Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction

Hudson, Michael; Armstrong, Paul W.; Rużyłło, Witold; Brum, José M.; Cusmano, Lisa; Krzeski, Piotr; Lyon, Robert A.; Quiñones, Miguel Á.; Théroux, Pierre; Sydlowski, Diana; Kim, Henry E.; García, Mario J.; Jaber, Wael A.; Weaver, W. Douglas

doi:10.1016/j.jacc.2006.02.055

Cited by 196 publications

(151 citation statements)

References 31 publications

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“…In patients with myocardial infarction, therapeutic interventions directly targeting ECM metabolism through MMP inhibition have produced mixed results. Administration of a selective oral MMP inhibitor in patients with STEMI and reduced ejection fraction showed no significant protection from adverse remodeling (132), despite significant antiremodeling effects in animal models. In contrast, early nonselective MMP inhibition with doxycycline attenuated progression to dilative remodeling in patients with STEMI and left ventricular dysfunction (133).…”

Section: Therapeutic Ecm Targeting In Injured and Remodeling Myocardiummentioning

confidence: 91%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

390

318

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Section: Therapeutic Ecm Targeting In Injured and Remodeling Myocardiummentioning

confidence: 91%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

390

318

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“…To date the pharmaceutical industry has failed to provide effective and safe DMOADs for clinical use [13]. The main reasons are that despite their specific targeted action DMOADs still can cause side effects when administered systemically [14][15][16], or when injected intra-articular have a short residence time within the joint [17,18]. It remains unclear how long particular drugs have to remain in the joint for an effective pain relief and/or disease modification after an intra-articular injection.…”

Section: Clinical Needsmentioning

confidence: 99%

Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

et al. 2014

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Osteoarthritis (OA) is a big burden of disease worldwide and one of the most common causes of disability in the adult population. Currently applied therapies consist of physical therapy, oral medication, intra-articular injections, and surgical interventions, with the main goal being to reduce pain and improve function and quality of life. Intra-articular (IA) administration of drugs has potential benefits in OA treatment because it minimizes systemic bioavailability and side effects associated with oral administration of drugs without compromising the therapeutic effect in the joint. However, IA drug residence time is short and there is a clinical need for a vehicle that is able to provide a sustained release long enough for IA therapy to fulfill its promise. This review summarizes the use of different polymeric systems and the incorporated drugs for IA drug delivery in the osteoarthritic joint with a primary focus on clinical needs and opportunities.

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“…Increased MMPs activation (such as MMP-1, -2, -3, -8, -9 and -14) is a well-accepted pathway leading to early ECM damage and LV remodeling [21]. The inhibition of MMPs by synthetic inhibitors has been shown to be able to reduce post-infarction adverse remodeling in animals [22][23][24][25], but not in humans [26].…”

Section: Discussionmentioning

confidence: 99%

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial

Cerisano

Buonamici

Parodi

et al. 2017

International Journal of Cardiology

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Aim: Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). Methods and results: Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p = 0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p = 0.026), doxycycline (p = 0.033), and on admission to pre-discharge LVEF changes (p = 0.044) were found to be associated with predischarge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. Conclusions: In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI.© 2017 Elsevier B.V. All rights reserved. . Thus, a major unresolved question is how to optimally manage AMI patients having advanced LV diastolic dysfunction [6].For the first time in the clinical setting, the TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodeling) trial [7] demonstrated that a timely, short-term therapy with doxycycline is safe and able to induce a significant decrease in LV dilation in patients successfully treated with primary percutaneous coronary intervention (pPCI) for a first ST-elevation AMI (STEMI) and LV dysfunction. Several pleiotropic properties of International Journal of Cardiology xxx (2017) xxx-xxx Abbreviations: STEMI, ST-elevation myocardial infarction; MMPs, mealloproteinases; NFP, normal filling pressure; HFP, high filling pressure; E-wave, transmitral early peak velocity; A-wave, transmitral late peak velocity; DT, deceleration time of transmitral early peak velocity; E', early peak velocity on the septal side of the mitral annulus; Vp, left ventricular flow propagation velocity during early filling; LVEDVi, left ventricular end diastolic volume index; LVESVi, left ventricular end systolic vo...

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Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction

Abstract: Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI.

Cited by 196 publications

References 31 publications

The extracellular matrix in myocardial injury, repair, and remodeling

The extracellular matrix in myocardial injury, repair, and remodeling

Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial

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