Posts Tagged ‘Bare-metal stent’

The Cost to Value Conundrum in Cardiovascular Healthcare Provision

The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Author: Larry H. Bernstein, MD, FCAP

I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:

1. Pathogenesis
2. Diagnosis
3. Treatment

Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances.  Curation requires:

  • meaningful selection,
  • enrichment, and
  • sharing combining sources and
  • creation of new synnthesis

Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.

Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities.  It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)).  One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions.  One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care.  This is a holdout that persists in for-profit managed care as an option.  A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.

In this respect, the problem is not simple, but is resolvable.  A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.


Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed.  If we tie together Part 1 and Part 2, there is ample room for considering  clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.  Why should this be?  Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.

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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, ETA and ETA-ETB 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, ETA and ETA-ETB 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, ETA and ETA-ETB 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, ETA and ETA-ETB

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 ETB 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, ETA & ETB 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, ETA & ETB have been cloned and sequenced. ETA 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. ETB 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, ETA & ETB can be blocked selectively, or both can be blocked with nonselective ETA – ETB antagonists. Bosentan is a nonselective antagonist, available both intravenously and orally. It blocks the initial transient depressor (ETB ) and the prolonged pressor (ETA) 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 ETA 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 ETA 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)


Thiazides, Spironolactone (Aldactone), Hydralazine


Prozac, Lithium, MOA’s, Tricyclics

Stomach Medicine:

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


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

Heart Medicine:

Clofibrate (Atromid), Gemfibrozil, Diagoxin


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

Cytotoxic agents:

Cyclophosphamide, Methotrexate, Roferon Non-steroidal anti-inflammatories


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.


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.


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


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.


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, ETA and ETA-ETB inhibition

  • time and dose concentration dependence for ETA and ETA-ETB inhibition

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


ETA and ETA-ETB 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:


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, ETA and ETA-ETB

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


  •       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, ETA and ETA-ETB as 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. 


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:

Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography


 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



Nitric Oxide production in Systemic sclerosis July 25, 2012

Curator: Aviral Vatsa, PhD, MBBS



Nitric Oxide Signalling Pathways August 22, 2012 by

Curator/ Author: Aviral Vatsa, PhD, MBBS



Nitric Oxide: a short historic perspective August 5, 2012

Author/Curator: Aviral Vatsa PhD, MBBS



Nitric Oxide: Chemistry and function August 10, 2012

Curator/Author: Aviral Vatsa PhD, MBBS



Nitric Oxide and Platelet Aggregation August 16, 2012 by

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



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

Author: Larry Bernstein, MD


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



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



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

August 22, 2012

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


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


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



Bone remodelling in a nutshell June 22, 2012

Author: Aviral Vatsa, Ph.D., MBBS


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

AuthorL Aviral Vatsa, PhD, September 23, 2012


Calcium dependent NOS induction by sex hormones: Estrogen

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



Nitric Oxide and Platelet Aggregation,

Author V. Karra, PhD, August 16, 2012


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

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



Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

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



Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

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.


Drug Information

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

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).




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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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 

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.


  1. 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 infarctionCirc 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

 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.

From the American Heart Association:

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