RN - 0 (Isoenzymes) RN - 0 (Muscle Proteins) RN - 3OWL53L36A (Mannitol) RN - EC 2.7.3.2 (Creatine Kinase) RN - EC 2.7.3.2 (Creatine Kinase, MM Form) SB - IM MH - Acute Kidney Injury/etiology/prevention & control MH - Bicarbonates/therapeutic use MH - Biomarkers MH - Creatine Kinase/blood MH - Creatine Kinase, MM Form MH - Diuretics/therapeutic use MH - Electrolytes/blood MH - Fluid Therapy MH - Heart Arrest/etiology MH - Humans MH - Isoenzymes/blood MH - Mannitol/therapeutic use MH - Muscle Proteins/blood MH - *Rhabdomyolysis/complications/diagnosis/etiology/therapy MH - Wounds and Injuries/complications RF - 9 EDAT- 2002/10/31 04:00 MHDA- 2002/12/19 04:00 CRDT- 2002/10/31 04:00 PHST- 2002/10/31 04:00 [pubmed] PHST- 2002/12/19 04:00 [medline] PHST- 2002/10/31 04:00 [entrez] PST - ppublish SO - Ann Ital Med Int. 2002 Jul-Sep;17(3):146-8. PMID- 12044584 OWN - NLM STAT- MEDLINE DCOM- 20021204 LR - 20181130 IS - 1567-5688 (Print) IS - 1567-5688 (Linking) VI - 3 IP - 1 DP - 2002 May TI - Pharmacological interactions of statins. PG - 35-40 AB - The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of coronary events, and are generally very well tolerated. However, simvastatin, lovastatin, cerivastatin and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4, and clinical experience has shown that the risk of adverse effect, such as myopathy, increases with concomitant use of statins with drugs that substantially inhibit CYP 3A4 at therapeutic doses. Indeed, pharmacokinetic interactions (e.g. increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of atorvastatin, cerivastatin, simvastatin or lovastatin and cyclosporine A, mibefradil or nefazodone. In contrast, fluvastatin (mainly metabolized by CYP 2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, an increase in pravastatin bioavailability has been reported in the presence of cyclosporine A, possibly because of an interaction at the level of biliary excretion. In summary, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy. FAU - Paoletti, Rodolfo AU - Paoletti R AD - Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. rodolfo.paoletti@unimi.it FAU - Corsini, Alberto AU - Corsini A FAU - Bellosta, Stefano AU - Bellosta S LA - eng PT - Journal Article PT - Review PL - Netherlands TA - Atheroscler Suppl JT - Atherosclerosis. Supplements JID - 100973461 RN - 0 (Heptanoic Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Pyrroles) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - 9LHU78OQFD (Lovastatin) RN - A0JWA85V8F (Atorvastatin) SB - IM MH - Atorvastatin MH - Cytochrome P-450 Enzyme System/*drug effects MH - Drug Interactions MH - Drug Tolerance MH - Heptanoic Acids/adverse effects/pharmacology/therapeutic use MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology/therapeutic use MH - Hypercholesterolemia/*drug therapy MH - Lovastatin/*adverse effects/pharmacology/therapeutic use MH - Muscular Diseases/*etiology MH - Pyrroles/adverse effects/pharmacology/therapeutic use MH - Rhabdomyolysis/etiology RF - 41 EDAT- 2002/06/05 10:00 MHDA- 2002/12/05 04:00 CRDT- 2002/06/05 10:00 PHST- 2002/06/05 10:00 [pubmed] PHST- 2002/12/05 04:00 [medline] PHST- 2002/06/05 10:00 [entrez] AID - S1567-5688(02)00002-8 [pii] PST - ppublish SO - Atheroscler Suppl. 2002 May;3(1):35-40.