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Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

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Drug Eluting Stents: On MIT‘s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Author: Larry H Bernstein, MD, FACP

and

Curator: Aviva Lev-Ari, PhD, RN
http://PharmaceuticalIntelligence.com/2013/04/25/Contributions
-to-vascular-biology/

This is the first of a three part series on the evolution of vascular biology and the studies of the effects of biomaterials in vascular reconstruction and on drug delivery, which has embraced a collaboration of cardiologists at Harvard Medical School , Affiliated Hospitals, and MIT, requiring cardiovascular scientists at the PhD and MD level, physicists, and computational biologists working in concert, and an exploration of the depth of the contributions by a distinguished physician, scientist, and thinker.

The first part – Vascular Biology and Disease – will cover the advances in the research on

vascular biology,
signaling pathways,
drug diffusion across the endothelium and
the interactions with the underlying muscularis (media),
with additional considerations for type 2 diabetes mellitus.

The second part – Stents and Drug Delivery – will cover the

purposes,
properties and
evolution of stent technology with
the acquired knowledge of the pharmacodynamics of drug interactions and drug distribution.

The third part – Problems and Promise of Biomaterials Technology – will cover the shortcomings of the cardiovascular devices, and opportunities for improvement

Vascular Biology and Cardiovascular Disease

Early work on endothelial injury and drug release principles

The insertion of a catheter for the administration of heparin is not an innocuous procedure. Heparin is infused to block coagulation, lowering the risk of a dangerous

clot formation and
dissemination.

It was shown experimentally that the continuous infusion of heparin

suppresses smooth muscle proliferation after endothelial injury. It may lead to
hemorrhage as a primary effect.

The anticoagulant property of heparin was removed by chemical modification without loss of the anti-proliferative effect.

In this study, MIT researches placed ethylene-vinyl acetate copolymer matrices containing standard and modified heparin adjacent to rat carotid arteries at the time of balloon deendothelialization.

Matrix delivery of both heparin compounds effectively diminished this proliferation in comparison to controls without producing systemic anticoagulation or side effects.

This mode of therapy appeared more effective than administering the agents by either

intravenous pumps or

heparin/polymer matrices placed in a subcutaneous site distant from the injured carotid artery

This indicated that the site of placement at the site of injury is a factor in the microenvironment, and is a preference for avoiding restenosis after angioplasty and other interventions.

This raised the question of why the proliferation of vascular muscle occurs in the first place.  Edelman, Nugent and Karnovsky (1) showed that the proliferation required first the denudation of vascular surface endothelium. This exposed the underlayer to the effect of basic fibroblast growth factor, which stimulates mitogenesis of the exposed cell, explained by the endothelium as a barrier from circulating bFGF.

To answer this question, they compared the effect of

125I-labelled bFGF intravenously given with perivascular controlled bFGF release.
Polymeric controlled release devices delivered bFGF to the extravascular space without transendothelial transport.  Deposition within the blood vessel wall was rapidly distributed circumferentially and was substantially greater than that observed following intravenous injection.

The amount of bFGF deposited in arteries adjacent to the release devices was 40 times that deposited in similar arteries in animals who received a single intravenous bolus of bFGF.

The presence of intimal hyperplasia increased deposition of perivascularly released bFGF 2.4-fold but decreased the deposition of intravenously injected bFGF by 67%.

bFGF was 5- to 30-fold more abundant in solid organs after intravenous injection than it was following perivascular release, and
bFGF deposition was greatest in the kidney, liver, and spleen and was substantially lower in the heart and lung.

This result indicated that vascular deposition of bFGF is independent of endothelium, and

bFGF delivery is effectively perivascular. (2)

Drug activity studies have to be done in well controlled and representative conditions.  Edelsman’s Lab researchers studied the

dose response of injured arteries to exogenous heparin in vivo by providing steady and predictable arterial levels of drug.
Controlled-release devices were fabricated to direct heparin uniformly and at a steady rate to the adventitial surface of balloon-injured rat carotid arteries.

Researchers predicted the distribution of heparin throughout the arterial wall using computational simulations and correlated these concentrations with the biologic response of the tissues.

Researchers determined from this process that an in vivo arterial concentration of 0.3 mg/ml of heparin is required to maximallyinhibit intimal hyperplasia after injury.

This estimation of the required tissue concentration of a drug is

independent of the route of administration and
applies to all forms of drug release.

In this way the Team was able to

evaluate the potential of widely disparate forms of drug release and, to finally
create some rigorous criteria by which to guide the development of particular delivery strategies for local diseases. (3)

Chiefly, the following three effects:

(1) Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. ER Edelman, DH Adams, and MJ Karnovsky. PNAS May 1990; 87: 3773-3777. 

(2) Perivascular and intravenous administration of basic fibroblast growth factor: Vascular and solid organ deposition. ER Edelman, MA Nugent, and MJ Karnovsky. PNAS Feb 1993; 90: 1513-1517. 

(3) Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo. MA Lovich and ER Edelman. PNAS Sep 1999; 96: 11111–11116.

Vascular Injury and Repair

Perlecan is a heparin-sulfate proteoglycan that might be critical for regulation of vascular repair by inhibiting the binding and mitogenic activity of basic fibroblast growth factor-2 (bFGF-2) in vascular smooth muscle cells .

The Team generated

Clones of endothelial cells expressing an antisense vector targeting domain III of perlecan. The transfected cells produced significantly less perlecan than parent cells, and they had reduced bFGF in vascular smooth muscle cells.
Endothelial cells were seeded onto three-dimensional polymeric matrices and implanted adjacent to porcine carotid arteries subjected to deep injury.
The parent endothelial cells prevented thrombosis, but perlecan deficient cells were ineffective.

The ability of endothelial cells to inhibit intimal hyperplasia, however, was only in part suppressed by perlecan. The differential regulation by perlecan of these aspects of vascular repair may clarify why control of clinical clot formation does not lead to full control of intimal hyperplasia.

The use of genetically modified tissue engineered cells provides a new approach for dissecting the role of specific factors within the blood vessel wall.(1) Successful implementation of local arterial drug delivery requires transmural distribution of drug. The physicochemical properties of the applied compound govern its transport and tissue binding.

Hydrophilic compounds are cleared rapidly.
Hydrophobic drugs bind to fixed tissue elements, potentially prolonging tissue residence and biological effect.

Local vascular drug delivery provides

elevated concentrations of drug in the target tissue while
minimizing systemic side effects.

To better characterize local pharmacokinetics the Team examined the arterial transport of locally applied dextran and dextran derivatives in vivo.

Using a two-compartment pharmacokinetic model to correct

The measured transmural flux of these compounds for systemic
Redistribution and elimination as delivered from a photo-polymerizable hydrogel.
The diffusivities and the transendothelial permeabilities were strongly dependent on molecular weight and charge
For neutral dextrans, the diffusive resistance increased with molecular weightapproximately 4.1-fold between the molecular weights of 10 and 282 kDa.
Endothelial resistance increased 28-fold over the same molecular weight range.
The effective medial diffusive resistance was unaffected by cationic charge as such molecules moved identically to neutral compounds, but increased approximately 40% when dextrans were negatively charged.

Transendothelial resistance was 20-fold lower for the cationic dextrans, and 11-fold higher for the anionic dextrans, when both were compared to neutral counterparts.

These results suggest that, while

low molecular weight drugs will rapidly traverse the arterial wall with the endothelium posing a minimal barrier,

the reverse is true for high molecular weight agents.

The deposition and distribution of locally released vascular therapeutic compounds might be predicted based upon chemical properties, such as molecular weight and charge. (2)

Paclitaxel is hydrophobic and has therapeutic potential against proliferative vascular disease.  The favorable preclinical data with this compound may, in part, result from preferential tissue binding.  The complexity of Paclitaxel pharmacokinetics required in-depth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.

Equilibrium distribution of Paclitaxel reveals partitioning above and beyond perfusate concentration and a spatial gradient of drug across the arterial wall.

The effective diffusivity (Deff) was estimated from the Paclitaxel distribution data to

facilitate comparison of transport of Paclitaxel through arterial parenchyma with that of other vasoactive agents and to
characterize the disparity between endovascular and perivascular application of drug.

This transport parameter described the motion of drug in tissues given an applied concentration gradient and includes, in addition to diffusion,

the impact of steric hindrance within the arterial interstitium;
nonspecific binding to arterial elements; and, in the preparation used here,
convective effects from the applied transmural pressure gradient.

At all times, the effective diffusivity for endovascular delivery exceeded that of perivascular delivery. The arterial transport of Paclitaxel was quantified through application ex vivo and measurement of the subsequent transmural distribution.

Arterial Paclitaxel deposition at equilibrium varied across the arterial wall.
Permeation into the wall increased with time, from 15 minutes to 4 hours, and
varied with the origin of delivery.

In contrast to hydrophilic compounds, the concentration in tissue exceeded the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and perivascular Paclitaxel application led to differences in deposition across the blood vessel wall.

This leads to a conclusion that Paclitaxel interacts with arterial tissue elements as it moves under the forces of

diffusion and
convection and
can establish substantial partitioning and spatial gradients across the tissue. (3)

Endovascular drug-eluting stents have changed the practice of cardiovascular vascularization, and yet it is unclear how they so dramatically reduce restenosis

We don’t know how to distinguish between the different formulations available.  Researchers are now questioning whether individual properties of different drugs beyond lipid avidity effect arterial transport and distribution.

In bovine internal carotid segments, tissue-loading profiles for

Hydrophobic Paclitaxel and Rapamycin are indistinguishable, reaching load steady state after 2 days.
Hydrophilic dextran reaches equilibrium in hours.

Paclitaxel and Rapamycin bind to the artery at 30–40 times bulk concentration, and bind to specific tissue elements.

Transmural drug distribution profiles are markedly different for the two compounds.

Rapamycin binds specifically to FKBP12 binding protein and it distributes evenly through the artery,
Paclitaxel binds specifically to microtubules, and remains primarily in the subintimal space.

The binding of Rapamycin and Paclitaxel to specific intracellular proteins plays an essential role in

determining arterial transport and distribution and in
distinguishing one compound from another.

These results offer further insight into the

mechanism of local drug delivery and the
specific use of existing drug-eluting stent formulations. (4)

The Role of Amyloid beta (A) in Creation of Vascular Toxic Plaque

Amyloid beta (A) is a peptide family produced and deposited in neurons and endothelial cells (EC). It is found at subnanomolar concentrations in the plasma of healthy individuals.  Simple conformational changes produce a form of A-beta , A-beta 42, which creates toxic plaque in the brains of Alzheimer’s patients.

Oxidative stress induced blood brain barrier degeneration has been proposed as a key factor for A-beta 42 toxicity.

This cannot account for lack of injury from the same peptide in healthy tissues. Researchers hypothesized that cell state mediates A-beta’s effect.  They examined the viability in the presence of A-beta secreted from transfected Chinese hamster ovary cells (CHO) of

aortic Endothelial Cells (EC),
vascular smooth muscle cells (SMC) and
epithelial cells (EPI) in different states

A-beta was more toxic to all cell types when they were subconfluent.  Subconfluent EC sprouted and SMC and EPI were inhibited by A-beta. Confluent EC were virtually resistant to A-beta and suppressed A-beta production by A-beta +CHO.

Products of subconfluent EC overcame this resistant state, stimulating the production and toxicity of A-beta 42. Confluent EC overgrew >35% beyond their quiescent state in the presence of A-beta conditioned in media from subconfluent EC.

These findings imply that A-beta 42 may well be even more cytotoxic to cells in injured or growth states and potentially explain the variable and potent effects of this protein.

One may now need to consider tissue and cell state in addition to local concentration of and exposure duration to A-beta.

The specific interactions of A-beta and EC in a state-dependent fashion may help understand further the common and divergent forms of vascular and cerebral toxicity of A-beta and the spectrum of AD. (5)

(1) Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. MA Nugent, HM Nugent, RV Iozzoi, K Sanchack, and ER Edelman. PNAS Jun 2000; 97(12): 6722-6727 

(2) Correlation of transarterial transport of various dextrans with their physicochemical properties. O Elmalak, MA Lovich, E Edelman. Biomaterials 2000; 21: 2263-2272 

(3) Arterial Paclitaxel Distribution and Deposition. CJ Creel, MA Lovich, ER Edelman. Circ Res. 2000;86:879-884 

(4) Specific binding to intracellular proteins determines arterial transport properties for rapamycin and Paclitaxel. AD Levin, N Vukmirovic, Chao-Wei Hwang, and ER Edelman. PNAS Jun 2004; 101(25): 9463–9467. www.pnas.org/cgi/doi/10.1073/pnas.0400918101 

(5) Amyloid beta toxicity dependent upon endothelial cell state. M Balcells, JS Wallins, ER Edelman. Neuroscience Letters 441 (2008) 319–322

Endothelial Damage as an Inflammatory State

Autoimmunity may drive vascular disease through anti-endothelial cell (EC) antibodies. This raises a question about whether an increased morbidity of cardiovascular diseases in concert with systemic illnesses may involve these antibodies.

Matrix-embedded ECs act as powerful regulators of vascular repair accompanied by significant reduction in expected systemic and local inflammation.

The Lab researchers compared the immune response against free and matrix-embedded ECs in naive mice and mice with heightened EC immune reactivity. Mice were presensitized to EC with repeated subcutaneous injections of saline-suspended porcine EC (PAE) (5*10^5 cells).

On day 42, both naive mice (controls) and mice with heightened EC immune reactivity received 5*10^5 matrix-embedded or free PAEs. Circulating PAE-specific antibodies and effector T-cells were analyzed 90 days after implantation for –

PAE-specific antibody-titers,
frequency of CD4+-effector cells, and
xenoreactive splenocytes

These were 2- to 4-fold lower (P<0.0001) when naıve mice were injected with matrix-embedded instead of saline-suspended PAEs.

Though basal levels of circulating antibodies were significantly elevated after serial PAE injections (2210+341 mean fluorescence intensity, day 42) and almost doubled again 90 days after injection of a fourth set of free PAEs, antibody levels declined by half in recipients of matrix-embedded PAEs at day 42 (P<0.0001), as did levels of CD4+-effector cells and xenoreactive splenocytes.

A significant immune response to implantation of free PAE is elicited in naıve mice, that is even more pronounced in mice with pre-developed anti-endothelial immunity.

Matrix-embedding protects xenogeneic ECs against immune reaction in naive mice and in mice with heightened immune reactivity.

Matrix-embedded EC might offer a promising approach for treatment of advanced cardiovascular disease. (1)

Researchers examined the molecular mechanisms through which

mechanical force and hypertension modulate

endothelial cell regulation of vascular homeostasis.

Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells.

Mechanical strain stimulated the production by endothelial cells of perlecan and heparan-sulfate glycosaminoglycans. By inhibiting the expression of perlecan with an antisense vector researchers demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control.

Mechanical regulation of perlecan expression in endothelial cells was

governed by a mechano-transduction pathway
requiring transforming growth factor (TGF-β) signaling and
intracellular signaling through the ERK pathway.

Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between

endothelial TGF-β,
phosphorylated signaling intermediates, and
arterial thickening.

Studies on ex vivo arteries exposed to varying levels of pressure demonstrated that

ERK and TGF-beta signaling were required for pressure-induced upregulation of endothelial HSPG.

The Team’s findings suggest a novel feedback control mechanism in which

net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from vSMCs and
growth inhibitory signals from endothelial cells. (2)

Heparan-sulfate proteoglycans (HSPGs) are potent regulators of vascular remodeling and repair.  The major enzyme capable of degrading HSPGs is heparanase, which led us to examine the role of heparanase in controlling

arterial structure,
mechanics, and
remodeling.

In vitro studies suggested heparanase expression in endothelial cells serves as a negative regulator of endothelial inhibition of vascular smooth muscle cell (vSMC) proliferation.

ECs inhibit vSMC proliferation through the interplay between

growth stimulatory signals from vSMCs and
growth inhibitory signals from ECs.

This would be expected if ECs had HSPGs that are degraded by heparanase. Arterial structure and remodeling to injury is modified by heparanase expression. Transgenic mice overexpressing heparanase had

increased arterial thickness,
cellular density, and
mechanical compliance.

Endovascular stenting studies in Zucker rats demonstrated increased heparanase expression in the neointima of obese, hyperlipidemic rats in comparison to lean rats.

The extent of heparanase expression within the neointima strongly correlated with the neointimal thickness following injury. To test the effects of heparanase overexpression on arterial repair, researchers developed a novel murine model of stent injury using small diameter self-expanding stents.

Using this model, researchers found that increased

neointimal formation and
macrophage recruitment occurs in transgenic mice overexpressing heparanase.
Taken together, these results support a role for heparanase in the regulation of arterial structure, mechanics, and repair. (3)

The first host–donor reaction in transplantation occurs at the blood–tissue interface. When the primary component of the implant (donor) is the endothelial cells, it incites an immunologic reaction. Injections of free endothelial cell implants elicit a profound major histocompatibility complex (MHC) II dominated immune response.

Endothelial cells embedded within three-dimensional matrices behave like quiescent endothelial cells.

Perivascular implants of such embedded ECs cells are the most potent inhibitor of intimal hyperplasia and thrombosis following controlled vascular injury, but without any immune reactivity.

Allo- and even exenogenic endothelial cells evoke no significant humoral or cellular immune response in immune-competent hosts when embedded within matrices.  Moreover, endothelial implants are immune-modulatory, reducing the extent of the memory response to previous free cell implants.

Attenuated immunogenicity results in muted activation of adaptive and innate immune cells. These findings point toward a pivotal role of matrix–cell-interconnectivity for

the cellular immune phenotype and might therefore assist in the design of
extracellular matrix components for successful tissue engineering. (4)

Because changes in subendothelial matrix composition are associated with alterations of the endothelial immune phenotype, researchers sought to understand if

cytokine-induced NF-κB activity and
downstream effects depend on substrate adherence of endothelial cells (EC).

The team compared the upstream

phosphorylation cascade,
activation of NF-ĸβ, and
expression/secretion

of downstream effects of EC grown on tissue culture polystyrene plates (TCPS) with EC embedded within collagen-based matrices (MEEC).

Adhesion of natural killer (NK) cells was quantified in vitro and in vivo.

NF-κβ subunit p65 nuclear levels were significantly lower and
p50 significantly higher in cytokine-stimulated MEEC than in EC-TCPS.

Despite similar surface expression of TNF-α receptors, MEEC had significantly decreased secretion and expression of IL-6, IL-8, MCP-1, VCAM-1, and ICAM-1.

Attenuated fractalkine expression and secretion in MEEC (two to threefold lower than in EC-TCPS; p < 0.0002) correlated with 3.7-fold lower NK cell adhesion to EC (6,335 ± 420 vs. 1,735 ± 135 cpm; p < 0.0002).

Furthermore, NK cell infiltration into sites of EC implantation in vivo was significantly reduced when EC were embedded within matrix.

Matrix embedding enables control of EC substratum interaction.

This in turn regulates chemokine and surface molecule expression and secretion, in particular – of those compounds within NF-κβ pathways,

chemoattraction of NK cells,
local inflammation, and
tissue repair. (5)

Monocyte recruitment and interaction with the endothelium is imperative to vascular recovery.

Tie2 plays a key role in endothelial health and vascular remodeling. Researchers studied monocyte-mediated Tie2/angiopoietin signaling following interaction of primary monocytes with endothelial cells and its role in endothelial cell survival.

The direct interaction of primary monocytes with subconfluent endothelial cells

resulted in transient secretion of angiopoietin-1 from monocytes and

the activation of endothelial Tie2. This effect was abolished by preactivation of monocytes with tumor necrosis factor-α (TNFα).

Although primary monocytes contained high levels of

both angiopoietin 1 and 2,
endothelial cells contained primarily angiopoietin 2.

Seeding of monocytes on serum-starved endothelial cells reduced caspase-3 activity by 46+5.1%, and 52+5.8% after TNFα treatment, and it decreased single-stranded DNA levels by 41+4.2% and 40+ 3.5%, respectively.

This protective effect of monocytes on endothelial cells was reversed by Tie2 silencing with specific short interfering RNA.

The antiapoptotic effect of monocytes was further supported by the

activation of cell survival signaling pathways involving phosphatidylinositol 3-kinase,
STAT3, and
AKT.

Monocytes and endothelial cells form a unique Tie2/angiopoietin-1 signaling system that affects endothelial cell survival and may play critical a role in vascular remodeling and homeostasis. (6)

(1) Cell–Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity. H Methe, ER Edelman. Circulation. 2006;114[suppl I]:I-233–I-238. http://www.circulationaha.org/DOI/10.1161/CIRCULATIONAHA.105.000687

(2) Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGFβ Signaling Pathway. AB Baker, DS Ettenson, M Jonas, MA Nugent, RV Iozzo, ER Edelman. Circ. Res. 2008;103;289-297 http://dx.doi.org/10.1161/CIRCRESAHA.108.179465 http://circres.ahajournals.org/cgi/content/full/103/3/289

(3) Heparanase Alters Arterial Structure, Mechanics, and Repair Following Endovascular Stenting in Mice. AB Baker, A Groothuis, M Jonas, DS Ettenson…ER Edelman. Circ. Res. 2009;104;380-387; http://dx.doi.org/10.1161/CIRCRESAHA.108.180695 http://circres.ahajournals.org/cgi/content/full/104/3/380

(4) The effect of three-dimensional matrix-embedding of endothelial cells on the humoral and cellular immune response. H Methe, S Hess, ER Edelman. Seminars in Immunology 20 (2008) 117–122. http://dx.doi.org/10.1016/j.smim.2007.12.005

(5) NF-kB Activity in Endothelial Cells Is Modulated by Cell Substratum Inter-actions and Influences Chemokine-Mediated Adhesion of Natural Killer Cells. S Hess, H Methe, Jong-Oh Kim, ER Edelman. Cell Transplantation 2009; 18: 261–273 

(6) Primary Monocytes Regulate Endothelial Cell Survival Through Secretion of Angiopoietin-1 and Activation of Endothelial Tie2. SY Schubert, A Benarroch, J Monter-Solans and ER Edelman. Arterioscler Thromb Vasc Biol 2011;31;870-875 http://dx.doi.org/10.1161/ATVBAHA.110.218255

Neointimal Formation, Shear Stress, and Remodelling with Reference to Diabetes

Innate immunity is of major importance in vascular repair. The present study evaluated whether

systemic and transient depletion of monocytes and macrophages with
liposome-encapsulated bisphosphonates inhibits experimental in-stent neointimal formation.

The Experiment

Rabbits fed on a hypercholesterolemic diet underwent bilateral iliac artery balloon denudation and stent deployment.

Liposomal alendronate (3 or 6 mg/kg) was given concurrently with stenting.

Monocyte counts were reduced by 90% 24 to 48 hours aftera single injection of liposomal alendronate, returning to basal levels at 6 days.

This treatment significantly reduced

intimal area at 28 days, from 3.88+0.93 to 2.08+0.58 and 2.16 +0.62 mm2.
Lumen area was increased from 2.87+0.44 to 3.57+0.65 and 3.45+0.58 mm2, and

arterial stenosis was reduced from 58 11% to 37 8% and 38 7% in controls, in rabbits treated with 3 mg/kg, and with 6 mg/kg, respectively (mean+SD, n=8 rabbits/group, P< 0.01 for all 3 parameters).

No drug-related adverse effects were observed. Reduction in neointimal formation was associated with

reduced arterial macrophage infiltration and proliferation at 6 days and with an
equal reduction in intimal macrophage and smooth muscle cell content at 28 days after injury.

Conversely, drug regimens ineffective in reducing monocyte levels did not inhibit neointimal formation. Researchers have shown that a

single liposomal bisphosphonates injection concurrent with injury reduces in-stent neointimal formation and
arterial stenosis in hypercholesterolemic rabbits, accompanied by systemic transient depletion of monocytes and macrophages. (1)

Diabetes and insulin resistance are associated with increased disease risk and poor outcomes from cardiovascular interventions.

Even drug-eluting stents exhibit reduced efficacy in patients with diabetes. Researchers reported the first study of vascular response to stent injury in insulin-resistant and diabetic animal models.

Endovascular stents were expanded in the aortae of

obese insulin-resistant and
type 2 diabetic Zucker rats,
in streptozotocin-induced type 1 diabetic Sprague-Dawley rats, and
in matched controls.

Insulin-resistant rats developed thicker neointima (0.46+0.08 versus 0.37+0.06 mm2, P 0.05), with decreased lumen area (2.95+0.26 versus 3.29+0.15 mm2, P 0.03) 14 days after stenting compared with controls, but without increased vascular inflammation (tissue macrophages).

Insulin-resistant and diabetic rat vessels did exhibit markedly altered signaling pathway activation 1 and 2 weeks after stenting, with up to a 98% increase in p-ERK (anti-phospho ERK) and a 54% reduction in p-Akt (anti-phospho Akt) stained cells. Western blotting confirmed a profound effect of insulin resistance and diabetes on Akt and ERK signaling in stented segments. p-ERK/p-Akt ratio in stented segments uniquely correlated with neointimal response (R2 = 0.888, P< 0.04) , but not in lean controls.

Transfemoral aortic stenting in rats provides insight into vascular responses in insulin resistance and diabetes.

Shifts in ERK and Akt signaling related to insulin resistance may reflect altered tissue repair in diabetes accompanied by a

shift in metabolic : proliferative balance.

These findings may help explain the increased vascular morbidity in diabetes and suggest specific therapies for patients with insulin resistance and diabetes. (2)

Researchers investigated the role of Valsartan (V) alone or in combination with Simvastatin (S) on coronary atherosclerosis and vascular remodeling, and tested the hypothesis that V or V/S attenuate the pro-inflammatory effect of low endothelial shear stress (ESS).

Twenty-four diabetic, hyperlipidemic swine were allocated into Early (n = 12) and Late (n=12) groups. Diabetic swine in each group were treated with Placebo (n=4), V (n = 4) and V/S (n = 4) and followed for 8 weeks in the Early group and 30 weeks in the Late group.

Blood pressure, serum cholesterol and glucose were similar across the treatment subgroups. ESS was calculated in plaque-free subsegments of interest (n = 109) in the Late group at week 23. Coronary arteries of this group were harvested at week 30, and the subsegments of interest were identified, and analyzed histopathologically.

Intravascular geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated

in plaque-free subsegments of interest (n=142) with computational fluid dynamics, and
the coronary arteries (n=31) were harvested and the same subsegments were identified at 30 weeks.

V alone or with S

reduced the severity of inflammation in high-risk plaques. Both regimens attenuated the severity of enzymatic degradation of the arterial wall, reducing the severity of expansive remodeling.
attenuated the pro-inflammatory effect of low ESS. V alone or with S
exerts a beneficial effect of reducing and stabilizing high-risk plaque characteristics independent of a blood pressure- and lipid-lowering effect. (3)

This study tested the hypothesis that low endothelial shear stress augments the

expression of matrix-degrading proteases, promoting the
formation of thin-capped atheromata.

Researchers assessed the messenger RNA and protein expression, and elastolytic activity of selected elastases and their endogenous inhibitors.

Subsegments with low endothelial shear stress at week 23 showed

reduced endothelial coverage,
enhanced lipid accumulation, and
intense infiltration of activated inflammatory cells at week 30.

These lesions showed increased expression of messenger RNAs encoding

matrix metalloproteinase-2, -9, and -12, and cathepsins K and S
relative to their endogenous inhibitors and
increased elastolytic activity.

Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation.

Thin-capped atheromata in regions with

lower preceding endothelial shear stress had
reduced endothelial coverage,
intense lipid and inflammatory cell accumulation,
enhanced messenger RNA expression and
elastolytic activity of MMPs and cathepsins with
severe internal elastic lamina fragmentation.

Low endothelial shear stress induces endothelial discontinuity and

accumulation of activated inflammatory cells, thereby
augmenting the expression and activity of elastases in the intima and
shifting the balance with their inhibitors toward matrix breakdown.

Team’s results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps. (4)

Elevated CRP levels predict increased incidence of cardiovascular events and poor outcomes following interventions. There is the suggestion that CRP is also a mediator of vascular injury.

Transgenic mice carrying the human CRP gene (CRPtg) are predisposed to arterial thrombosis post-injury.

Researchers examined whether CRP similarly modulates the proliferative and hyperplastic phases of vascular repair in CRPtg when thrombosis is controlled with daily aspirin and heparin at the time of trans-femoral arterial wire-injury.

Complete thrombotic arterial occlusion at 28 days was comparable for wild-type and CRPtg mice (14 and 19%, respectively). Neointimal area at 28d was 2.5 fold lower in CRPtg (4190±3134 m2, n = 12) compared to wild-types (10,157±8890 m2, n = 11, p < 0.05).

Likewise, neointimal/media area ratio was 1.10±0.87 in wild-types and 0.45±0.24 in CRPtg (p < 0.05).

Seven days post-injury, cellular proliferation and apoptotic cell number in the intima were both less pronounced in CRPtg than wild-type.
No differences were seen in leukocyte infiltration or endothelial coverage. CRPtg mice had significantly reduced p38 MAPK signaling pathway activation following injury.

The pro-thrombotic phenotype of CRPtg mice was suppressed by aspirin/heparin, revealing CRP’s influence on neointimal growth after trans-femoral arterial wire-injury.

Signaling pathway activation,
cellular proliferation, and
neointimal formation

were all reduced in CRPtg following vascular injury.  Increasingly the Team was aware of CRP multipotent effects.  Once considered only a risk factor, and recently a harmful agent, CRP is a far more complex regulator of vascular biology. (5)

(1) Liposomal Alendronate Inhibits Systemic Innate Immunity and Reduces In-Stent Neointimal Hyperplasia in Rabbits. HD Danenberg, G Golomb, A Groothuis, J Gao…, ER Edelman. Circulation. 2003;108:2798-2804 

(2) Vascular Neointimal Formation and Signaling Pathway Activation in Response to Stent Injury in Insulin-Resistant and Diabetic Animals. M Jonas, ER Edelman, A Groothuis, AB Baker, P Seifert, C Rogers. Circ. Res. 2005;97;725-733. http://dx.doi.org/10.1161/01.RES.0000183730.52908.C6 http://circres.ahajournals.org/cgi/content/full/97/7/725

(3) Attenuation of inflammation and expansive remodeling by Valsartan alone or in combination with Simvastatin in high-risk coronary atherosclerotic plaques. YS Chatzizisis, M Jonas, R Beigel, AU Coskun… ER Edelman, CL Feldman, PH Stone. Atherosclerosis 203 (2009) 387–394 

(4) Augmented Expression and Activity of Extracellular Matrix-Degrading Enzymes in Regions of Low Endothelial Shear Stress Colocalize With Coronary Atheromata With Thin Fibrous Caps in Pigs. YS Chatzizisis, AB Baker, GK Sukhova,…P Libby, CL Feldman, ER Edelman, PH Stone Circulation 2011;123;621-630 http://dx.doi.org/10.1161/CIRCULATIONAHA.110.970038 http://circ.ahajournals.org/cgi/content/full/123/6/621 

(5) Neointimal formation is reduced after arterial injury in human crp transgenic mice HD Danenberg, E Grad, RV Swaminathan, Z Chenc,…ER Edelman Atherosclerosis 201 (2008) 85–91

A Rattle Bag of Science and the Art of Translation

Science Translational Medicine – A rattle bag of science and the art of translation E. R. Edelman, G. A. FitzGerald. Sci.Transl. Med. 3, 104ed3 (2011). http://dx.doi.org/10.1126/scitranslmed.3002131

Elazer R. Edelman is the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT, Professor of Medicine at Harvard Medical School, a coronary care unit cardiologist at the Brigham and Women’s Hospital, and Director of the Harvard-MIT Biomedical Engineering Center. E-mail: ere@mit.edu

Garret A. FitzGerald is the McNeil Professor in Translational Medicine and Therapeutics, Chair of the Department of Pharmacology, and Director of the Institute for Translational Medicine & Therapeutics, University of Pennsylvania. E-mail: garret@upenn.edu

In 2011, the American Association for the Advancement of Science (AAAS) founded Science Translational Medicine (STM) to disseminate interdisciplinary science integrating basic and clinical research that defines and fosters new therapeutics, devices, and diagnostics.

Conceived and nourished under the creative vision of Elias Zerhouni and Katrina Kelner, the journal has attracted widespread attention. Now, as we assume the mantle of co-chief scientific advisors, we look back on the journal’s early accomplishments, restate our mission, and make clear the kinds of manuscripts we seek and accept for publication.

STM’s mission, as articulated by Elias and Katrina, was to

“promote human health by providing a forum for communication and cross-fertilization among basic, translational, and clinical research practitioners and trainees from all relevant established and emerging disciplines.”

This statement remains relevant and accurate today.  With this mission on our masthead, STM now receives ~25 manuscripts (full-length research articles) per week and publishes ~10% of them. Roughly half of the submissions are deemed inappropriate for the journal and are returned without review within 8 to 10 days of receipt.

Of those papers that undergo full peer review,

decisions to reject are made within 48 days and

the mean time to acceptance (including the revision period) is 125 days.

There is now an average wait of only 24 days between acceptance and publication.

Defining TRANSLATIONAL Medicine

In accord with the journal’s broad readership, the ideal manuscript meets five criteria: It (i) reports a discovery of translational relevance with high-impact potential; (ii) has a conceptual focus with interdisciplinary appeal; (iii) elucidates a biological mechanism; (iv) is innovative and novel; and (v) is presented in clear, broadly accessible language.  STM seeks to publish research that describes

how innovative concepts drive the creative biomedical science
that ultimately improves the quality of people’s lives—

This is the broadest of our journal’s criteria but is the one that sets us apart as well. Translational relevance does not require demonstration of benefit in humans but does require the evident potential to advance clinical medicine, thus impacting the direction of our culture and the welfare of our communities. Conceptual focus and mechanistic emphasis discriminate our papers from those that contain observational descriptions of technical findings for which value is restricted to a specific discipline.

However, innovation and novelty may apply to a fundamental scientific discovery or to the nature of its application and relevance to the translational process. Criteria enable the journal to consider versatile technological advances that apply new and creative thinking but may not necessarily offer fresh insights into biological mechanisms. Finally, while the subsequent additional efforts of the STM editorial staff are not to be discounted, the clarity of writing and coherence of argument presented within a submitted manuscript are likely to facilitate its progress through the challenge of peer review.

On Causes – Hippocrates, Aristotle, Robert Koch, and the Dread Pirate Roberts

Elazer R. Edelman Circulation 2001;104:2509-2512

The idea of risk factors for vascular disease has evolved

from a dichotomous to continuous hazard analysis and
from the consideration of a few factors to
mechanistic investigation of many interrelated risks.

However, confusion still abounds regarding issues of association and causation. Originally, the simple presence of

tobacco abuse, hypertension, and/or hypercholesterolemia were tallied, and
the cumulative score was predictive of subsequent coronary artery disease.

Since then, dose responses have been defined for these and other factors and it has been suggested that almost 300 factors place patients at risk; these factors include elevations in plasma homocysteine.  Recent studies shed interesting light on the mechanism of this potentially causal relationship, which was first noted in 1969.

Aside from putative effects on vessel wall dynamics, there is now direct evidence that homocysteine is atherogenic. Twenty-fold increases in plasma homocysteine achieved by dietary manipulation of apoE–/– mice increased aortic root lesion size 2-fold and produced a prolonged chronic inflammatory mural response accompanied by elevations in vascular cell adhesion molecule-1 (VCAM) and tumor necrosis factor-a (TNF-a).

In long term followup, homocysteine levels elevated by

dietary supplementation with methionine or homocysteine
promoted lesion size and plaque fibrosis in these
atherosclerosis-prone mice early in life, but without influencing ultimate plaque burden as the animals aged.

A number of mechanisms were proposed by which homocysteine achieved this effect, including

promotion of inflammation,
regulation of lipoprotein metabolism, and
modification of critical biochemical pathways and
metabolites including nitric oxide (NO).

See p 2569 In the present issue of Circulation,

Stühlinger et al 7 advance these mechanistic insights one critical step further by defining homocysteine’s effects at an enzymatic level.

The group led by Lentz published an association between levels of the

endogenous inhibitor of Nirtic Oxide synthase,
asymmetric dimethyl arginine (ADMA), and

homocysteine in cultured endothelial cells and in the serum of cynomolgus monkeys.

Such an association is interesting because the L-arginine–NO synthase pathway seems to be a critical component in the full range of endothelial cell biology and vascular dysfunction.

Stühlinger et al 7 now show that increased cultured endothelial cell elaboration of ADMA by homocysteine and its precursor L-methionine is associated with a dose-dependent impairment of the activity of endothelial dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Homocysteine directly inhibited DDAH activity in a cell-free system by targeting a critical sulfhydryl group on this enzyme.

Thus, one could envision that the balance of cardiovascular health and disease could well be determined by the ability of an intact Nirtic Oxide synthase system to overcome environmental, dietary, and even genetic factors.

In patients with altered enzymatic defense systems,

elevated homocysteine,
oxidized lipoproteins,
inflammation, and other
vasotoxins

may dominate even the most potent defense mechanisms. These studies raise a number of issues. Do we need to add to our list of established cardiovascular risk factors to accommodate new findings and associations? Is there a final common pathway for all risk factors or perhaps even a unified factor theory into which all potential risks can be grouped? And, as always, should we consider Nirtic Oxide at the core of this universality? Finally, should we change our focus altogether and speak not of risk factors but of

genetic predisposition,
extent of biochemical aberration, and
degree of physical damage?

Some would view these remarkable success stories and the repeated association of hyperhomocyst(e)inemia with coronary, cerebral, and peripheral vascular disease and simply advocate for increased folic acid intake for all.

Indeed, this intervention of negligible cost and

insignificant side effect is already partially in place;
many foods are fortified with folate to prevent congenital neural tube defects.

This reader considers the seminal work by Vernon Young and Yves Ingenbleek on the relationship between

S8 and regions distant from lava flows in Asia and Indian subcontinents,
where they have determined hyperhomocysteinemia and the consequence associated with:
veganism (not voluntary)
impaired methyl donor reactions and transsulfuration pathways (not corrected by B12, folate)
loss of lean body mass due to the constant relationship of S:N (insufficient from plant sources)

What happens, when we fail to continue to pursue causality,

the linkage of biological significance or scientific plausibility with
epidemiologically or statistically significant association?

In medicine, risk becomes the likelihood that people without a disease will acquire the disease through contact with factors thought to increase disease risk.

All of these risk factors are then, by nature, imprecise and nonspecific.  They are stochastic measures of what will happen to normal people who fall into particular measures of these parameters.

The daring may be willing to accept these risks, citing friend and foe who live well beyond or for far lesser times than anticipated by risk alone. Such concerns may well become moot if we can simultaneously identify patients at risk

by linking phenotype with genotype,
gene expression with protein elaboration, and
environmental exposures with the biochemical consequences and
direct anatomic aberrations they induce.

This kind of characterization may well replace a family history of arterial disease as a rough estimate of

genotype,

serum cholesterol as an indirect measure of the health of lipoprotein metabolism,
serum glucose as a crude determinant of the ravages of diabetes mellitus,
blood pressure measurement as a marker of long-standing endogenous exposure to altered flow, and
tobacco abuse as a maker of long-standing exposure to exogenous toxins.

Rather than identifying patients on the basis of their serum cholesterol, we will have a direct measure of their

LDL receptor number,
internalization rate,
macrophage content in the blood vessel wall,
metalloproteinase activity, etc.
insulin receptor metabolism,
oxidative state, and
glycated burden.
Serum glucose will similarly give way to these tests

Evaluating a new way to open clogged arteries: Computational model offers insight into mechanisms of drug-coated balloons.

A new study from MIT analyzes the potential usefulness of a new treatment that combines the benefits of angioplasty balloons and drug-releasing stents, but may pose fewer risks. With this new approach, a balloon is inflated in the artery for only a brief period, during which it releases a drug that prevents cells from accumulating and clogging the arteries over time.

While approved for limited use in Europe, these drug-coated balloons are still in development in the United States and have not received FDA approval. The MIT study, which models the behavior of the balloons, should help scientists optimize their performance and aid regulators in evaluating their effectiveness and safety.

“Until now, people who evaluate such technology could not distinguish hype from promise,” says Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology and senior author of the paper describing the study, which appeared online recently in the journal Circulation.

Lead author of the paper is Vijaya Kolachalama, a former MIT postdoc who is now a principal member of the technical staff at the Charles Stark Draper Laboratory.

Edelman’s lab is investigating a possible alternative to the current treatments: drug-coated balloons. “We’re trying to understand how and when this therapy could work and identify the conditions in which it may not,” Kolachalama says. “It has its merits; it has some disadvantages.”

Modeling drug release

The drug-coated balloons are delivered by a catheter and inflated at the narrowed artery for about 30 seconds, sometimes longer. During that time, the balloon coating, containing a drug such as Zotarolimus, is released from the balloon. The properties of the coating allow the drug to be absorbed in the body’s tissues. Once the drug is released, the balloon is removed.

In their new study, Kolachalama, Edelman and colleagues set out to rigorously characterize the properties of the drug-coated balloons. After performing experiments in tissue grown in the lab and in pigs, they developed a computer model that explains the dynamics of drug release and distribution. They found that factors such as the size of the balloon, the duration of delivery time, and the composition of the drug coating all influence how long the drug stays at the injury site and how effectively it clears the arteries.

One significant finding is that when the drug is released, some of it sticks to the lining of the blood vessels. Over time, that drug is slowly released back into the tissue, which explains why the drug’s effects last much longer than the initial 30-second release period.

“This is the first time we can explain the reasons why drug-coated balloons can work,” Kolachalama says. “The study also offers areas where people can consider thinking about optimizing drug transfer and delivery.”

http://circ.ahajournals.org/content/127/20/2047.short
http://www.mit.edu/people/vbk/Circulation_2013.pdf
http://www.sciencedaily.com/…13/05/130521121513.ht…
Circulation, 2013; 127 (20): 2047 – 2055
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002051;

Conclusion

MIT’s Edelman’s Lab conducted the pioneering work in Vascular biology, animal models of drug eluting stents and was at the forefront of Empirical Molecular Cardiology in its studies in vascular physiology, biology and biomaterials for medical devices.

Related articles

MUC1* Ligand, NM23-H1, Is a Novel Growth Factor That Maintains Human Stem Cells in a More Naïve State (plosone.org)

Mass. General team develops implantable, bioengineered rat kidney (eurekalert.org)

Suppression of JAK2/STAT3 Signaling Reduces End-to-End Arterial Anastomosis Induced Cell Proliferation in Common Carotid Arteries of Rats (plosone.org)

Blood Vessel Function and Breathing Control Adversely Affected by Cutting Back on Sleep (medindia.net)

miRNA Biogenesis Enzyme Drosha Is Required for Vascular Smooth Muscle Cell Survival (plosone.org)

Cell-Permeable Peptide Shows Promise For Controlling Cardiovascular Disease (medicalnewstoday.com)

The Heart Revolution By Kilmer McCully, Martha McCully

HarperCollinsPublishers, 1969

http://books.google.com/books?id=iYLbuZFxEt8C&pg=PR20&dq=New+York+Times+homocysteine+and+Cholesterol&hl=en&sa=X&ei=_0F7UfDRA8zB4APozIHQAQ&ved=0CEMQ6AEwAg

Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

Posted in Cardiac & Vascular Repair Tools Subsegment, Drug Delivery Platform Technology, Frontiers in Cardiology and Cardiovascular Disorders, Interviews with Scientific Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, PCI, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, tagged Beth Israel Medical Center, Biology, Cardiovascular disease, Cardiovascular Disorders, Cell Biology, Conditions and Diseases, Conventional PCI, Coronary circulation, DES, Drug-eluting stent, Endothelium, Food and Drug Administration, Heart disease, myocardial infarction, nanotechnology, Personalized medicine, research, Small Business Innovation Research, United States, University of Massachusetts Lowell, VasoTech on January 14, 2013| 2 Comments »

Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

Author: Ed Kislauskis, PhD

Article ID #18: Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur. Published on 1/14/2013

WordCloud Image Produced by Adam Tubman

Welcome readers to the first in a series of interviews with future scientific leaders in biotechnology and medicine. In this post I interview a close colleague and clinical scientist who appears to be on a fast-track to achieving his vision for the future of interventional cardiology – at the very vanguard of applied nanotechnology.

Tim (Tiangen) Wu, M.D has graciously accepted my invitation to answer a few questions about how his career path and primary goal to develop and commercialize his first product, a fully-biodegradable drug-eluting stent he calls the PowerStent® Absorb (see insert). This technology combines three especially innovations: a unique balloon-expandable stent design (PowerStent®), a bioabsorbable nanoparticle composition (BioDe®), and a formulation of two commercially-available anti-restenosis drugs (Combo®).

About the Subject

Dr. Wu received his clinical education in China and research training in the USA. In 1988, he graduated with an MD from the prestigious Linyli Medical School and completed a fellowship in clinical cardiology at the Tonji Medical University. In 1993, presented with an opportunity to travel to the US, he uprooted to accept a position as visiting scholar, and ultimately post-doctoral fellow,in Jeffrey Isner’s lab at St. Elizabeth Hospital (Tufts University) and the Beth Israel Medical Center (Harvard Medical). There he investigated the biology of stenosis, and directed sponsored research projects to evaluate the safety and efficacy of the latest commercially-developed drug-coated stents (DES) in animals.

After a decade in academia, Dr. Wu made the successful transition to industry and joined Nitromed Inc. as a Research Scientist. His next stop was as a Research Director at Biomedical Research Models, Inc (2000-2006) where we met and collaborated on developing and characterizing macrovascular disease in an inbred, type 2 diabetic rat model. After a 20 year career, and upon gaining additional qualification in Mechanical Engineering (Wentworth Institute), Business Administration (MIT), Clinical Research Affairs (Mass. Biotech Council), and Medical Device Regulatory Affairs (North Eastern Univ.), he was ready to take the entrepreneurial leap. His first company, VasoTech would aim to re-engineer the clinical standards of stent design and drug delivery.

In 2007, Dr. Wu founded VasoTech, Inc. from inside his home garage. Less than a year later, VasoTech received a $1.5M SBIR fast-track grant award from the NIH. With funding, VasoTech joined the newly announced M2D2 facility on the University of Massachusetts Lowell campus, and expanded operations in China. With the support of one of his closest advisors, Dr. Stephen McCarthy and other research faculty, Dr. Wu was appointed as an adjunct faculty in the Dept. of BioMedical Engineering at the UMass/Lowell where he mentored a number of talented graduate students. Dr. Wu is recognized as a senior reviewer on the NIH Bioengineering, Surgical Science and Technology Study Section, and Biomaterials, Delivery Systems and Nanotechnology Special Emphasis Panels servicing the Small Business Innovation Research (SBIR) grant program.

Dr. Wu’s work at Vasotech is devoted to developing a 3^rd generation of fully biodegradable DES coronary stents to solve two major complications associated with stenting, restenosis and late-stage thrombosis. Thusfar, his ideas have attracted well over $1.5 Million (USD) in Small Business Innovation Research (SBIR) grant awards from the National Institute of Diabetes and Digestive and Kidney Diseases, and $1million (USD) from China Innovative Talent Leadership Program. Through his efforts VasoTech is well positioned to attract the strategic partnerships and venture capital investments necessary to translate his research through clinical stages of development both in China and the US.

The Interview

Kislauskis: Please help our readers understand the current clinical approach to CAD.

Wu: Most patients with advanced atherosclerosis diseases are at risk for occlusive coronary arterial disease and stroke. Consequently, it is recommended they undergo a percutaneous intervention (PCI); essentially, balloon angioplasty followed by instillation of one or more expandable metal stents. A properly expanded stent will dilate the vessel and increase blood flow to cardiac muscle tissue. Current 2^nd generation drug-eluting-stents (DES) release drugs to inhibit the process of vascular remodeling leading to restenosis. Because the DES approach is remarkably successful and lowers the rate of restenosis to < 10%, DESs is now performed in 85% of the 2 million percutaneous coronary interventions (PCI) procedures annually in the U.S.

Kislauskis: What is your impression of the recent 5 yr update of the FREEDOM trial comparing effectiveness of coronary artery bypass grafting (CABG) to PCI among diabetics? ¹

Wu: It makes perfect sense. There are other reports evaluating PCI in patients within high risk categories, including those with small diameter vessels, diabetes, and extensive, systemic vascular disease, showing unacceptably high rates of restenosis with bare metal stents (30%-60%) and DESs (6%-18%) ^2-4. We also know first-hand using an inbred rat strain that develops macrovascular disease 4 months after onset of spontaneous diabetes. In our experiment model, just 4weeks following balloon-induced injury to the coratid artery (PTCA), we observed 2x greater restenosis in female obese rats, and 4x greater stenosis in obese, diabetic rats littermates (syndrome X) relative to the non-obese, non-diabetic littermates. These results predicted that obesity (dyslipidemia) and diabetes (severe hyperglycemia) were major risk factors promoting the complication of restenosis (Wu and Kislauskis, unpublished).

Kislauskis: Can you tell our readers a bit more about the significance of restenosis and thrombosis and the concept behind your approach.

Wu: Two significant drawbacks to conventional PCI are the need for costly, long-term anti-platelet therapy; and having a metal artifact within the coronary vessel. In fact, once installed, the purpose of DES is to maintain patency and provide a scaffold until remodeling is complete, maybe 6 months. The period of drug elution is typically shorter in duration. In the event of restenosis, a second DES procedure is recommended and performed with satisfactory results. However, leaving another metal artifact is problematic.

Most concerning to PCI patients, however, should be an increased risk of sudden death from heart attack from a clot (thrombosis) and tissue ischemia (myocardial infarction). No available DES technology (eg. Cypher®or Taxus® DES) demonstrates any advantage over bare metal stents in this regard ^5-7. So the thinking is a metal artifact create an irregular vessel surface and micro-eddys in blood flow which ultimately result in late-stage thrombosis, particularly in patients who go off anti-their platelet therapy too soon ⁸. Therefore and conceptually, by combining potent DES technology with a fully-biodegradable scaffold, designed to be absorbed fully into the tissue, likely will reduce the rate in-stent stenosis and prevents late-stage thrombosis.

Kislauskis: How did you come up with your unique polymer formulation?

Wu: It turns out that through a process of trial and error in the lab I was able to identify a biodegradable formulation which reduces the local inflammatory response common to all DES formulations while improving the stent’s radial strength. With a stable drug delivery platform (BioDe®), the process of remodeling will contribute far less to restenosis. Furthermore, and unlike all prior art, my BioDe® formulation can neutralize acidic intermediates generated during stent degradation that induce inflammation. The combination of anti-restenosis drugs (Combo®) also is effective at inhibiting signaling pathways that contribute to restenosis.

Kislauskis: How did you come to design the PowerStent®?

Wu: Again, a long process of trial and error, initially using computer applied design (CAD) principals I learned while earning attending a mechanical engineering certificate program at Wentworth Institute of Technology in Boston. Elements behind my concept for BioDe® came to me while I was involved in a home renovation project, working with grout. Although the formulation is simple and may be duplicated, the process of manufacturing is complicated.

Kislauskis: So it’s your trade secret.

Wu: Absolutely.

Kislauskis: Can you summary its other advantages and your plans to commercialize the PowerStent®?

Wu: Preclinical, short duration (30 day) studies in porcine models with the PowerStent® Absorb deployed indicate that it will be non-inferior to the current metal DES and competing biodegradable stent technologies. Important functional attributes of the BioDe® polymer include better biocompatibility (less inflammatory), excellent radial strength, potent anti-restenosis activity, and a unique microporous surface that promotes integration into neointimal layer of stented vessel. Ongoing and much longer duration studies may also support our contention that this design can reduce risks of late-stage in-stent thrombosis.

Kislauskis: What path and difficulties to you foresee in obtaining a regulatory approval to conduct clinical trials with the PowerStent® Absorb?

Wu: FDA Guidance to commercialize conventional DES technology is available. Unfortunately, no guidance is published for a fully-biodegradable stent. Therefore, I anticipate seeking advice from the regulatory bodies prior to petitioning for approval to perform clinical trials. It will no doubt be a complicated process as this technology involves a novel drug combination (albeit FDA-approved drugs), and a novel formulation (albeit FDA-approved components), and a novel indwelling and bioabsorbable medical device (stent). We are presently completing several required engineering studies for the final phase of pre-clinical safety and efficacy testing, in China. The goals are to obtain FDA pre-market and NDA approvals, and to receive a CE mark from major international markets including Europe and the BRICK nations.

Kislauskis: How will you commercialize this 3^rd generation, fully-biodegradable stent?

Wu: There are likely 3 scenarios to complete development and commercialization. One involves securing bridge funding from the NIH SBIR program, supplemented with angel financing to complete preclinical program. I project that a minimum of $6 Million (USD) will be required to complete regulatory approval and pivotal clinical trials. Therefore, it is conceivable that a Series A round of equity financing from venture capitalists, in either US or China, will be required. A third scenario is to partner or sell the technology to a major player in this space to complete clinical testing and commercialization. Potential partners include Boston Scientific Company, J&J, etc. Any of these partners could facilitate the processes of regulatory approval, manufacturing, global distribution and marketing. Discussions are underway with one such prospective partner and with several VC groups.

Kislauskis: What is its likely impact of this product on patient care and the field of interventional cardiology?

Wu: According to US statistics, approximately 14 million Americans suffer from CAD, and 500,000 people die from acute myocardial infarction. One million more survive but with a 1.5 to 15 times greater risk of mortality or morbidity than the rest of the population each year. In the U.S., the annual health care costs of CAD are estimated to be in excess of $112 billion, and the estimated annual total direct cost associated with PCI with stents is over $2 billion. I anticipate that our PowerStent® Absorb stent will be competitive in a marketplace estimated to be over $5 billion in 2010. Although CAD patients are the primary market, other related applications for our PowerStent Absorb technology include peripheral arteries, intracerebral vascular and small vessels which are also significant.

Kislauskis: Thank you for your contribution to this site. For more information about MMG, LLC and Dr. Wu’s technology please refer to his publications ^9-13 or contact him directly at tiangenwu@yahoo.com.

REFERENCES

1. Mark A. Hlatky, M.D. Compelling Evidence for Coronary-Bypass Surgery in Patients with Diabetes. N Engl J Med 2012; 367:2437-2438.

2. Stamler, J. (1989) Epidemiology. Established major risk factors, and the primary prevention of coronary heart disease. In: Chatterjee K, Karliner J, Rapaport E, Cheitlin MD, Parmlee WW, Sheinman, M eds. Cardiology, Philadelphia Penn: JB Lippincott, 1991, 7.2-7.35. (volume 2).

3. Tanabe, K, Regar, E et al. Sirolimus-eluting stent for treatment of in-stentrestenosis: One-year angiographic and intravascular ultrasound follow-up. J. Am Col.Cardi. (2003) 41: 12A.

4. Grube, Eberhard; Silber, Sigmund. Six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003: 107, 38-42.

5. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130.

6. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088–2092.

7. Wang F, Stouffer GA, Waxman S, et al. Late coronary stent thrombosis: Early vs late stent thrombosis in the stent era. Catheter Cardiovasc Interven 2002;55:142–147.

8. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519–1521.

9. Ma X, Oyamada S, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Bianchi CF, Sellke FW, Laham R. In vitro and in vivo degradation of poly(D, L-lactide-co-glycolide)/amorphous calcium phosphate copolymer coated on metal stents. J Biomed Mater Res A. 2011 Mar 15;96(4):632-8. doi: 10.1002/jbm.a.33016. Epub 2011 Jan 25.

10. Oyamada S, Ma X, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Bianchi CF, Sellke FW, Laham R. Trans-iliac rat aorta stenting: a novel high throughput preclinical stent model for restenosis and thrombosis. J Surg Res. 2011 Mar;166(1):e91-5. Erratum in: J Surg Res. 2012 May 1;174(1):184.

11. Ma X, Oyamada S, Gao F, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Gu Z, Bianchi CF, Sellke FW, Laham R Paclitaxel/sirolimus combination coated drug-eluting stent: in vitro and in vivo drug release studies. J Pharm Biomed Anal. 2011 Mar 25;54(4):807-11. Erratum in: J Pharm Biomed Anal. 2012 Feb 5;59:217.

12. Ma X, Wu T, Robich MP, Wang X, Wu H, Buchholz B, McCarthy S. Drug-eluting stents. Int J Clin Exp Med. 2010 Jul 15;3(3):192-201.

CABG or PCI: Patients with Diabetes – CABG Rein Supreme

Posted in Bio Instrumentation in Experimental Life Sciences Research, CABG, Cardiac & Vascular Repair Tools Subsegment, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Origins of Cardiovascular Disease, PCI, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, tagged CABG, Coronary artery bypass surgery, Coronary artery disease, Drug-eluting stent, National Heart Lung and Blood Institute, Percutaneous coronary intervention, Stanford University School of Medicine on November 5, 2012| 8 Comments »

CABG or PCI: Patients with Diabetes – CABG Rein Supreme

Reporter: Aviva Lev-Ari, PhD, RN

VIEW VIDEO

105

Compelling Evidence for Coronary-Bypass Surgery in Patients with Diabetes

Mark A. Hlatky, M.D.

November 4, 2012DOI: 10.1056/NEJMe1212278

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert1 that coronary-artery bypass grafting (CABG) had better rates of survival than percutaneous coronary intervention (PCI) in patients with diabetes. The alert was based on the results of the Bypass Angioplasty Revascularization Investigation (BARI) trial,2 in which patients with multivessel coronary artery disease were randomly assigned to undergo either CABG or PCI.

This recommendation has been controversial ever since, largely because subsequent trials comparing CABG and PCI have enrolled only small numbers of patients with diabetes. A pooled analysis of 10 randomized trials involving 1233 patients with diabetes confirmed that such patients had a particular survival advantage after CABG, as compared with PCI.3 But this evidence was discounted because drug-eluting stents were not used in PCI procedures in the earlier trials, and more recent trials in which drug-eluting stents were used4,5 enrolled relatively few patients with diabetes. Settling this controversy would require a trial with a large number of patients with both diabetes and multivessel coronary artery disease in whom CABG or PCI would be performed with the use of contemporary methods.

Farkouh et al.6 now report in the Journal the results of the definitive Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial, in which 1900 patients with diabetes (about as many patients with diabetes as in all previous trials combined) were randomly assigned to undergo either CABG or PCI with drug-eluting stents.

As a cardiologist who does not perform either procedure, I find that the FREEDOM trial provides compelling evidence of the comparative effectiveness of CABG versus PCI in patients with diabetes and multivessel coronary artery disease. After 5 years of follow-up, the 947 patients assigned to undergo CABG had significantly lower mortality (10.9% vs. 16.3%) and fewer myocardial infarctions (6.0% vs. 13.9%) than the 953 patients assigned to undergo PCI. However, patients in the CABG group had significantly more strokes (5.2% vs. 2.4%), mostly because of strokes that occurred within 30 days after revascularization. In the CABG group, the primary composite outcome of death, myocardial infarction, or stroke over 5 years was reduced by 7.9 percentage points, or a relative decrease of 30%, as compared with PCI (18.7% vs. 26.6%, P=0.005). These results are consistent with the findings of multiple previous trials comparing CABG and PCI in patients with diabetes,3 as well as the most recent trials in which drug-eluting stents were used during PCI.4,5

Despite the results of BARI and other trials, over time more and more patients with diabetes have undergone PCI rather than CABG to treat multivessel coronary disease.7,8 The reasons for this trend are uncertain, yet there are two broad potential explanations. First, because PCI technology continues to evolve, many cardiologists simply have dismissed the results of earlier randomized studies as outdated because they used earlier techniques. This is a catch-22, since long-term studies are needed to compare hard outcomes, but evidence from long-term studies may be ignored if therapies are evolving. The results of the FREEDOM trial suggest that the comparative effectiveness of CABG and PCI on hard outcomes remains similar whether PCI is performed without stents, with bare-metal stents, or with drug-eluting stents. Mortality has been consistently reduced by CABG, as compared with PCI, in more than 4000 patients with diabetes who have been evaluated in 13 clinical trials. The controversy should finally be settled.

Another potential reason for the increasing use of PCI in patients with multivessel coronary disease is that the clinical-decision pathway leads patients toward PCI over alternative treatments. Many PCIs today are ad hoc procedures, performed at the time of diagnostic coronary angiography, with the same physician making the diagnosis, recommending the treatment, and performing the procedure. There is little time for informed discussion about alternative treatment options, either medical therapy on the one hand or CABG on the other. Well-informed patients might choose any of those options on the basis of their concerns about the various outcomes of treatment, such as survival, stroke, myocardial infarction, angina, and recovery time. This is a complicated decision, and clinical guidelines in the United States9 and Europe10 now emphasize the importance of more deliberate decision making about coronary revascularization, including discussions with a multidisciplinary heart team.

The results of the FREEDOM trial suggest that patients with diabetes ought to be informed about the potential survival benefit from CABG for the treatment of multivessel disease. These discussions should begin before coronary angiography in order to provide enough time for the patient to digest the information, discuss it with family members and members of the heart team, and come to an informed decision.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article was published on November 4, 2012, at NEJM.org.

SOURCE INFORMATION

From Stanford University School of Medicine, Stanford, CA.

REFERENCES:

REFERENCES

National Heart, Lung, and Blood Institute (NHLBI). Clinical alert: bypass over angioplasty for patients with diabetes. US National Library of Medicine, National Institutes of Health, September 21, 1995 (http://www.nlm.nih.gov/databases/alerts/bypass_diabetes.html).
The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217-225[Erratum, N Engl J Med 1997;336:147.]Full Text | Web of Science
Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373:1190-1197CrossRef | Web of Science | Medline
Kappetein AP, Feldman TE, Mack MJ, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J 2011;32:2125-2134CrossRef | Web of Science
Hall R. Coronary Artery Revascularisation in Diabetes trial: five year follow-up data. ESC Clinical Trial and Registry update, Munich, August 27, 2012 (http://www.escardio.org/congresses/esc-2012/congress-reports/Pages/710-5-CARDia.aspx).
Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012. DOI: 10.1056/NEJMoa1211585.
Hassan A, Newman A, Ko DT, et al. Increasing rates of angioplasty versus bypass surgery in Canada, 1994-2005. Am Heart J 2010;160:958-965CrossRef | Web of Science
Frutkin AD, Lindsey JB, Mehta SK, et al. Drug-eluting stents and the use of percutaneous coronary intervention among patients with class I indications for coronary artery bypass surgery undergoing index revascularization: analysis from the NCDR (National Cardiovascular Data Registry). JACC Cardiovasc Interv 2009;2:614-621CrossRef | Web of Science
Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123-e210CrossRef | Web of Science
Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J2010;31:2501-2555CrossRef | Web of Science | Medline

SOURCE:

http://www.nejm.org/doi/full/10.1056/NEJMe1212278?query=OF

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Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Health Law & Patient Safety, HTN, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Resident-cell-based, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, tagged Bare-metal stent, Biotechnology and Pharmaceuticals, BMS, Cardiovascular disease, Circulation Endothelial Progenitor Cells, DES, Drug-eluting stent, Endothelin Receptors, eNOS, nitric oxide, Peroxisome proliferator-activated receptor gamma, Thiazolidinedione on October 4, 2012| 17 Comments »

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Author and Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

A Three Component Method for Endogenous Augmentation of cEPCs

Macrovascular Disease: The Therapeutic Potential of cEPCs

Observations on Intellectual Property Development For an Unrecognized Future Fast Acting Therapy for Patients at High Risk for Macrovascular events

ElectEagle represents a discovery of a novel “multimarker biomarker” for cardiovascular disease that innovates on four counts.

First, it proposes new therapeutic indications for acceptable drugs.

Second, it defines a specific combination of therapeutic agents, thus, it put forth a proprietary drug combination.

Third, it targets receptor systems that have not been addressed in the context of cEPCs augmentation methods. Chiefly, modulation of the following three-targeted receptor systems: (a) inhibition of ET-1, ET_A and ET_A-ET_B receptors by antagonists (b) induction of eNOS, by agonists and NO stimulation and (c) upregulation of PPAReceptor-gamma by agonists (TZD). While (b) and (c) are implicated as having favorable effects of cEPCs count, each exerting its effect by a different pathway, it is suggested in this project that (a) might be identify to be the more powerful of the three markers. Our method, ElectEagle is the FIRST to postulate the following: (1) time concentration dependence on eNOS reuptake (2) dose concentration dependence on NO production (3) time and dose concentration dependence for ET-1, ET_A and ET_A-ET_B inhibition, and (4) dose concentration dependence on PPAReceptor-gamma. Points First, Second and Third are covered in Part II where a special focus is placed on ET-1, ET_A and ET_A-ET_B receptors.

Fourth, ElectEagle proposes a platform with triple modes of delivery and use of the test, as described in Part III. The triple modes are as follows: (A) an automated platform from a centralized lab with integration to Lab’s information management system. (B) a point-of-care testing device with appropriate display of test results (small benchtop analyzers in PCP office). (C) a device used for home monitoring of analytes (the hand-held device facilitates rapid read of scores and their translation to drug concentration of each of the three therapeutic agents, with computation of the three drug concentrations done by the device. Thus, it offers quicker optimization of treatment. ElectEagle is the FIRST to propose a CVD patient kit, hand-held device, which calculates on demand an adjustable therapeutic regimen as a function of cEPCs count biomarker. In this regard, a similarity to the pump, in management of blood sugar in DM patients, exists. Since there is a high co-morbidity between DM and CVD, our methods, ElectEagle may eventually become a targeted therapy for the DM Type 2 population.

Postulates of Multiple Indications for the Method Presented: Positioning of a Therapeutic Concept for Endogenous Augmentation of cEPCs

Potential Therapeutic Indications for ElectEagle

ElectEagle can become the drug therapy of choice for the following indications:

CAD patients
Endothelial Dysfunction in DM patients with or without Erectile Dysfunction
Atherosclerosis patients: Arteries and or veins
pre-stenting treatment phase
post-stenting treatment phase
if stent is a Bare Metal stent (BMS)
if stent is Drug Eluting stent (DES)
if stent is EPC antibody coated (the ElectEagle method increase cEPCs generation in vitro) so availability of cEPCs is increased
post CABG patients (the ElectEagle enhances healing by endogenous augmentation of cEPCs)
target sub segments of CVD patients on blood thinner drugs (the ElectEagle does not require treatment with antiplatelet agents, it is suitable for all patients on Coumadin. This population have a counter indication for antiplatelet agents which is a follow up treatment after stent implantation for 30 days, with stent-eluting long term regimen of antiplatelet agents, 6 months and in some cases indefinitely (Tung, 2006).
ElectEagle is based on systemic therapeutics (versus the localized stent solution requiring multiple and even overlapping stents)
ElectEagle will be having potential in two contexts

1. Coronary disease

2. Periphery vascular disease

Comparative analysis of endogenous and exogenous cEPCs augmentation methods:

A. endogenous augmentation method properties:

temporal – while drug therapy in use – drug action is interruptible
time concentration on eNOS reuptake
dose concentration on NO production
time and dose concentration manner for ETB inhibition
dose concentration on PPAR-gamma

B. cell-based and other exogenous methods

permanent colonization till apoptosis if no repeated attempts of re-transfer, re-implantation as the protocol usually has several stages

ElectEagle will be resulting in potential delay of stenting implantation. Patients that are target for stenting may benefit form ElectEagle that will facilitate and accelerate healing after the stent is in place. EPC antibody coated stents will work if and only if the patient has more that just low cEPCs, most patient undergoing stenting tend to have low level of cEPC. The ElectEagle method can be coupled with that type of new stents, called Genous, now in clinical trials (HEALING II, III). These stents enhance the body ability in mobilization of cEPCs, only. However, if the initial population of cEPCs is low, an endogenous fast acting cell augmentation method is needed for pretreatment before the PCI procedure with Genous is scheduled.

Mechanism of action (MOA) for ElectEagle‘s component 1

Inhibition of ET-1, ET_A and ET_A-ET_B

Source for vasodilators substances in the endothelium are PGI2 and NO. A potent vasoconstrictor peptide is the endothelin family, first isolated in the aortic endothelial cells.

Endothelins: Biosynthesis, Structure & Clearance

Three isoforms of endothelin (ET) have been identified. ET-1, ET-2 and ET-3. Each isoform is the product of a different gene and is synthesized as a prepro form that is processed to a propeptide and then to the mature peptide. Endothelin-converting enzyme (ECE) converts a prepro into a mature peptide. Each ET is a 21-amino-acid peptide containing two disulfide bridges. ETs are widely distributed in the body. ET-1 is the predominant ET secreted by the vascular endothelium. It is also produced by neurons and astrocytes in CNS and in endometrial, renal mesangial, sertoli, breast epithelial and other cells. ETs are present in the blood in low concentrations, they act locally in a paracrine or autocrine fashion rather than as circulating hormones.

Expression of ET-1 gene is increased by Growth Factors and cytokines, transforming factor-beta (TGF-beta) and interleukin 1 (IL-1), vasoactive substances including angiotensin II and vasopressing and mechanical stress. Expression is inhibited by NO, prostacyclin and ANP (source for vasodilators substances in the endothelium are PGI2 and NO.) Clearance of ETs from the circulation is rapid and involves enzymatic degradation by NEP 24.11 and clearance by the ET_B receptor.

Endothelins: Action

ET exerts many actions on the body. In particular dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid decease in BP followed by a prolonged increase. The depressor response results PGI2 and NO release from the vascular endothelium. The pressor response is due to direct constriction of vascular smooth muscle. ETs exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. ETs actions on other organ is described in (Reid, 2004). ETs interact with several endocrine systems, increase secretion of renin, aldosterone, vasopressin and Atrial natriuretic peptide (ANP.) Action exerted on CNS and PNS, GI system, liver, GU, reproductive system, eye, skeletal and skin. ET-1 is a potent mitogen for vascular smooth muscle cells, cardiac myocytes and glomerular mesangial cells.

ET receptors are present in many tissues and organs, blood vessel wall, cardiac muscle, CNS, lung, kidney, adrenal, spleen, and GI. The signal transduction mechanism triggered by binding of ET-1 to its receptors, ET_A & ET_B includes effects of stimulation of phospholipase C, formation of inositol triphosphate and release of calcium from the ER which results in vasoconstriction. Stimulation of PGI2 and NO synthesis result in decreased intracellular calcium concentration and vasodilation.

Two receptor subtypes, ET_A & ET_Bhave been cloned and sequenced. ET_A receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction. ET_B receptors have an equal affinity for ET-1 and ET-3 and are located on vascular ECs, where they mediate release of PGI2 and NO. Both receptor types belong to the G protein-coupled seven-transmembrane domain family of receptors.

Inhibitors of Endothelin Synthesis & Action

ETs can be blocked with receptor antagonists and with drugs that block the Endothelin-converting enzyme (ECE), Endothelin-converting enzyme inhibitors (ECEI). Two receptor subtypes, ET_A & ET_Bcan be blocked selectively, or both can be blocked with nonselective ET_A – ET_Bantagonists. Bosentan is a nonselective antagonist, available both intravenously and orally. It blocks the initial transient depressor (ET_B ) and the prolonged pressor (ET_A) responses to intravenous ET. Oral ET antagonists are available for research purposes. The formation of Endothelin-converting enzyme (ECE) can be blocked with Phosphoramidon. The therapeutic potential of ECEI is similar to that of the ET receptor antagonist, Bosentan, an active competitive inhibitor of ET [it has teratogenic and hepatotexic effects].

Physiologic & Pathologic Roles of Endothelin Antagonists

Systemic administration of ET receptor antagonists or ECEI causes vasodilation and decreases arterial pressure in human and in experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. This is an evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions (Reid, 2004).

There is evidence that ETs participate in CVD, including hypertension, cardiac hypertrophy, CHF, atherosclerosis, CAD, MI. ETs have been implicated in pulmonary diseases, PA HTN, asthma, renal diseases. Increased ET levels was found in the blood, increased expression of ET mRNA in endothelial or vascular smooth muscle cells and the responses to administration of ET antagonists. ET antagonists have potential for treatment of these diseases. In clinical trials, Bosentanand other nonselective antagonists as well as ET_A selective antagonists produce beneficial effects on hemodynamics and symptoms of CHF, PA HTN and essential HTN (Sütsch et al., 1998), (Haynes, 1996), (Lahav et al., 1999). Currently, it is approved for use in pulmonary hypertension (Benowitz, 2004).

ElectEagle Project Drug combination Therapy has selected Bosentan or other nonselective ET antagonists as well as ET_A selective antagonists to enhance the effects an eNOS agonist and a PPAR-gamma agonist will have on CVD patient’s propensity to achieve beneficial effects for endogenous augmentation of cEPCs. The impact the ETs have on the body is of a very wide range and of a most important from a physiological point of view, respectively, we did not leave Big ET-1 out of the therapeutic treatment design.

Proposed integration plan for ElectEagle’s Version I with CVD patients current medication regimen for selective medical diagnoses

Blood Pressure Medicine:

Beta blockers, Verapamil (Calan), Reserpine (Hydropes), Clonidine (Catapres), Methyldopa (Aldomet)

Diuretics:

Thiazides, Spironolactone (Aldactone), Hydralazine

Antidepressants:

Prozac, Lithium, MOA’s, Tricyclics

Stomach Medicine:

Tagamet and Zantac, plus other compounds containing Cimetidine and Ranitidine or associated compounds in Anticholesterol Drugs

Antipsychotics:

Chlorpromazine (Thorazine), Pimozide (Orap), Thiothixine (Navane), Thiordazine (Mellaril), Sulpiride, Haloperidol (haldol), Fluphenazine (Modecate, Prolixin)

Heart Medicine:

Clofibrate (Atromid), Gemfibrozil, Diagoxin

Hormones:

Estrogen, Progesterone, Proscar, Casodex, Eulexin, Corticosteroids Gonadotropin releasing antagonists: Zoladex and Lupron

Cytotoxic agents:

Cyclophosphamide, Methotrexate, Roferon Non-steroidal anti-inflammatories

Others

Alprazolam, Amoxapine, Chlordiazepoxide, Sertraline, Paroxetine, Clomipramine, Fluvoxamine, Fluoxetine, Imipramine, Doxepine, Desipramine, Clorprothixine, Bethanidine, Naproxen, Nortriptyline, Thioridazine, Tranylcypromine, Venlafaxine, Citalopram.

INTERACTIONS for Nebivolol

Calcium Antagonists:

Caution should be exercised when administering beta-blockers with calcium antagonists of the verapamil or diltiazem type because of their negative effect on contractility and atrio-ventricular conduction. Exaggeration of these effects can occur particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. Neither medicine should therefore be administered intravenously within 48 hours of discontinuing the other.

Anti-arrhythmics:

Caution should be exercised when administering beta-blockers with Class I anti-arrhythmic drugs and amiodarone as their effect on atrial conduction time and their negative inotropic effect may be potentiated. Such interactions can have life threatening consequences.

Clonidine:

Beta-blockers increase the risk of rebound hypertension after sudden withdrawal of chronic clonidine treatment.

Digitalis:

Digitalis glycosides associated with beta-blockers may increase atrio-ventricular conduction times. Nebivolol does not influence the kinetics of digoxin & clinical trials have not shown any evidence of an interaction.

Special note: Digitalisation of patients receiving long term beta-blocker therapy may be necessary if congestive cardiac failure is likely to develop. The combination can be considered despite the potentiation of the negative chronotropic effect of the two medicines. Careful control of dosages and of individual patient’s response (notably pulse rate) is essential in this situation.

Insulin & Oral Antidiabetic drugs:

Glucose levels are unaffected, however symptoms of hypoglycemia may be masked.

Anaesthetics:

Concomitant use of beta-blockers & anaesthetics e.g. ether, cyclopropane & trichloroethylene may attenuate reflex tachycardia & increase the risk of hypotension

Testing ElectEagle’s a-priori postulates presented in Part I

a-priori postulates presented in Part I for Component 1:ET-1, ET_A and ET_A-ET_B inhibition

time and dose concentration dependence for ET_A and ET_A-ET_B inhibition

In the literature we found evidence for dose concentration dependence manner (Reid, 2004).

ET_A and ET_A-ET_B inhibitor	time concentration dependence manner	dose concentration dependencemanner	time and dose	dose
Bosentan		(Reid, 2004)		62.5, 125 mg tablets

a-priori postulates presented in Part I for Component 2: NO, eNOS induction and stimulation

time concentration dependence on eNOS reuptake
dose concentration dependence on NO production

In the literature we found evidence for dose concentration dependence manner

Ach, Histamine, Genistein, ACEI, Fenofibrates, NEBIVOLOL, Calcium channel blocker, Enzyme S-nitrosylation

In the literature we found evidence for time concentration dependence manner:

Ach, BRL37344, a 3-adrenoceptor agonist

In the literature we found evidence for time and dose concentration dependence manner:

Histamine

NO, eNOS AgonistsStimulate phosphorylation of eNOS at serine 1177, 1179, 116 Conversion of L-arginine toL-citrulline	time concentration dependence manner	dose concentration dependencemanner	time and dose	dose (nmol·mg of protein-1) Grovers et al., (2002)
A23187				(5µM)
Acetylcholine	Xu et al., (2002)	Sanchez et al., (2006)		(1µM)
5-Hydroxytryptamine				(1µM)
VEGF (				(20ng/ml)
Bradykinin				(1µM)
Histamine		McDuffie et al., (1999)	McDuffie et al., (2000)	(10µM)
genistein		Liu et al., (2004)		(1µM)
ACEI		Skidgel et al., (2006)
Fenofibrates		Asai et al., (2006)
BRL37344, a 3-adrenoceptor agonist	Pott et al., (2005)
NEBIVOLOLß1-selective adrenergic receptor antagonist with nitric oxide (NO)–mediation for vasodilation		Ritter et al., (2006)
Calcium channel blocker		Church and Fulton, (2006),
Enzyme S-nitrosylation		Erwin et al., (2006)

a-priori postulates presented in Part I for Component 3: PPAR-gamma

dose concentration dependence on PPAReceptor-gamma – confirmed by a study for Rosiglitazone and a study for Ciglitazone

PPAReceptor-gamma agonists	time concentration dependence manner	dose concentration dependencemanner	time and dose	dose
Rosiglitazone		Polikandriotis et al., (2005)		maximum recommended daily dose of 8 mg to 2,000 mg.
Ciglitazone		Polikandriotis et al., (2005)

Development of an Experimental Treatment Protocol for

ElectEagle Version I

Therapeutic Strategy for cEPCs Endogenous Augmentation for measuring the number of circulating Endothelial Progenitor Cells (cEPCs) before and after a newly design treatment with Pharmacological agents

Component 1: Inhibition of ET-1, ET_A and ET_A-ET_B

Bosentan (Tracleer) Oral: 62.5, 125 mg tablets

Component 2: Induction of NO production and stimulation of eNOS

Nebivolol – ß1-selective adrenergic receptor antagonist with nitric oxide (NO)– mediation for vasodilation

A single daily dose of 5 mg was appropriate, with no evident advantage at 10 mg (Van Nueten et al.,1997)

Component 3: Treatment Regime with PPAR-gamma agonists (TZD)

A Substitute for Rosiglitazone, 2-8 mg once daily

The combination drug therapy for endogenous augmentation of cEPCs in CVD patients for achievement of reduction in risk for macrovascular events is recommended to be applied for Clinical Trial Phase One in the following regimen:

Use the following combination of drugs for the following Stages

Bosentan (Tracleer), Oral: 62.5 mg tablets

Nebivolol, Oral: 5mg once daily

A substitute for Rosiglitazone, 8 mg once daily

Stage 1: ET-1 Antagonist Effect on eEPC

1.0 Measurement of the Baseline of number of cEPC

1.1 Administer ET-1 antagonist for 10 days

1.2 Measurement of number of cEPC after 10 days of treatment with ET-1 antagonist

Stage 2: Nitric Oxide Effect on cEPC

2.0 Measurement of number of cEPC obtained in 1.2

2.1 Administer Nitric Oxide Agonist for 10 days

2.2 Measurement of number of cEPC after 10 days of

treatment with Nitric Oxide Agonist

Stage 3: Comparison of ET-1 and NO Effects on cEPC Proliferation

3.0 Comparison of number of cEPC in 1.2 to 2.2

¨ IF number of cEPC in 1.2 > number of cEPC in 2.2

-> continue 1.1 only

[ET-1 antagonist more effective for proliferation of cEPC than NO Agonist]

3.1.1 Measurement of number of cEPC every 10 days

¨ IF number of cEPC in 1.2 < number of cEPC in 2.2

-> continue 2.1 only

[ET-1 antagonist less effective for proliferation of cEPC than NO Agonist]

3.2.1 Measurement of number of cEPC every 10 days

¨ IF number of cEPC in 1.2 = number of cEPC in 2.2

-> continue 1.1 AND 2.1

[ET-1 antagonist equal NO Agonist in effectiveness for proliferation of cEPC]

-> Administer a Combination therapy of ET-1 antagonist and NO Agonist for 10 days

3.3.1 Measurement of number of cEPC every 10 days

Stage 4: ET-1 and/or NO Effect on Cardiovascular (CV) Events

q After 12 months Comparison of CV events in patient population in

Stage 3.1, 3.2, 3.3

Cardiovascular events in patients in 3.1
Cardiovascular events in patients in 3.2
Cardiovascular events in patients in 3.3

Conclusions

Most favorable and unexpected to us was finding in the literature new indications for TDZs as stimulators of eNOS, in addition to the new indication for atherosclerosis besides the classic indication in pharmacology books, being in the reduction of insulin resistance. Reassuring our selection of a substitute for Rosiglitazone.
Most favorable and unexpected to us was finding in the literature new indications for beta blockers as NO stimulant, nebivolol, a case in point, thus, fulfilling two indications in one drug along the direction of the study to identify eNOS agonists.
The following combination of drugs was selected for ElectEagle Version I

Bosentan (Tracleer), Oral: 62.5 mg tablets

Nebivolol, Oral: 5mg once daily

A Substitute for Rosiglitazone, 8 mg once daily

We confirmed time and dose concentrations postulating apriori in most cases. Additional literature searches will benefit the project for the three drugs selected
We have identified Inhibition of ET-1, ET_A and ET_A-ET_Bas one of the agent in the drug combination. The entire literature on cEPCs does not implicate Endothelin with impact on eEPCs while it is known that mechanical stress increase its secretion, this type of stress is implicated with hypertension. To leave out ET-1 from the cEPCs function in CVD risk equates to leaving out Thrombin from the coagulation cascade. ElectEagle Version I corrects that ommission.

REFERENCES

Benowitz, NL., (2004). Antihypertensive Agents. Chapter 11 in Katzung, BG., Basic & Clinical Pharmacology. McGraw-Hill, 9th Edition, pp. 160-183.

Haynes WG, Ferro CJ, O’Kane KP, Somerville D, Lomax CC, Webb DJ, (1996). Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation, 15;93(10):1860-70.

N S Kirkby, P W F Hadoke, A J Bagnall, and D J Webb (2008)

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol. 2008 March; 153(6): 1105–1119.

Ohkita Mamoru, Masashi Tawa, Kento Kitada and Yasuo Matsumura (2012). Pathophysiological Roles of Endothelin Receptors in Cardiovascular Diseases, J Pharmacol Sci 119, 302 – 313 (2012)

Reid, Ian A., (2004). Vasoactive Peptides. Chapter 17 in Katzung, BG., Basic & Clinical Pharmacology. McGraw-Hill, 9th Edition, pp. 281 – 297, in particular, Endothelins, pp. 290-293.

For a comprehensive Bibliography on the Three Therapeutic Componenets and the pathophysiology of Cardiovascular Disease, follow this link:

Other aspects of Nitric Oxide involvement in biological systems in humans are covered in the following posts on this site:

Nitric Oxide in bone metabolism July 16, 2012

Author: Aviral Vatsa PhD, MBBS

http://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/?goback=%2Egde_4346921_member_134751669

Nitric Oxide production in Systemic sclerosis July 25, 2012

Curator: Aviral Vatsa, PhD, MBBS

http://pharmaceuticalintelligence.com/2012/07/25/nitric-oxide-production-in-systemic-sclerosis/?goback=%2Egde_4346921_member_138370383

Nitric Oxide Signalling Pathways August 22, 2012 by

Curator/ Author: Aviral Vatsa, PhD, MBBS

http://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/?goback=%2Egde_4346921_member_151245569

Nitric Oxide: a short historic perspective August 5, 2012

Author/Curator: Aviral Vatsa PhD, MBBS

http://pharmaceuticalintelligence.com/2012/08/05/nitric-oxide-a-short-historic-perspective-7/

Nitric Oxide: Chemistry and function August 10, 2012

Curator/Author: Aviral Vatsa PhD, MBBS

http://pharmaceuticalintelligence.com/2012/08/10/nitric-oxide-chemistry-and-function/?goback=%2Egde_4346921_member_145137865

Nitric Oxide and Platelet Aggregation August 16, 2012 by

Author: Dr. Venkat S. Karra, Ph.D.

http://pharmaceuticalintelligence.com/2012/08/16/no-and-platelet-aggregation/?goback=%2Egde_4346921_member_147475405

The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure August 20, 2012

Author: Larry Bernstein, MD

http://pharmaceuticalintelligence.com/2012/08/20/the-rationale-and-use-of-inhaled-no-in-pulmonary-artery-hypertension-and-right-sided-heart-failure/

Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad August 16, 2012

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/16/nitric-oxide-the-nobel-prize-in-physiology-or-medicine-1998-robert-f-furchgott-louis-j-ignarro-ferid-murad/

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents August 13, 2012

Author: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Nano-particles as Synthetic Platelets to Stop Internal Bleeding Resulting from Trauma

August 22, 2012

Reported by: Dr. V. S. Karra, Ph.D.

http://pharmaceuticalintelligence.com/2012/08/22/nano-particles-as-synthetic-platelets-to-stop-internal-bleeding-resulting-from-trauma/

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production July 19, 2012

Curator and Research Study Originator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

July 2, 2012

An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPCs) as a Therapeutic Target for Pharmacological Therapy Design for Cardiovascular Risk Reduction: A New Multimarker Biomarker Discovery

Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

Bone remodelling in a nutshell June 22, 2012

Author: Aviral Vatsa, Ph.D., MBBS

http://pharmaceuticalintelligence.com/2012/06/22/bone-remodelling-in-a-nutshell/

Targeted delivery of therapeutics to bone and connective tissues: current status and challenges- Part, September

AuthorL Aviral Vatsa, PhD, September 23, 2012

http://pharmaceuticalintelligence.com/2012/09/23/targeted-delivery-of-therapeutics-to-bone-and-connective-tissues-current-status-and-challenges-part-i/

Calcium dependent NOS induction by sex hormones: Estrogen

Curator: S. Saha, PhD, October 3, 2012

http://pharmaceuticalintelligence.com/2012/10/03/calcium-dependent-nos-induction-by-sex-hormones/

Nitric Oxide and Platelet Aggregation,

Author V. Karra, PhD, August 16, 2012

http://pharmaceuticalintelligence.com/2012/08/16/no-and-platelet-aggregation/

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Progenitor Cells endogenous augmentation

Curator: Aviva Lev-Ari, PhD, July 16, 2012

http://pharmaceuticalintelligence.com/?s=Nebivolol

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Author: Aviva Lev-Ari, PhD, 10/4/2012

http://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

Curator: Aviva Lev-Ari, 10/4/2012.

Nitric Oxide Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Author and Reporter: Meg Baker, 10/7/2012.

http://pharmaceuticalintelligence.com/2012/10/07/no-nutritional-remedies-for-hypertension-and-atherosclerosis-its-12-am-do-you-know-where-your-electrons-are/

Drug Information

Component 1: Inhibition of ET-1, ET_A and ET_A-ET_B

Bosentan (Tracleer)

BACKGROUND: Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men. METHODS AND RESULTS: Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L x min(-1) x m(-2) compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilation. CONCLUSIONS: The endothelin ETA/B receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically (Haynes et al., 1996).

http://www.tracleer-pph.com/

http://www.medicinenet.com/script/main/art.asp?articlekey=44221&pf=3&page=1

GENERIC NAME: BOSENTAN – ORAL (boh-SEN-tan)

BRAND NAME(S): Tracleer

WARNING: This medication may cause serious liver problems. Your doctor should monitor your liver function closely to decrease your risk of liver-related side effects. Tell your doctor immediately if you notice any of these symptoms of liver problems: nausea, vomiting, stomach pain, unusual tiredness, and yellowing eyes or skin. These effects, if they occur, may go away over time (are reversible). This medication must not be used during pregnancy because it can cause fetal harm (e.g., birth defects). See the pregnancy warning information below (in Precautions section).

USES: Bosentan is used to treat a condition of high blood pressure in the lungs (pulmonary arterial hypertension). It works by causing the blood vessels (arteries) in the lungs to relax and expand, thus decreasing the pressure.

HOW TO USE: Before using, review the bosentan Medication Guide for information on the safe use of this medicine. Take this medication by mouth usually twice daily in the morning and evening with or without food; or as directed by your doctor. The dosage is based on your medical condition and response to therapy. Your doctor may recommend to gradually increase your dose over time so your body may better adjust to the effects of this drug. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is abruptly stopped. Your dose may need to be gradually decreased.

SIDE EFFECTS: Headache, nose/throat irritation, itching, flushing, or stomach upset may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly. Tell your doctor immediately if any of these unlikely but serious side effects occur: irregular heartbeat, unusual tiredness and weakness, swelling of the feet or ankles, trouble breathing, dizziness or lightheadedness. If you notice any of the following very serious side effects of liver problems, stop taking bosentan and consult your doctor immediately: vomiting, stomach pain, yellowing eyes or skin. A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, dizziness, severe trouble breathing. If you notice other effects not listed above, contact your doctor or pharmacist.

PRECAUTIONS: Tell your doctor your medical history, especially of: liver problems, blood disorders (e.g., anemia), any allergies. Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug. This medication must not be used during pregnancy because it may cause fetal harm. If you are pregnant or think you may be pregnant, do not take this medication and consult your doctor immediately. It is recommended that you use two reliable forms of birth control while taking this medicine. It is also recommended to have a pregnancy test done before treatment and every month during treatment with this drug. It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended.

DRUG INTERACTIONS: This drug is not recommended for use with: cyclosporine, glyburide. Ask your doctor or pharmacist for more details. Tell your doctor of all prescription and nonprescription medication you may use, especially: azole antifungals (e.g., itraconazole, ketoconazole), statins for high cholesterol (e.g., lovastatin, simvastatin), HIV protease inhibitors (e.g., indinavir, ritonavir), tacrolimus. This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details. Do not start or stop any medicine without doctor or pharmacist approval.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others. Laboratory and/or medical tests (e.g., liver function tests- LFT’s, blood tests) will be performed to monitor your progress and for side effects.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68 and 77 degrees F (20 and 25 degrees C) away from light and moisture. Brief storage between 59 and 86 degrees F (15 and 30 degrees C) is permitted.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507

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Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

Posted in Bio Instrumentation in Experimental Life Sciences Research, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, Exec Compensation in the Cardiac & Vascular Repair Tools Subsegment, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, HTN, Massachusetts Niche Suppliers and National Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, tagged Abbott Laboratories, Absorb™ Bioresorbable Vascular Scaffold, Coronary artery disease, Coronary circulation, Drug-eluting stent, PR Newswire on September 29, 2012| 6 Comments »

Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

Reporter: Aviva Lev-Ari, PhD, RN

Abbott Laboratories (ABT) Announces International Launch of the Absorb™ Bioresorbable Vascular Scaffold

9/25/2012 10:26:30 AM

ABBOTT PARK, Ill., Sept. 25, 2012 /PRNewswire/ — Abbott (NYSE: ABT) announced today that Absorb, the world’s first drug eluting bioresorbable vascular scaffold (BVS), is now widely available across Europe and parts of Asia Pacific and Latin America. Absorb is a first-of-its-kind device for the treatment of coronary artery disease (CAD). It works by restoring blood flow to the heart similar to a metallic stent, but then dissolves into the body, leaving behind a treated vessel that may resume more natural function and movement because it is free of a permanent metallic stent. Absorb is made of polylactide, a naturally dissolvable material that is commonly used in medical implants such as dissolving sutures.

The potential long-term benefits of a scaffold that dissolves are significant. The vessel may expand and contract as needed to increase the flow of blood to the heart in response to normal activities such as exercising; treatment and diagnostic options are broadened; the need for long-term treatment with anti-clotting medications may be reduced; and future interventions would be unobstructed by a permanent implant.

“This innovation represents a true paradigm shift in how we treat coronary artery disease. With the launch of Absorb, a scaffold that disappears after doing its job is no longer a dream, but a reality,” said Patrick W. Serruys, M.D., Ph.D., professor of interventional cardiology at the Thoraxcentre, Erasmus University Hospital, Rotterdam, the Netherlands. “Patients are excited about Absorb since it may allow blood vessels to return to a more natural state and expand long-term diagnostic and treatment options.”

The international launch of Absorb is supported by a robust clinical trial program that encompasses five studies in more than 20 countries around the world. Study data indicate that Absorb performs similar to a best-in-class drug eluting stent across traditional measures such as major adverse cardiovascular events (MACE) and target lesion revascularization (TLR), while providing patients with the added benefits associated with a device that dissolves over time. As the Absorb scaffold dissolves, vascular function is potentially restored to the blood vessel, allowing more blood to flow through the vessel as the body requires.

“Absorb is a leading example of Abbott’s dedication to advancing patient outcomes through innovative technology. Abbott has remained committed to meeting the growing physician and patient demand for a bioresorbable vascular scaffold from the initial device developed nearly 10 years ago to the expansion of our manufacturing capabilities to support this international launch,” said John M. Capek, executive vice president, Medical Devices, Abbott. “We are proud to be the first company to commercialize a drug eluting bioresorbable vascular scaffold, which has the potential to revolutionize the way physicians treat their patients with coronary artery disease.”

Heart disease is the leading cause of death for men and women around the world, and CAD is the most common type of heart disease.^1,2 CAD occurs when arteries that supply blood to the heart become narrowed or blocked, leading to chest pain or shortness of breath and increased risk of heart attack.

About the Absorb Bioresorbable Vascular Scaffold

Absorb is now available in a broad size matrix to support the needs of physicians treating patients with CAD.

The Absorb bioresorbable vascular scaffold, similar to a small mesh tube, is designed to open a blocked heart vessel and restore blood flow to the heart. Absorb is referred to as a scaffold to indicate that it is a temporary structure, unlike a stent, which is a permanent implant. The scaffold provides support to the vessel until the artery can stay open on its own, and then dissolves naturally. Absorb leaves patients with a vessel free of a permanent metallic stent and may allow the vessel to resume more natural function and movement, enabling long-term benefits.^3,4

Abbott’s BVS delivers everolimus, an anti-proliferative drug used in Abbott’s XIENCE coronary stent systems. Everolimus was developed by Novartis Pharma AG and is licensed to Abbott by Novartis for use on its drug eluting vascular devices. Everolimus has been shown to inhibit in-stent neointimal growth in the coronary vessels following stent implantation, due to its anti-proliferative properties.

Absorb is neither approved nor authorized for sale and currently is in development with no regulatory status in the United States. Absorb is authorized for sale in CE Mark countries. Absorb is now available in Europe, the Middle East, parts of Asia Pacific, including Hong Kong, Singapore, Malaysia and New Zealand, and parts of Latin America.

About Abbott Vascular

Abbott Vascular is the world’s leader in drug eluting stents. Abbott Vascular has an industry-leading pipeline and a comprehensive portfolio of market-leading products for cardiac and vascular care, including products for coronary artery disease, vessel closure, endovascular disease and structural heart disease.

About Abbott

Abbott is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 91,000 people and markets its products in more than 130 countries.

Abbott’s news releases and other information are available on the company’s Web site at www.abbott.com.

¹The top 10 causes of death, World Health Organization. June 2011 Available at: http://www.who.int/mediacentre/factsheets/fs310/en/index.html² Coronary Artery Disease. National Heart, Lung and Blood Institute. May 2011 Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/cad/³Absorb completely dissolves except for two pairs of tiny metallic markers, which help guide placement and remain in the artery to enable a physician to see where the device was placed.⁴Early evidence indicates natural vessel function is possible to achieve improved long term outcomes. Absorb is a trademark of the Abbott Group of Companies.

On this Scientific Web Site the, Cardiovascular Medical Devices are addressed in the following posts:

Lev-Ari, A. (2012U). Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

http://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Lev-Ari, A. (2012K). Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Lev-Ari, A. (2012C). Treatment of Refractory Hypertension via Percutaneous Renal Denervation

http://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

Lev-Ari, A. (2012G). Heart Remodeling by Design: Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

SOURCE Abbott

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New Drug-Eluting Stent Works Well in STEMI: Meta-analysis makes the Case

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, tagged Abbott, Bare-metal stent, Drug-eluting stent, Journal of the American Medical Association, myocardial infarction, New York University School of Medicine, ST elevation, Swiss National Science Foundation, TVR on August 22, 2012| 16 Comments »

New Drug-Eluting Stent Works Well in STEMI

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 8/8/2013

Meta-analysis makes case for drug-eluting stents in STEMI

AUGUST 7, 2013 Michael O’Riordan

New York, NY – Newer-generation drug-eluting stents, particularly the everolimus-eluting stent (Xience V, Abbot; Promus, Boston Scientific), significantly reduce the risk of target vessel revascularization (TVR) in patients with ST-segment-elevation MI (STEMI) without increasing the risk of adverse safety outcomes, including rates of stent thrombosis, when compared with bare-metal stents [1].

These are the principal findings of a new meta-analysis of 28 randomized, controlled clinical trials involving more than 34 000 patient-years of follow-up.

Published online August 6, 2013 in Circulation: Cardiovascular Interventions, the analysis showed that compared with the sirolimus-eluting stent (Cypher, Cordis), the paclitaxel-eluting stent (Taxus, Boston Scientific), and bare-metal stents, the use of an everolimus-eluting stent reduced the relative risk of stent thrombosis 62%, 61%, and 58%, respectively.

“I would make a strong argument to say that the current guidelines should change,” lead investigator Dr Sripal Bangalore (New York University School of Medicine) told heartwire. “The reduction in TVR is not surprising. We know that drug-eluting stents compared with bare-metal stents reduce TVR, but the biggest thing we were able show was that stent thrombosis is also reduced when compared with a bare-metal stent, as well as compared with first-generation drug-eluting stents.”

The current American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) clinical guidelines state that drug-eluting-stent implantation is a class IIa indication in STEMI patients. The recommendations are based on concerns about an increased risk of stent thrombosis with the drug-eluting stents compared with their bare-metal counterparts. Bangalore said concerns have also been raised about the risk of stent thrombosis beyond one year with the first-generation drug-eluting stents, a time point when dual antiplatelet therapy is stopped.

The newer-generation drug-eluting stents, however, have been shown in various studies to be as safe asbare-metal stents in the STEMI setting. For this reason, they conducted a meta-analysis of randomized, controlled trials comparing the sirolimus-, paclitaxel-, everolimus-, and zotarolimus-eluting stents against each other and against bare-metal stents.

When compared with bare-metal stents, the sirolimus-, paclitaxel-, and everolimus-eluting stent reduced the relative risk of TVR by 53%, 31%, and 57%, respectively. The sirolimus-eluting stent was significantly more effective than the paclitaxel-eluting stent at reducing TVR, as was the everolimus-eluting stent. Overall, there was a 67% probability that the Endeavor Resolute zotarolimus-eluting stent (Medtronic) had the lowest risk of TVR, although the data are based on just one trial with 281 patients, note the investigators.

Median rate of efficacy and definite/probable stent thrombosis

Stent type	TVR rate (per 1000 patient-years of follow-up)	Definite/probable stent thrombosis (per 1000 patient-years of follow-up)
Bare metal	64.00	16.60
Sirolimus	28.93	15.75
Paclitaxel	44.38	18.46
Everolimus	26.55	6.54
Zotarolimus	59.01	11.41
Zotarolimus (Resolute)	14.76	NA*

*For stent thrombosis, there were no available data on the Resolute stent

When compared with bare-metal stents, the everolimus-eluting stent reduced the risk of any stent thrombosis by 58%. The Xience stent was also associated with a statistically significant 62% and 61% reduction in the risk of stent thrombosis compared with the first-generation Cypher and Taxus stents.

Bangalore said that a previous patient-level analysis conducted by Dr Giuseppe De Luca (Ospedale Maggiore della Carità, Novara, Italy), reported by heartwire at that time, showed there was a significant 50% increase in the risk of late (more than one year) reinfarction with drug-eluting stents and an almost doubling of very late stent thrombosis with first-generation stents. In this newest meta-analysis, however, the researchers did not observe a similarly increased risk of very late stent thrombosis with the everolimus-eluting stent.

“Based on the totality of data, I would say that it’s time the guidelines make drug-eluting stents and especially the everolimus-eluting stent a class I indication in STEMI patients who can take dual antiplatelet therapy,” said Bangalore.

Source

Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Outcomes with various drug-eluting or bare-metal stents in patients with ST-segment elevation myocardial infarction. Circ Cardiovasc Interv 2013; DOI:10.1161/CIRCINTERVENTIONS.113.000415. Available at: http://circinterventions.ahajournals.org.

New Drug-Eluting Stent Works Well in STEMI

By Michael Smith, North American Correspondent, MedPage Today

Published: August 21, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Watch Video

34311?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g99985d0r&userid=99985&email=avivalev-ari@alum.berkeley.edu&mu_id=5099207

A new-generation biodegradable drug-eluting stent had a lower rate of major cardiac events than similar bare-metal devices, researchers reported.

In a randomized trial, patients with ST-segment elevation myocardial infarction (STEMI) needed fewer revascularization procedures and had a lower risk of a new heart attack in the target blood vessel, according to Stephan Windecker, MD, of Bern University Hospital in Bern, Switzerland, and colleagues.

On the other hand, rates of cardiac death were not significantly different, Windecker and colleagues reported in the Aug. 22/29 issue of the Journal of the American Medical Association.

Drug-eluting stents have been shown to reduce the need for repeat revascularization, compared with bare-metal stents, but at the cost of delayed healing, chronic inflammation, and late stent thrombosis, the researchers noted.

The long-term effects result from the persistence of the polymer, Windecker and colleagues noted — something that might be avoided by using a biodegradable polymer.

The biodegradable BioMatrix Flex stent, which delivers the immunosuppressant drug biolimus, was non-inferior in a 4-year trial to the sirolimus-eluting Cypher stent, which does not break down over time.

But it had not been tested against bare-metal stents. To help fill the gap, Windecker and colleagues studied 1-year outcomes in 1,161 STEMI patients randomly assigned to get either the biolimus-eluting biodegradable stent or a similar bare-metal device.

The primary endpoint of the trial was the 1-year rate of major adverse cardiac events — a composite of cardiac death, target vessel-related re-infarction, and ischemia-driven target-lesion revascularization.

Windecker and colleagues found that 24 patients (4.3%) with biodegradable stents had a major adverse cardiac event at 1 year, compared with 49 (8.7%) who were given the bare-metal devices (HR 0.49, 95% CI 0.30 to 0.80, P=0.004).

The difference was driven by a lower risk of two of the elements of the combined endpoint: target vessel-related reinfarction and ischemia-driven target-lesion revascularization. Specifically:

Three patients getting the biodegradable stent (0.5%) had a re-infarction related to the target vessel, compared with 15 (2.7%) of those with bare-metal devices (HR 0.20, 95% CI 0.06 to 0.69, P=0.01).
Nine patients (1.6%) with biodegradable stents and 32 (5.7%) with bare-metal devices needed target-lesion revascularization (HR 0.28, 95% CI 0.13 to 0.59, P<0.001).
Rates of cardiac death were numerically lower, but not significantly so, in the biodegradable stent patients — 16 deaths, or 2.9%, versus 20, or 3.5%.

Definite stent thrombosis occurred in five patients treated with the drug-eluting stents and 12 patients with bare-metal stents, but the difference did not reach significance.

The findings should be “reassuring” to both doctors and patients, Windecker said in a video released by the journal.

The study is “a well-done trial with convincing results regarding its primary end point,” commented Salvatore Cassese, MD, and Adnan Kastrati, MD, both of the Technische Universitat in Munich, Germany.

But, in an accompanying editorial, they argued that it still may not settle the question of long-term complications.

Despite “positive signals,” they wrote, the study has “neither the required sample size nor the sufficient length of follow-up to provide the definitive answer about the long-term safety” of the new biodegradable drug-eluting stents.

The researchers cautioned that the biodegradable drug-eluting stent is not yet approved in the U.S., although European authorities have given it the nod.

They also noted that the study, while demonstrating superiority on the overall endpoint, did not have sufficient statistical power to address the individual components definitively.

The study had support from the Swiss National Science Foundation and Biosensors Europe SA. Windecker reported financial links through his institution with Abbott, Boston Scientific, Biosensors, Biotronik, Cordis, Medtronic, and St. Jude Medical.

The editorial authors reported support from the European Commission. Kastrati reported holding a patent related to polymer-free sirolimus and probucol coating, as well as financial links with Abbott, Biosensors, Cordis, and Medtronic.

http://www.medpagetoday.com/Cardiology/PCI/34311?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g99985d0r&userid=99985&email=avivalev-ari@alum.berkeley.edu&mu_id=5099207

From the American Heart Association:

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Posts Tagged ‘Drug-eluting stent’

Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

About the Subject

The Interview

Other articles related to this subject were published in this Open Access OnlIne Scientific Journal:

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Posts Tagged ‘Drug-eluting stent’

Drug Eluting Stents: On MIT‘s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Vascular Biology and Cardiovascular Disease

Perlecan is a heparin-sulfate proteoglycan that might be critical for regulation of vascular repair by inhibiting the binding and mitogenic activity of basic fibroblast growth factor-2 (bFGF-2) in vascular smooth muscle cells .

The Role of Amyloid beta (A) in Creation of Vascular Toxic Plaque

Endothelial Damage as an Inflammatory State

Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells.

Neointimal Formation, Shear Stress, and Remodelling with Reference to Diabetes

A Rattle Bag of Science and the Art of Translation

Defining TRANSLATIONAL Medicine

Evaluating a new way to open clogged arteries: Computational model offers insight into mechanisms of drug-coated balloons.

Modeling drug release

http://circ.ahajournals.org/content/127/20/2047.short http://www.mit.edu/people/vbk/Circulation_2013.pdf http://www.sciencedaily.com/…13/05/130521121513.ht… Circulation, 2013; 127 (20): 2047 – 2055 http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002051;

Conclusion

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Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

About the Subject

The Interview

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CABG or PCI: Patients with Diabetes – CABG Rein Supreme

Compelling Evidence for Coronary-Bypass Surgery in Patients with Diabetes

SOURCE INFORMATION

REFERENCES

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Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

A Three Component Method for Endogenous Augmentation of cEPCs

Postulates of Multiple Indications for the Method Presented: Positioning of a Therapeutic Concept for Endogenous Augmentation of cEPCs

Mechanism of action (MOA) for ElectEagle‘s component 1

Inhibition of ET-1, ETA and ETA-ETB

Development of an Experimental Treatment Protocol for

ElectEagle Version I

Conclusions

Other aspects of Nitric Oxide involvement in biological systems in humans are covered in the following posts on this site:

Component 1: Inhibition of ET-1, ETA and ETA-ETB

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Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

On this Scientific Web Site the, Cardiovascular Medical Devices are addressed in the following posts:

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http://circ.ahajournals.org/content/127/20/2047.short
http://www.mit.edu/people/vbk/Circulation_2013.pdf
http://www.sciencedaily.com/…13/05/130521121513.ht…
Circulation, 2013; 127 (20): 2047 – 2055
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002051;

Inhibition of ET-1, ET_A and ET_A-ET_B

Component 1: Inhibition of ET-1, ET_A and ET_A-ET_B