October | 2012 | Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Archive for October, 2012

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Posted in Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, HTN, Metabolomics, Molecular Genetics & Pharmaceutical, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Proteomics, tagged eNOS, micro and macrocirculation, vascular relaxation, vasorelaxation on October 8, 2012| 18 Comments »

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Curator, Author,Writer, Reporter: Larry Bernstein, MD, FACP

Categories of Research:

Disease biology, Cell Biology and Cell Signaling, Biological Networks and Gene Regulation, Pharmacotherapy of Cardiovascular Disease, Nitric Oxide, HMG Co A inhibitors, Endothelial Receptor, Hypertension, Therapeutic Targets

Introduction

Statins have an effect on the vascular endothelium, which plays an important role in the development of atherosclerosis and angiogenesis, a role independent of the lipid lowering effect. The vascular endothelium plays an important role regulating vascular wall contraction and as a mediator for the vascular wall. Endothelial dysfunction, the hallmark of which is reduced activity of endothelial cell derived nitric oxide (NO), is a key factor in developing atherosclerosis and cardiovascular disease. Vascular endothelial cells play a pivotal role in modulation of leukocyte and platelet adherence, thrombogenicity, anticoagulation, and vessel wall contraction and relaxation, so that endothelial dysfunction has become almost a synonym for vascular disease. A single layer of endothelial cells is the only constituent of capillaries, which differ from other vessels, which contain smooth muscle cells and adventitia. Capillaries directly mediate nutritional supply as well as gas exchange within all organs. The failure of the microcirculation leads to tissue apoptosis/necrosis. expanded cultured EPC transplantation and cytokine-induced EPC mobilization from bone marrow have been shown to enhance angiogenesis with significant improvement of microcirculation in ischemic tissue.

It has been generally assumed that cholesterol reduction by statins mechanism underlying their beneficial effects in cardiovascular disease. The statins — potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that plays a critical role in cholesterol metabolism — block substrate accessibility to HMG-CoA reductase , effectively subverting cholesterol metabolism. Sufficient evidence now supports a hypothesis that cholesterol-independent or “pleiotropic” effects of statins improve endothelial dysfunction, effects on angiogenesis, and reduce vascular inflammation. The statins’ cholesterol-independent vascular effects appear to directly restore or improve endothelial function by increasing NO production, promote endothelial repair after arterial injury, and decrease vascular inflammation. Statins improve endothelial function by:

increasing production of nitric oxide,
promoting blood flow,
dampening inflammation,
antagonizing thrombogenicity, and
reducing endothelial vasoresponses.

The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme HMG-CoA reductase. (Photo credit: Wikipedia)

We review effects of statins on endothelial cells and endothelial progenitor cells that identifies a novel therapeutic potential of statin drugs.

Evidence in support of the new “pleiotrophic” non-lipid effects of Statins
Endothelial cell progenitors leave the bone marrow in response to cytokines or ischemic Injury.
They proliferate, migrate, and acquire resistance to apoptotic cell death.

Transplanting mice with the bone marrow of a transgenic animal carrying the LacZ reporter gene under control of the Tie2 promoter, which is active in endothelial cells…showed that statin-treated animals accumulate marrow-derived endothelial cells at the site of corneal neovascularization, administering statins is probably safer than giving VEGF to promote angiogenesis or vasculogenesis.

Akt activation has emerged as an indispensable signaling gateway at the crossroads between angiogenesis and endothelial stem cell recruitment and differentiation
Placental growth factor, which seems preferentially involved in facilitating postnatal blood vessel formation, is another “vasculogenic factor” that acts very much like the statins
Increase in endothelial nitric oxide synthase expression and activity is clearly stimulated by statins, which results in Akt activation a multifaceted developmental pathway of stem cell mobilization and differentiation is exploited by statins

Altieri DC. Statins’ benefits begin to sprout. J. Clin. Invest. 108:365–366 (2001). DOI:10.1172/JCI200113556

“Pleiotropic” Effect of statins

Recent studies have shown the restoration of endothelial function before significant reduction of serum cholesterol levels effect of statins on the endothelium were first defined by their ability to enhance endothelial NO production, upregulating endothelial nitric oxide synthase (eNOS) PI3 kinase/Akt signaling, which is a crucial regulator of cell metabolism and apoptosis, appears to mediate statin-induced eNOS upregulation.
The mechanism of eNOS activation by phosphorylation by statins
Statins can also inhibit Rho isoprenylation/activation resulting in enhanced eNOS mRNA stability and increased eNOS expression statins inhibit ox-LDL-induced endothelin-1 (ET-1) expression and the biological function of angiotensin II, and its receptor subtype 1 (AT1), which are both potent vasoconstrictors/mitogens thought to contribute to the development of atherosclerotic lesions.

Vascular inflammation

Statins have been shown to reduce the number of inflammatory cells in atherosclerotic lesions. Inhibitory effects of statins on adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1) and E-selectin, which are involved in the adhesion/rolling/extravasation of inflammatory cells.

Statin therapy in humans has also been shown to lower high-sensitivity C-Reactive Protein (hs-CRP), which reflects low-grade systemic/vascular inflammation, in hypercholesterolemic patients. This has been shown to correlate with reductions in the rates of acute major or recurrent coronary events.

Re-endothelialization

Accelerated re-endothelialization after angioplasty/de-endothelialization is known to inhibit neointimal hyperplasia, which leads to luminal narrowing or restenosis at the injured site. Re-endothelialization has been shown to be promoted by vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), estrogen, prostacyclin, blockade of TNFα, and now Statins.
Ii M, Losordo DW. Statins and the endothelium. Vascular Pharmacology 2007; 46: 1–9.
Altieri DC. Statins’ benefits begin to sprout. J. Clin. Invest. 108:365–366 (2001). DOI:10.1172/JCI200113556

Further observations

Statins exert cholesterol-independent effects on the endothelium, which lead to the improvement of endothelial function.
Statins exert biphasic, dose dependent effects on angiogenesis. At low doses, statins induce angiogenesis, whereas angiogenesis is inhibited at higher doses. These biphasic activities of statins on endothelial cell biology can be explained by the properties of the biosynthetic pathways that originate from mevalonic acid.

It appears that low concentrations of statins (such as those achieved in vivo) induce pro-angiogenic effects through activating PI3 kinase/Akt signaling leading to eNOS phosphorylation and NO production.
High (supra-physiologic) concentrations of statins will inhibit the synthesis of the non-sterol products mevalonate, leading to decreases in protein prenylation, inhibition of cell growth, or apoptosis.

The sum-up of two factors: the loss of the vascular relaxation directly dependent of the endothelium (flow – dependent) and the NO dependent are the main reason for endothelial dysfunction and play a very important role in the pathogenesis of heart failure.

Endothelial dysfunction on vascular peripheral levels contributes to the increased peripheral resistance in patients with heart failure. Endothelial dysfunction, as a pathophysiology disorder, is present early.
Statins’ benefits begin to sprout in the initiation of the atherosclerotic process.
The injury of eNOS activity seems to occur with impaired coronary vasodilatation in response to acetylcholine in patients with hypertension, hypercholesterolemia, diabetes, smokers.

Summary of Key Points

Mechanisms which are essential for the impairment of eNOS activity for the appearance of endothelial dysfunction are:

• dysfunctional signal transduction receptor – endothelial cell;
• decreased bioavailability of the substrate L- arginine;
• altered expression of gene NOS3 and stability of mARN; polymorphism NOS3;
• altered eNOS activity;
• increased destruction of NO;
• changes in the balance between NO derived endothelium and the hyperpolarizing factor (EDHF);
• decreased sensitivity of atherosclerotic smooth muscle to NO.

Effects other than those due to lowering LDL levels and independent of the LDL level

• improved endothelial function
• diminish vascular inflammation
• improve ventricular function of heart failure
• antithrombotic effect
• reduce the rate of vascular events
• antioxidant effect

Statins improve endothelial function through the following mechanisms:

• enhanced endothelial NO production by decrease of cholesterol, by up regulating posttranscriptional mRNA of eNOS and by antioxidative effects (reduction of reactive oxygen species, increase of super oxide elimination and decrease of oxidized LDL);
• reduced production of endothelin-1, endothelial vasoconstrictor factor;
• diminish the affinity for AT1 receptors ;
• stimulation of angiogenesis through proliferation, migration and survival of the circulating endothelial progenitor cells

Statins decrease the swell of the vascular wall by:

• decreasing the level of C – Reactive Protein
• decreasing the synthesis of proinflammatory cytokines (IL-1, IL-6, IL-8, TNF α)
• diminishing the leukocyte adhesion to endothelial cells inhibiting macrophage growth and smooth muscle cell migration and proliferation

Suciu M. The Role Of Nitric Oxide (No) And Statins In Endothelial Dysfunction And Atherosclerosis. Farmacia 2009; 57 (2): 131-139

Relevant observations

ECs treated with rosuvastatin increase eNOS activation. The increased NO production is involved in modulating S-nitrosylation and translation of proteins.
Bin Huang, Fu An Li, Chien Hsing Wu, Danny Ling Wang. The role of nitric oxide on rosuvastatin-mediated S-nitrosylation and translational proteomes in human umbilical vein endothelial cells. Proteome Science 2012, 10:43. doi:10.1186/1477-5956-10-43

Emerging evidence from both clinical trials and basic science studies suggest that statins have anti-inflammatory properties, which may additionally lead to clinical efficacy. Measurement of markers of inflammation such as high sensitivity C-Reactive Protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy.
Blake GJ and Ridker PM. Are statins anti-inflammatory? Curr Control Trials Cardiovasc Med 2000, 1:161–165.

Most favorable and unexpected findings were:

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.

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. Nebivolol is a vasodilator, thus functions as an antihypertensive.

Aviva Lev-Ari. Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production. July 19, 2012 pharmaceuticalintelligence.com

https://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/

References

Heeba G, Hassan MK, Khalifa, M; Malinski T. Adverse Balance of Nitric Oxide/ Peroxynitrite in the Dysfunctional Endothelium Can be Reversed by Statins. Journal of Cardiovascular Pharmacology. 2007; 50(4):391-398.
Tandon VR, Gupta BM, Tandon R. Non-lipid Actions of Statins. JK Science 2004; 6(3): 124-126.
Sacks FM. Do statins play a role in the early management of the acute coronary syndrome? European Heart Journal Supplements (2004) 6 (Supplement A), A32–A36.
Alonso D, Radomski MW. Nitric oxide, platelet function, myocardial infarction and reperfusion therapies. Heart Fail Rev 2003; 8:47–54.
Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production. PharmaceuticalIntelligence.WordPress.com
Nitric oxide and signalling pathways. PharmaceuticalIntelligence.WordPress.com
Rationale of NO use in hypertension and heart failure. PharmaceuticalIntelligence.WordPress.com
LH Bernstein. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation in cancer (Warburg effect). PharmaIntell.Wordpress.com
R Saxena. Mitochondria: More than just the powerhouse of the cell. PharmaIntell.WordPress.com
Bernstein LH. Expanding the Genetic Alphabet and linking the genome to the metabolome. PharmaIntell.wordpress.com. luly 24, 2012.
R saxena. β Integrin emerges as an important player in mitochondrial dysfunction associated Gastric Cancer. PharmaIntell.wordpress.com 2012

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium (pharmaceuticalintelligence.com)
Angiogenesis Impairment in Diabetes: Role of Methylglyoxal-Induced Receptor for Advanced Glycation Endproducts, Autophagy and Vascular Endothelial Growth Factor Receptor 2 (plosone.org)
Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs (pharmaceuticalintelligence.com)
Inhibition of Proliferation, Migration and Proteolysis Contribute to Corticosterone-Mediated Inhibition of Angiogenesis (plosone.org)
Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function (pharmaceuticalintelligence.com)
Nitric Oxide Covalent Modifications: A Putative Therapeutic Target? (pharmaceuticalintelligence.com)
Discovery of nitric oxide and its role in vascular biology (pharmaceuticalintelligence.com)

Read Full Post »

Genes involved in Male Fertility and Sperm-egg Binding

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Biology & Bio Instrumentation, tagged DEFB126 protein, fertility, gene, genetics, In vitro fertilisation, infertility, male fertility, mutation, sperm, sperm-egg binding on October 8, 2012| 3 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

An estimated 10 to 15% of couples suffer from infertility, and many treatment decisions rely on trial and error. A team of international scientists has found a common genetic variant which may explain why some men with normal sperm counts and good quality sperm are affected by infertility.

The study findings suggested that men with a variation in a gene which codes for a sperm-coating protein called beta defensin 126 (DEFB126) have a reduction in the protein coat on the outside of the sperm which makes it difficult for the sperm to ‘swim’ to the egg.

Dr Edward Hollox of the University of Leicester and co-author of the study said: ‘If you’ve got this gene variant you should allow that little bit longer if your partner’s planning to get pregnant’. The researchers, including scientists from the University of California and the Anhui Medical University in China, carried out the study on over 500 newly-wed Chinese couples who were trying for a baby.

They found that when men’s sperm lacked a coat of the DEFB126 protein, their wives were significantly less likely than expected to become pregnant.

Previous studies have shown that two copies of the genetic variant may be found in up to one quarter of men around the world, with about half of all men having one copy. The DEFB126 protein coat helps sperm to swim through cervical mucus and evade the woman’s immune system, as well as enabling it to attach to the walls of fallopian tubes.

The study showed, however, that men with two copies of the variant produced sperm that were less able to swim through a substitute to cervical mucus, hyaluronic acid gel. In macaques, it has already been shown that this protein is important in evading the immune system and the researchers believe the protein coat plays the same role in humans. Commenting on the study, Dr Allan Pacey, senior lecturer in Andrology at the University of Sheffield, said: ‘We actually understand very little about the subtle molecular events which occur in sperm as they make their journey through the woman’s body to fertilise an egg’. The research was published in the journal Science Translational Medicine. If replicated in future studies, these findings promise to guide choices about the timing and type of assisted reproduction interventions—and further hint at the possibility of treating sperm from del/del homozygotes to promote fertility.

A gene which helps sperm bind to an egg has been identified by scientists. Sperm-to-egg binding is an essential process during fertilization and although the preliminary studies were performed on mice, the gene may represent a new target for infertility treatments. Sperm from mice that had the gene switched off were only able to fertilise eggs from female mice three percent of the time compared to 80 percent fertilisation success in normal mice.

The gene codes for a protein called PDILT which helps another gene product to form and assemble correctly and then to reach the surface of a sperm. Once this happens the sperm is able to navigate the uterus and oviduct and penetrate the sticky outer layers of an egg. The study, which is published in PNAS (Proceedings of the National Academy of Sciences), also demonstrates the importance of cumulus cells, a cluster of cells that surround and protect the egg, as their presence allows sperm to bind to their target. Sperm from mice that had their PDILT gene switched off would not bind to a bare egg, but would bind to an egg surrounded by cumulus cells.

Co-author Dr Adam Benham from Durham University in the UK said that the PDILT protein is ‘an essential part of the navigation system of sperm. Like any navigation system, you have to programme where it is that you want to go and this protein plays an essential role in getting sperm to the right destination, in good shape, and in good time’. A question now for the scientists is whether the PDILT gene has as much importance in human fertility as it does in mice. ‘Mutations in the gene may be responsible for unexplained male fertility problems and further research may aid more effective IVF treatment‘, said Dr Benham.

Source References:

http://stm.sciencemag.org/content/3/92/92ps31.abstract

http://www.bionews.org.uk/page_142955.asp

http://www.itv.com/news/update/2012-05-01/scientists-discover-new-gene-key-to-fertility/

http://www.bionews.org.uk/page_102705.asp

Read Full Post »

A new treatment for depression and epilepsy – Approval of external Trigeminal Nerve Stimulation (eTNS) in Europe

Posted in Bio Instrumentation in Experimental Life Sciences Research, Innovations in Neurophysiology & Neuropsychology, Medical Devices R&D Investment, tagged brain stimulation, depression, ECT, epilepsy, eTNS, Neurosigma, SSRI on October 7, 2012| 2 Comments »

The eTNS System. (PRNewsFoto/NeuroSigma)

Reporter: Howard Donohue, PhD (EAW)

Following the arrival in the 1990s of a drug for treating depression called fluoxetine (better known by its brand name, Prozac) – a “selective serotonin reuptake inhibitor” (SSRI) – it’s probably fair to say that not many drugs have become as deeply engrained in the public’s general awareness as those of this type. Perhaps one reason for this could be the sheer number of people affected by depression and to whom SSRIs are relevant as a possible treatment (one study has estimated that depression affected upwards of 30 million Europeans in the year 2010 [1]). Perhaps another reason could be the various controversies that have surrounded SSRIs over the years, from stories of increased suicide risk in children [2] to evidence of biases and the “selective” publishing of clinical data favoring the effectiveness of these drugs [3]. Of course, despite the controversies, SSRIs (along with other classes of antidepressant drug) continue to be a mainstay, but let’s not forget, amid their popularity, that there are other ways to treat depressive illnesses. And in maximizing the benefits of treatment for the individual, it’s important to realize that any one of these approaches might work well for one person, but not for another. Among the non-pharmacologic ways to treat depression are psychological approaches, for example cognitive behavioral therapy, or alternatively, “brain stimulation” approaches such as electroconvulsive therapy (ECT). ECT is a method to induce a mild seizure in the patient by means of electrical activity applied to the brain via electrodes connected to the temples.

On the subject of ECT; you could be forgiven for thinking that it’s not very nice, especially if you’ve seen the plights of characters like Randle Patrick “Mac” McMurphy, portrayed by Jack Nicholson in One Flew Over the Cuckoo’s Nest or Russell Crowe’s portrayal of Dr. John Nash (based on the real-life Nobel Laureate in Economics by the same name) in A Beautiful Mind. Nonetheless, despite the treatment in Hollywood of ECT as a sinister, repressive, and even brutal procedure, the reality is obviously different and it continues to have a place in medical practice for the treatment of severely depressed patients to this day. This isn’t to say that controversies don’t exist within the medical community concerning certain side effects (such as memory loss), but in balancing this, we should remember that many – if not most – medical procedures have their drawbacks (hopefully, the benefits will far outweigh the drawbacks). Putting aside any thoughts on whether ECT is good or bad, it is recognition and consideration of the drawbacks that helps drive the evolution of medical technologies.

So, in illustrating the evolution that is happening in the field of brain stimulation for treating neurological disorders (in this case, depression and also epilepsy), the recent approval in Europe of an “external Trigeminal Nerve Stimulation” (eTNS) technique provides an excellent example. The technique, called the Monarch^TM and exclusively licensed to Neurosigma Inc. (a Los Angeles-based medical device company) “for the adjunctive treatment of epilepsy and major depressive disorder, for adults and children 9 years and older”, is a non-invasive form of neuromodulation therapy [4]. It was invented at the University of California, Los Angleles (UCLA) and has been in development for over 10 years [4]. It works by using a low-energy stimulus to stimulate branches of the trigeminal nerve, a nerve that can affect the activity of several key brain regions believed to be involved in depression and epilepsy. In contrast to ECT, the stimulus is restricted to the soft tissues of the forehead without direct penetration to the brain, which thereby facilitates a non-invasive form of neuromodulation [4]. Following European approval, Neurosigma affirmed in a press release that eTNS is “supported by years of safety and compelling efficacy data generated in clinical trials conducted at UCLA and the University of Southern California (USC)” [4]. In realizing the future potential of eTNS, Neurosigma’s business strategy is now geared toward steps for its adoption at major epilepsy and depression centers in the EU, as well as endeavors to make it available to patients in the US and other countries [4].

To answer the question of whether eTNS will rise to prominence as an effective treatment in the fight against depression and epilepsy, only time will tell. But if it does, as well as being a valuable addition to the armamentarium against these debilitating diseases, maybe its non-invasive nature will mean that the film directors have a harder time in “demonizing” it for dramatic effect. Well anyway, let’s hope so.

References

Read Full Post »

NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Posted in Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Metabolomics, Nitric Oxide in Health and Disease, Nutrigenomics, Nutrition, tagged Atherosclerosis, Citrulline, Hypertension, L-Arg, L-Cit, nitric oxide, Nitric oxide synthase, NO, NOS, Nutritional Supplements on October 7, 2012| 12 Comments »

Author and Reporter: Meg Baker, Ph.D., Registered Patent Agent

The 1998 Noble Prize for medicine was for the discovery that nitric oxide (NO) was the chemical messenger responsible for relaxing vascular tissue and thereby increasing blood flow and reducing blood pressure. Alfred Noble himself had been prescribed nitro-glycerin for heart problems over 100 years before, a compound which is metabolized to NO.

NO, a gas at room temperature, has an exceedingly short half-life in the body. Normally, NO is produced from an amino acid, L-arginine (L-Arg), a normal component of the dietary protein, and molecular oxygen (O2) by the one of the several Nitric Oxide Synthases (EC 1.14.13.39): endothelial (eNOS, NOS III), inducible (iNOS, NOS II), and neural (nNOS, NOS I). In human studies, supplementation with l-arginine improved endothelium-dependent vasodilation.

The reaction of iNOS with L-Arg to produce NO leaves another amino acid, citrulline. Excess L-Arg can also be degraded by arginase (enzyme having two isoforms, I and II) which may be coinduced with iNOS in some cell types.

Citrulline formed as a by-product of the NOS reaction can be recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL).

Mori (2007) http:// www.ncbi.nlm.nih.gov/ pubmed/ 17513437 found that AS and sometimes AL are coinduced with inducible NOS (iNOS) in various cells. In these cells, NO was synthesized from citrulline (via arginine) as well as from arginine, indicating operation of the citrulline-NO cycle.

Whereas, low concentrations of NO protect cells from apoptosis, excessive NO causes apoptosis. NO causes endoplasmic reticulum (ER) stress, induces a transcription factor, CAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), and leads to apoptosis.

The active site of NOS is formed by a heme-containing substrate-binding cavity, where L-arginine (Arg) and O₂ are converted to L-citrulline and NO. The electrons required for reductive O₂ activation are transferred from NADPH via the NOS-bound flavins (riboflavin, Vitamin B2) FMN and FAD. All NOS isoforms are only active as homodimers.

Generation of NO occurs in two discrete O2-requiring steps, with intermediate formation of N-hydroxy-L-arginine (NHA or NOHLA). NHA formation consumes one molecule of O₂ and two electrons. Conversion of NHA to L-citrulline and NO requires another molecule of O₂ and one more electron (http://en.wikipedia.org/wiki/Nitric_oxide_synthase). The overall stoichiometry, reflecting the three electrons derived from NADPH, that pass through the flavin co-factors and are transferred one by one via the heme iron, is then:

L-arginine + 3/2 NADPH + H⁺ + 2 O₂ = citrulline + nitric oxide + 3/2 NADP⁺

Another factor affecting NOS activity is the availability of essential co-factors such as tetrahydrobiopterin (BH4) (Boeger et al. Cardiovasc Res (2003) 59 (4): 824-833 http://cardiovascres.oxfordjournals.org/content/59/4/824.full, Vasquez-Vivar J., et al . Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc. Natl. Acad. Sci. USA 1998;95:9220-9225 http://www.pnas.org/content/95/16/9220.full). H₄-biopterin binds in the immediate vicinity of the heme at the dimer interface, interacting with residues from both subunits. When BH4 availability is limiting, electron transfer from NOS flavins becomes “uncoupled” from l-arginine oxidation and the ferrous-dioxygen complex formed as an intermediate in the reaction sequence, dissociates and superoxide(O2−·) is produced.

See Figure 1 in Werner et al. 2003 Exp Biol Med 228: 1291-1302.

RADICALS

The conversion of Arg to NHA and of NHA to L-citrulline and NO both depend on the presence of H₄-biopterin. In the absence of substrate or pterin, NADPH oxidation by NOS is accompanied by formation of O₂⁻ and peroxide (H₂O₂). Uncoupled eNOS is assumed to produce superoxide (O2−·) in addition to or instead of NO (·NO) which will react with itself, with NO, or with -hydroxyl, -sulfhydryl, or or side groups of proteins, lipids, or glycans. Reaction of ·NO produced by eNOS, with O2−· produced by eNOS or by other enzymes, such as NADPH and xanthine oxidases, decreases the amount of ·NO available to stimulate vascular relaxation. At the very low BH4 concentration of 100 nmol/L, recombinant human eNOS activity is fully developed. However, biopterin is formed from the pterin heterocycle also present in folic acid (Vitamin B9,
pteroyl-L-glutamate)
and which is synthesized from GTP. Human GTP cyclohydrolase I (GTPCH), is the rate-limiting enzyme in BH4 synthesis (Crabtree et al. JBC 2008, http://www.jbc.org/content/284/2/1136.full).

In addition to the NOS reaction, which generates a H₃-biopterin radical cation, a neutral H₃-biopterin radical is formed when H₄-biopterin reacts with various radicals and which can be reduced back to H₄-biopterin by ascorbate (Vitamin C). Folate species are also required to synthesize pyrimidines and purines (for DNA synthesis and repair and NADH and NADPH).

Enhancing NO Synthesis

The normal way to increase vascular nitric oxide is through vascular stress, such as exercise. As oxygen demand increases, cardiac output increases and the endothelial lining of the arteries releases nitric oxide into the blood, which, in turn, relaxes and widens the vessel wall, allowing for enhanced blood flow.

Enhancing the presence of L-Arg or the one or more of the NOS enzymes are obviously essential for NO production. However, NOS enzymes are co-valently bound to heme (heme, iron), and flavin co-factors (Vit B2), and require soluble co-factors NADPH (a dinucleotide phosphate, containing niacin, Vitamin B3), and BH4 (from Vit B9).

Foods high in Arginine and Citrulline include melons and cucumber, peanuts, salmon, and soy. Arginine is found in varying degrees (3-15% by weight) in all animal proteins. Blue-fin tuna has 1.8 g of arginine per 100 g so 2 oz. of tuna will provide about 1 g of arginine. Other sources of 1 g of L-Arg: 2.7 oz. of chicken thighs, about 4 oz. of chicken breast, 2 oz. of 75 percent lean hamburger or about 2.5 oz. of pork.

Foods rich in antioxidants and polyphenols will provide protection against free radical assault on proteins and, in particular, act to protect the NOS enzyme and cofactors. Almost all fruit and vegetables such as blueberries, cranberries, carrots, grapefruit, soybeans, apples, and spinach contain high levels of antioxidants. In addition, nuts, tea, seeds, dark chocolate, red wine, and seafood generally contain antioxidants such as resveratrol, ascorbate, and other phytochemicals. Other free radical scavengers, tocopherols (alpha-tocopherol, Vit E) work predominantly in the lipid environment such as in cell membranes, while the sulfur-containing soluble molecule, glutathione (GSH) protects the cytosolic milieu.

Supplements

Both L-Arg or L-citrulline can be purchased over the counter. Dietary L-arginine will be taken up by the intestine and transported directly to the liver by the hepatic artery as are most of the products of digestion. Much of this L-Arg will be used in metabolic steps related to the urea cycle which is co-ordinated with the kidney to rid the body of excess nitrogen and prevent ammonia concentration from building. A small amount will enter the blood stream and be used for NO synthesis.

Proargi-9 Plus® is one product being sold containing mutltigram doses of L-Arg plus L-Citrulline in combination with anti-oxidants and folate. Proargi-9 Plus® is a registered trademark and copyright of Nature’s Sunshine Products, Inc. L-arginine Plus™ is formulation with similar ingredients and stated amounts of L-Arg and L-Citrulline and is not affiliated with the makers of Proargi-9-Plus. Niteworks® is a registered trademark and copyright of Herbalife International, Inc. and is not affiliated with or a sponsor of L-arginine Plus™.

Dr. Joe Prendergast is an endocrinologist using L-Arg therapy who, over 19 years, never had to admit any of his 7200 diabetes patients to the hospital for peripheral artery disease, recommends supplemental L-Arg formulations to his patients. The combination of L-Arg with L-citrulline a longer acting NO forming product. http://www.livingwithoutdisease.com/?route=references/prendergast

Supplements of L-Arg and, in particular, in combination with L-citrulline other B-vitamins and antioxidents may be an effective way to boost vascular NO synthesis for anyone not exercising or eating a balanced diet, having a deficiency in any of the L-Arg recycling enzymes, NOS enzymes, co-factor recycling or synthetic enzymes, or other risk factor. Specific risk factors, such as inherently elevated levels of the natural NOS inhibitor ADMA (asymmetric-dimethyl-L-arginine) are beginning to be uncovered and will be the subject of another post.

Additional References

Nitric Oxide: Biology and Pathobiology, LJ Ignarro Editor, Sep 13, 2000 http://books.google.com/books?id=h5FugARr4bgC&dq=pterin+ring&source=gbs_navlinks_s

Mori, M. Regulation of nitric oxide synthesis and apoptosis by arginase and arginine recycling. J Nutr. 2007 Jun;137(6 Suppl 2):1616S-1620S. http://www.ncbi.nlm.nih.gov/pubmed/17513437

Werner, et al. Tetrahydrobiopterin and Nitric Oxide: Mechanistic and Pharmacological Aspects Exp Biol Med December 2003 vol. 228 no. 11 1291-1302 Werner et al. Exp Biol Med 2003

Davel AP, Wenceslau CF, Akamine EH, Xavier FE, Couto GK, Oliveira HT, Rossoni LV. Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update. Braz J Med Biol Res. 2011 Sep;44(9):920-32. Epub 2011 Aug 19. Davel et al. Braz J Med Biol Res 2011

Rainer H Boeger. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism Schwedhelm E, et al. Br J Clin Pharmacol. 2008_65_51-9

Louise Ignarro, UCLA, Nobel Prize Recipient, Author “NO More Heart Disease”

John Cook, Peripheral artery disease study, Author “Cardiovascular Cure”

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/

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.

http://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

Read Full Post »

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

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

Read Full Post »

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

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, 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, HTN, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged Cell Biology, Endothelial microparticle, Endothelium, nitric oxide, Nitric oxide synthase on October 4, 2012| 14 Comments »

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

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

Alonso D, Radomski MW, (2003). Nitric oxide, platelet function, myocardial infarction and reperfusion therapies. Heart Fail Rev., 8:47–54.

Anthony MS, Clarkson TB, Williams JK, (1998). Effects of soy isoflavones on atherosclerosis: potential mechanisms. Am J Clin Nutr., 68(6 Suppl):1390S–1393S.

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

Bisoendial RJ, et al. (2003). Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation, 107:2944–2948.

Blair A, Shaul PW, Yuhanna IS, Conrad PA, Smart EJ., (1999). Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J. Biol. Chem., 274:32512–32519.

Brixius K, Song Q, Malick A, Boelck B, Addicks K, Bloch W, Mehlhorn U, Schwinger R, (2006). eNOS is not activated by nebivolol in human failing myocardium. Life Sci., 2006 Apr 25

Broeders MAW, Doevendans PA, Bekkers BCAM, Bronsaer R, van Gorsel E, Heemskerk JWM. oude Egbrink MGA, van Breda E, Reneman RS, van der Zee R, (2000). Nebivolol: A Third-Generation ß-Blocker That Augments Vascular Nitric Oxide Release, Endothelial ß2-Adrenergic Receptor–Mediated Nitric Oxide Production.Circulation,102:677.

Brown BG, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N. Engl. J. Med., 345:1583–1592.

Brugada P, Brugada J, Brugada R, (2001). Dealing with biological variation in the Brugada syndrome. Eur. Heart J., 22(24): 2231 – 2232.

Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa WC, Bender JR., (1997). 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ. Res., 81:885–892.

Cheng Y, Wang M, Yu Y, Lawson J, Funk CD, and Fitzgerald GA., (2006). Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J. Clin. Invest., 116:1391-1399

Church JE, Fulton D., (2006). Differences in eNOS activity because of subcellular localization are dictated by phosphorylation state rather than the local calcium environment. J Biol Chem., 2006 Jan 20;281(3):1477-88. Epub 2005 Oct 28.

Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frerart F, Belge C, Jnaoui K, Noirhomme P, Feron O, Balligand JL, (2005). Endothelial {beta}3-Adrenoreceptors Mediate Nitric Oxide-Dependent Vasorelaxation of Coronary Microvessels in Response to the Third-Generation {beta}-Blocker Nebivolol. Circulation, 112(8): 1198 – 1205.

Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM, (2001). HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt pathway. J Clin Invest., 108:391–397.

Dobrydneva Y, Williams RL, Morris GZ, Blackmore PF, (2002). Dietary phytoestrogens and their synthetic structural analogues as calcium channel blockers in human platelets. J Cardiovasc Pharmacol, 40:399–410.

Duarte J, Ocete MA, Perez-Vizcaino F, Zarzuelo A, Tamargo J, (1997). Effect of tyrosine kinase and tyrosine phosphatase inhibitors on aortic contraction and induction of nitric oxide synthase. Eur J Pharmacol, 338:25–33.

Erwin PA, Mitchell DA, Sartoretto J, Marletta MA, Michel T., (2006). Subcellular Targeting and Differential S-Nitrosylation of Endothelial Nitric-oxide Synthase. J. Biol. Chem., 281:1, 151-157.

George T. and P. Ramwell, (2004). Nitric Oxide, Donors, & Inhibitors. Chapter 19 in Katzung, BG., Basic & Clinical Pharmacology. McGraw-Hill, 9th Edition, pp. 313 – 318.

Gong M, et al., (2003). HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. J. Clin. Invest., 111:1579–1587.

Gonzalez E, Kou R, Lin AJ, Golan DE, Michel T., (2002). Subcellular Targeting and Agonist-induced Site-specific Phosphorylation of Endothelial Nitric-oxide Synthase. J. Biol. Chem., 277;42:39554-39560.

Goon, P.K.Y. Lip G.Y.H, Boos, CJ, Stonelake, PS, Blann, AD. (2006). Circulating Endothelial Cells, Endothelial Progenitor Cells, and Endothelial Microparticles in Cancer, Neoplasia, 8:79-88.

Gottstein N, Ewins BA, Eccleston C, Hubbard GP, Kavanagh IC, Minihane AM, Weinberg PD, Rimbach G, (2003). Effect of genistein and daidzein on platelet aggregation and monocyte and endothelial function. Br J Nutr, 89:607–616

Grovers R, Bevers L, De Bree P, Rabelink TJ, (2002). Endothelial nitric oxide synthase activity is linked to its presence at cell–cell contacts. Biochem. J., 361 (193–201) (Printed in Great Britain)

Iaccarino G, Cipolletta E, Fiorillo A, AnnecchiaricoM, Ciccarelli M, Cimini V, Koch WJ, B. Trimarco B, (2002). {beta}2-Adrenergic Receptor Gene Delivery to the Endothelium Corrects Impaired Adrenergic Vasorelaxation in Hypertension. Circulation, 106(3): 349 – 355.

Jordan J, Tank J, Stoffels, Franke MG, Christensen NJ, Luft CF, Boschmann M, (2001). Interaction between {beta}-Adrenergic Receptor Stimulation and Nitric Oxide Release on Tissue Perfusion and Metabolism.J. Clin. Endocrinol. Metab., 86(6): 2803 – 2810.

Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski, T, (2003). Third-Generation {beta}-Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux: A Novel Mechanism for Antihypertensive Action. Circulation, 107(21): 2747 – 2752.

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.

Kleinman, ME, Blei, F, Gurtner, GC, (2005). Circulating Endothelial Progenitor Cells and Vascular Anomalies, Lymphatic Research and Biology, 3;4: 234-239.

Koshimizu T-A, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T, Takeo S, Okamura H, Tsujimoto G., (2006). V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. PNAS, 103;20: 7807-7812.

Kotamraju S, Hogg N, Joseph J, Keefer LK, Kalyanaraman B, (2001). Inhibition of oxidized low-density lipoprotein-induced apoptosis in endothelial cells by nitric oxide. Peroxyl radical scavenging as an antiapoptotic mechanism. J Biol Chem, 276:17316–17323.

Kuvin JT, et al., (2002). A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am. Heart J., 144:165–172.

Lahav R, Heffner G, Patterson PH., (1999). An endothelin receptor B antagonist inhibits growth and induces cell death in human melanoma cells in vitro and in vivo. PNAS, 96;20: 11496-11500.

Lantin-Hermoso RL, et al., (1997). Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am. J. Physiol., 273:L119–L126.

Laszlo, F, Whittle BJR, Moncada S., (1994). Time dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors. Br. J. Pharmacol., 111, 1309–1315.

Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, Nickenig G, (2003). Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation, 109:220 –226.

Li AC, Binder, CJ, Gutierrez, A, Brown, KK, Plotkin, CR, Pattison, JW, Valledor, AF, Davis, RA, Willson, TM, Witztum, JL, Palinski, W, Glass, CK. (2004). Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPAR-alpha, Beta/delta, and gamma. J. Clin. Invest., 114:1564-1576.

Li XP, et al., (2000). Protective effect of high density lipoprotein on endothelium-dependent vasodilatation. Int. J. Cardiol., 73:231–236.

Liu D, Homan LL, Joseph, Dillon JS., (2004). Genistein Acutely Stimulates Nitric Oxide Synthesis in Vascular Endothelial Cells by a Cyclic Adenosine 5′-Monophosphate-Dependent Mechanism, Endocrinology, 145:12, 5532-5539.

Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T, (2001). HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest., 108:399–405.

McDuffie JE, Coaxum SD, Maleque MA, (1999) 5-Hydroxytryptamine evokes endothelial nitric oxide synthase activation in bovine aortic endothelial cell cultures. Proceedings of the Society for Experimental Biology and Medicine, 221, 386-390.

McDuffie JE, Motley ED, Limbird LE, Maleque, MA, (2000). 5-Hydroxytryptamine Stimulates Phosphorylation of p44/p42 Mitogen-Activated Protein Kinase Activation in Bovine Aortic Endothelial Cell Cultures. Journal of Cardiovascular Pharmacology, 35(3):398-402.

McEniery CM, Schmitt M, Qasem A, Webb DJ, Avolio AP, Wilkinson IB, Cockcroft JR, (2004). Nebivolol Increases Arterial Distensibility In Vivo. Hypertension, 44(3): 305 – 310.

Mason RP, Kalinowski L, Jacob RF, Jacoby AM, Malinski BT, (2005). Nebivolol Reduces Nitroxidative Stress and Restores Nitric Oxide Bioavailability in Endothelium of Black Americans. Circulation, 112(24): 3795 – 3801.

Mineo C, Yuhanna IS, Quon MJ, Shaul PW., (2003). HDL-induced eNOS activation is mediated by Akt and MAP kinases. J. Biol. Chem., 278:9142–9149.

Mollnau H, Schulz E, Daiber A, Baldus S, Oelze M, August M, Wendt M, Walter U, Geiger C, Agrawal R, Kleschyov AL, Meinertz T. Munzel T, (2003). Nebivolol Prevents Vascular NOS III Uncoupling in Experimental Hyperlipidemia and Inhibits NADPH Oxidase Activity in Inflammatory Cells. Arterioscler. Thromb. Vasc. Biol., 23(4): 615 – 621.

Moncada S., (2006). Adventures in vascular biology: a tale of two mediators. Phil. Trans. R. Soc. B 29 May 2006 vol. 361 no. 1469 735-759

Moncada S, and Higgs EA, (2006). The discovery of nitric oxide and its role in vascular biology. British Journal of Pharmacology, 147, S193–S201

Mukherjee S, Baksi S, Dart RA, Gollub S, Lazar J, Nair C, Schroeder D, Woolf SH, (2003). {beta}-Blockers With Vasodilatory Actions. Chest, 124(4): 1621 – 1621.

Murakami H, Murakami R, Kambe F, Cao X, Takahashi R, Asai T, Hirai T, Numaguchi Y, Okumura K, Seo H, Murohara T., (2006). Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. Biochem Biophys Res Commun., 341(4):973-8. Epub 2006 Jan 24.

Nebivolol is a long-acting, cardioselective beta-blocker currently licensed for the treatment of hypertension.

Nebivolol

http://www.intekom.com/pharm/adcock/nebilet.html – retrieved on 6/20/2006

Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, Owen A, Abbey M, (1997). Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol 17:3392–3398.

Nofer J-R, et al., (2004). HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J. Clin. Invest.,113:569–581.

Nolte MS and JH Karam, (2004). Pancreatic Hormones & Antidiabetic Drugs. Chapter 41 in Katzung, BG., Basic & Clinical Pharmacology. McGraw-Hill, 9th Edition, pp.693-715, in particular, Thiazolidinediones, pp.709-710, 713.

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)

Polikandriotis JA, Mazzella LJ, Rupnow HL, Hart CM, (2005). Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol., 25(9):1810-6. Epub 2005 Jul 14.

Pott C, Steinritz D, Bölck B, Mehlhorn U, Brixius K, Schwinger RHG, BlochW., (2006). eNOS translocation but not eNOS phosphorylation is dependent on intracellular Ca2+ in human atrial myocardium. Am J Physiol Cell Physiol 290: C1437-C1445.

Ramet ME, et al., (2003). High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life. J. Am. Coll. Cardiol., 41:2288–2297.

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.

Richardson SM, Maleque MA, Motley ED., (2003). 3-Morpholinosyndnonimine inhibits 5-hydroxytryptamine-induced phosphorylation of nitric oxide synthase in endothelial cells.Cell Mol Biol.,49(8):1385-1389.

Ritter JM, Ferro A, Chowienczyk PJ., (2006). Relation between beta-adrenoceptor stimulation and nitric oxide synthesis in vascular control. Eur J Clin Pharmacol., 62 (Supplement 13):109-113.

Rosenzweig A., (2005). Circulating Endothelial Progenitors – Cells as Biomarkers. NEJM., 353;10: 1055-1057.

Rubins et al., (1999). Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med., 341:410–418.

Sanchez FA, Savalia NB, Duran RG, Lal BK, Boric MP, Duran WN., (2006). Functional significance of differential eNOS translocation. Am J Physiol Heart Circ Physiol., May 5; [Epub ahead of print]

Satake N, Shibata S, (1999). The potentiating effect of genistein on the relaxation induced by isoproterenol in rat aortic rings. Gen Pharmacol, 33:221–227. Shaul PW., (2002). Regulation of endothelial nitric oxide synthase: location, location, location. Annu. Rev. Physiol., 64:749–774.

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

Shin WS, Hong YH, Peng HB, De Caterina R, Libby P, Liao JK, (1996). Nitric oxide attenuates vascular smooth muscle cell activation by interferon. The role of constitutive NF-B activity. J Biol Chem, 271:11317–11324.

Skidgel RA, Stanislavjevic S, Erdos EG., (2006). Kinin- and angiotensin-converting enzyme (ACE) inhibitor-mediated nitric oxide production in endothelial cells. Biol Chem., 387(2):159-65.

Spieker et al., (2002). High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation, 105:1399–1402.

Spyridopoulos I, Haendeler J, Urbich C, Brummendorf TH, Oh H, Schneider MD, Zeiher AM, Dimmeler S, (2004). Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation, 110:3136 –3142.

Squadrito F, Altavilla D, Crisafulli A, Saitta A, Cucinotta D, Morabito N, D’Anna R, Corrado F, Ruggeri P, Frisina N, Squadrito G, (2003). Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med, 114:470–476.

Sütsch G, Kiowski W, Yan X-W, Hunziker P, Christen S, Strobel W, Kim J-H, Rickenbacher P, Bertel O., (1998). Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure. Circulation, 98:2262-2268

Uittenbogaard A, Shaul PW, Yuhanna IS, Blair A, Smart EJ., (2000). High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J. Biol. Chem., 275:11278–11283.

van der Schouw YT, de Kleijn MJ, Peeters PH, Grobbee DE, (2000). Phyto-oestrogens and cardiovascular disease risk. Nutr Metab Cardiovasc Dis., 10:154–167.

Van Nueten L, Dupont AG, Vertommen C, Goyvaerts H, Robertson JI., (1997). A dose-response trial of nebivolol in essential hypertension. J Hum Hypertens.,11(2):139-44.

Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S. (2001a). Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation, 103:2885–2890.

Verma S, Szmitko, PE, (2006). The vascular biology of peroxisome proliferator-activated receptors: Modulation of atherosclerosis. Can J Cardiol, 22 (Suppl B):12B-17B.

Walker HA, Dean TS, Sanders TA, Jackson G, Ritter JM, Chowienczyk PJ, (2001). The phytoestrogen genistein produces acute nitric oxide-dependent dilation of human forearm vasculature with similar potency to 17ß-estradiol. Circulation, 103:258–262.

Walter DH, Rittig K, Bahlmann FH, Kirchmair R, Silver M, Murayama T, Nishimura H, Losordo DW, Asahara T, Isner JM, (2002). Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation, 105:3017–3024.

Wang C-H, Ciliberti N, Li S-H, Szmitko PE, Weisel RD, Fedak PWM, Al-Omran M, Cherng W-J, Li R-K, Stanford WL, Verma S., (2004). Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy. Circulation, 109:1392-1400.

Werner N, Junk S, Laufs L, Link A, Walenta K, Bohm M, Nickenig G., (2003). Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res., 93:e17– e24.

Wilson PW, Abbott RD, Castelli WP, (1988). High density lipoprotein cholesterol and mortality. The Framingham Heart Study.Arteriosclerosis, 8:737–741.

Xu H-L, Feinstein DL, Santizo RA, Koenig HM, Pelligrino DA., (2002).Agonist-specific differences in mechanisms mediating eNOS-dependent pial arteriolar dilation in rats. Am J Physiol Heart Circ Physiol., 282:H237-H243

Yu J, Rudic RD, Sessa WC, (2002). Nitric oxide-releasing aspirin decreases vascular injury by reducing inflammation and promoting apoptosis. Lab Invest, 82:825–832.

Yuhanna IS, et al., (2001). High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat. Med., 7:853–857.

Zeiher AM, Schachlinger V, Hohnloser SH, Saurbier B, Just H., (1994). Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis. Circulation, 89:2525–2532.

Read Full Post »

Building a Drug-Delivery System(DDS): choice of polymers and drugs

Posted in Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Nanotechnology for Drug Delivery, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, tagged Biology, Cancer - General, Proceedings of the National Academy of Sciences of the United States of America on October 4, 2012| 3 Comments »

Author: Tilda Barliya PhD

Title: Building a DSS: choice of polymers and drugs

Category: Nanotechnology and drug delivery

During the last 40 years, controlled drug delivery has become one of the most challenging and rapidly advancing scientific areas. Delivery systems can offer numerous advantages compared to conventional dosage forms. This coalition of polymeric science and pharmaceutical science led to the innovation in the design and development of drug delivery systems (DDS). Some of the challenges of most drug delivery systems include poor bioavailability, in vivo stability, solubility, intestinal absorption, sustained and targeted delivery to site of action, therapeutic effectiveness, side effects and patient compliance as well as plasma fluctuations of drugs which either fall below the minimum effective concentrations or exceed the safe therapeutic concentrations.

The purpose of these polymers in such system is to increase the delivery effectiveness of drugs to pathological cells by protecting them from degradation in the physiological environment, localize the drug to the desired site and be non-toxic. (1,3,4 ).

Grund S and colleagues nicely outlined the history of polymer-based drug delivery system, the types of polymers and drug combinations (1).

Classification:

– Origin (synthetic, natural or both)

– Chemical nature (polyester, polyanhydride etc)

– Backbone stability (biodegradable or not)

– Water solubility (hydrophilic, hydrophobic) and Electrical charges

Although intertwined, delivery systems can be generally grouped as:

– Biodegradable drug delivery systems

– Diffusion controlled drug delivery system

– Responsive drug delivery system (thermo, pH, enzymatic)

These DDS systems among others are differentiated on the basis of the mechanism controlling the release of the drug from the polymers (1,2).

Biodegradable polymers disintegrate into biocompatible compounds when exposed to chemicals (like water), enzymes or microbial which leaves the incorporated drug behind. The drug molecule present in the DDS is released due to the process of erosion. Moreover, the degradation of the polymers involves breakdown of polymers and reduction by the Kreb’s cycle to carbon dioxide and water. Furthermore, biodegradable polymers can be manipulated by the addition of functional/liable groups such as: esters, amine, urea, anhydride, carbonates etc to the backbone. Here are some examples to the most common biodegradable polymers; polyesters, polyacrylic acids, polyanhydride, polyurea etc

Diffusion controlled-polymer systems involve the dispersion of the therapeutic molecule within the polymer shell. The sustained release of the drug from this system is driven by diffusion through the pores or between the polymer chains. Drug: Progestasert (intra-uterine), Nicoderm (transdermal)

Responsive drug delivery systems release the drug in a more controlled manner which can be stimulated by the surrounding such as temperature, solvent, pH and/or concentration. Poly (N-isopropylacrylamide) is a well known example for a thermo-responsive polymer. Poly (ethylene glycol), poly lactic acid etc are known to be used for their thermogelling system. Drug: Atridox.

A different way to approach drug delivery system is:

– Temporal controlled

– Distribution controlled

In temporal control DDS, the aim is to deliver the drug a specific time during the treatment and controlled release over extended duration is highly beneficial for drugs that are rapidly metabolized and eliminated from the body after administration (2)

in distribution controlled DDS, the aim is to the deliver the drug to a specific site in the body. This delivery system is highly beneficial when natural distribution encounter body cells and cause major side effects that prohibit further treatment ( i.e chemotherapy) or when natural distribution can’t be facilitated using the regular systemic system (i.e passing the BBB and reaching brain tumors)

The choice of drugs imposed various restrictions on the type of the delivery system employed.

For example, a drug that is to be released over an extended period in a patient’s stomach where the pH is acidic and environmental conditions fluctuate widely will require a controlled release system very different from that of a drug that is to be delivered in a pulsatile manner within the blood system.

It is also very important to understand the fate of the polymer after the drug has been released, such as polymers that naturally excreted from the body (kidneys), removed after the drug release (patch or and insert) or extract through the GI track, are acceptable in medical application.

Four physicochemical properties of polymers can affect the opsonisation process and determine the degree of RES clearance (1):

Charge
Molecular size
Shape
Hydrophobicity/lipophilicity

In summary

Polymer science has become the motor for the development of new drug delivery systems in the past decades and requires an increasingly intensive cooperation between chemists, technologists and biologists.

“Over the years, especially induced by the introduction of micro- and nanosized carriers, they have changed their profile to parenteral drug applications and are now capable of offering advanced, more sophisticated and multifunctional approaches such as stealth effects and drug targeting for medicines. Combination therapy applying multiple types of drugs concurrently with one single drug delivery system will lead to more effective therapeutics and a more convenient application for the patients”

Novel, tailored polymers with more complicated and complex structures and functions may influence many related scientific and regulatory fields. However, several questions regarding regulatory approval of polymer-based carriers are still pending, and the establishment of new guidelines and policies especially adapted to nanosized polymer materials and their unique properties is still in the beginning. New criteria to determine identity, purity, and stability of the materials during manufacturing and storage have to be
defined and confirmed by new validated analytical methods.

References

Grund S, Bauer M and Fischer D. Polymers in drug delivery-State of the art and future trends. Advanced Engineering Materials 2011, 13(3); B61-B87. http://onlinelibrary.wiley.com/doi/10.1002/adem.201080088/abstract
Unrich K.E, Cannizzaro S.N and Langer R.S. Polymeric systems for controlled Drug release. Chem. Rev. 1999, 99; 3181−3198. http://www.qmc.ufsc.br/qmcweb/artigos/dor/bonus/Polymeric%20Systems%20for%20Controlled%20Drug%20Release.pdf
Mody V.V. Introduction ro polymeric drug delivery. Internet journal of medical update 2010; 5(2): 1-2 http://www.akspublication.com/Editorial_Jul2010_.pdf
Muhammad T, Nur Z, Piletska E.V, Yimit O and Piletsky S.A.Rational design of molecularly imprinted polymer: the choice of cross-linker. Analyst. 2012 Jun 7;137(11):2623-8. Epub 2012 Apr 26. http://pubs.rsc.org/en/content/articlelanding/2012/AN/C2AN35228
Torchilin VA. Polymeric Immunomicelles: Carriers of Choice for Targeted Delivery of Water-Insoluble Pharmaceuticals. Drug Delivery Tech 2004: 4(2). http://www.drugdeliverytech.com/ME2/dirmod.asp?sid=&nm=&type=Publishing&mod=Publications%3A%3AArticle&mid=8F3A7027421841978F18BE895F87F791&tier=4&id=5F2B931260F14B7786C80C84E46AEC1
William B. Liechty W.B, David R. Kryscio D.R, Brandon V. Slaughter B.V and Peppas N.A. Polymers for Drug Delivery Systems. Annual Review of Chemical and Biomolecular Engineering 2010 1: 149-173. http://www.annualreviews.org/doi/abs/10.1146/annurev-chembioeng-073009-100847.
Chen Y and Liu L. Modern methods for delivery of drugs across the blood–brain barrier. Adv Drug Deliv Rev 2012: 64(7); 640-665. http://www.sciencedirect.com/science/article/pii/S0169409X11002900.
Kaparissides C, Alexandridou S, Kotti K and Chaitidou S. Recent Advances in Novel Drug Delivery Systems. Journal on nanotechnology online. March 2006. http://www.azonano.com/article.aspx?ArticleID=1538

Key words: polymers, drug delivery system, materials, nanotechnology

Read Full Post »

Heart Risks and Hormones (HRT) in Menopause: Contradiction or Clarification?

Posted in Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, FDA Regulatory Affairs, Health Economics and Outcomes Research, Origins of Cardiovascular Disease, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Biology & Bio Instrumentation, tagged Brigham and Women's Hospital, Estrogen patch, Hormone therapy, North American Menopause Society, Progesterone, WHI on October 3, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Study Counters WHI on Heart Risk of Hormones in Menopause

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: October 03, 2012

Hormone therapy may actually help the heart in some respects for newly menopausal women, a randomized trial showed, although the impact on hard outcomes like stroke and breast cancer still remains to be seen.

Oral estrogen plus progesterone improved lipid levels, while a transdermal patch improved insulin sensitivity in the KEEPS trial, according to researchers led by S. Mitchell Harman, MD, PhD, of the nonprofit Kronos Longevity Research Institute, which sponsored the trial.

Neither combination hormone treatment altered atherosclerosis progression or raised blood pressure, according to a Kronos press release summarizing a report to be presented Wednesday at the North American Menopause Society meeting in Orlando.

“The results provide reassurance for women who are recently menopausal and taking hormone therapy for short-term treatment of menopausal symptoms,” the group concluded in the release.

The need for reassurance stems from results released a decade ago from the Women’s Health Initiative (WHI), which showed an elevated risk of cardiovascular disease, stroke, and thromboembolic events as well as breast cancer with estrogen plus progestin.

Subsequent studies largely affirmed those risks and pointed to others, including ovarian cancer, lung cancer mortality, and probable dementia.

Menopause organizations largely recommended “the lowest dose for the shortest time” but have started backing away from that stance, instead endorsing a more flexible approach based on type and timing of hormone therapy.

Contradiction or Clarification?

The new study didn’t show significant differences in adverse events between women taking oral or transdermal estrogen with progesterone and those on placebo, including:

Breast cancer
Endometrial cancer
Myocardial infarction
Transient ischemic attack
Stroke
Venous thromboembolic disease

“However, the absolute numbers of such events were extremely small in all three treatment groups, making definitive conclusions impossible,” the researchers acknowledged.

Nor is the KEEPS study ever likely to definitively determine safety, because it was too small to assess clinical events, session moderator and presenter JoAnn E. Manson, MD, DrPH, commented in an email to ABC News and MedPage Today.

But that wasn’t the point of the trial, said Manson, who serves as chief of preventive medicine at Brigham and Women’s Hospital in Boston and is outgoing president of the menopause society.

“The KEEPS trial does not challenge the conclusions of WHI about the risks of clinical events with hormone therapy,” she wrote. “KEEPS and WHI were addressing entirely different questions.”

The earlier study tested hormone therapy as it was in clinical use at the time, for cardiovascular prevention based on epidemiologic suggestion of benefit.

The evidence has clearly come down against hormone therapy for that use, Manson noted.

The question that KEEPS is now answering is how perimenopausal women should approach management of menopausal symptoms — if relatively short periods of hormone therapy are safe, noted Sharonne N. Hayes MD, of the Women’s Heart Clinic at the Mayo Clinic in Rochester, Minn.

So it may be enough that these risks weren’t substantially elevated in the trial, several experts contacted by ABC and MedPage Today agreed.

“The safety of HRT in this newly menopausal population is very reassuring and will likely increase usage as well as demand for HRT in women suffering with vasomotor symptoms,” commented neurologist Cynthia L. Harden, MD, of the North Shore-Long Island Jewish Health System in Great Neck, N.Y., who said the KEEPS data adds nuance rather than contradiction.

The results don’t change the post-WHI clinical approach of yearly reassessment targeting discontinuation after a few years of hormone therapy, added Wendy Vitek, MD, an ob/gyn at the University of Rochester Medical Center in Rochester, N.Y.

Different Populations, Different Drugs

There were some differences between the Women’s Health Initiative and the KEEPS trial that may lead to real differences in outcome, though, researchers suggested.

The KEEPS trial included 727 healthy women ages 42 to 58 who were all within 3 years of the onset of menopause at baseline.

The mean age was 52, whereas the vast majority of women in the nine hormone therapy trials done to date, including the WHI, were in their 60s.

KEEPS randomized its newly-menopausal population to double-blind treatment with cyclical micronized progesterone (Prometrium) plus one of the following:

Oral conjugated equine estrogen (Premarin) given at 0.45 mg/day, which was lower than the 0.625 mg/d used in the WHI
Transdermal estradiol (Climara) at 50 µg/day, an option not available in the WHI
Placebo

Even the two different estrogen administration routes showed some differential effects on cardiovascular risk factors, the investigators pointed out.

HDL cholesterol and triglycerides rose while LDL fell with the oral estrogen.

The patch didn’t affect any lipid levels, but it did lower insulin resistance, which the oral form did not.

Neither drug boosted systolic or diastolic blood pressure, unlike the blood pressure increases seen with oral estrogen in the WHI.

Atherosclerosis neither accelerated nor reversed with 48 months of either treatment as monitored by carotid ultrasound, although there was a nonsignificant trend for less coronary artery calcium accumulation compared with placebo, noted Harman, who also practices at the Phoenix VA Medical System.

But that’s not necessarily reassuring with regard to cardiovascular outcomes for this younger group of women, Jacques Rossouw, MBChB, MD, chief of the WHI Branch of the National Heart, Lung and Blood Institute, noted in an email to ABC and MedPage Today.

“Changes in arteries in younger women have little relation to risk of stroke,” he explained. “Estrogen/progestin have [effects] on clotting mechanisms, on inflammation mechanisms. Those are things that trigger acute heart attack or stroke [in younger women]. Perfectly healthy young women can have strokes but have completely normal arteries. ”

Really, “the lack of effect on atherosclerosis reinforces the results of the WHI that hormone therapy is not good preventive therapy for heart disease,” added Lewis H. Kuller, MD, DrPH, of the University of Pittsburgh.

As expected, hormone therapy cut down on hot flashes and night sweats while raising bone density and mood, co-investigator Sanjay Asthana, MD, of the University of Wisconsin in Madison, said in the Kronos press release.

Sexual function also improved compared with placebo, in accord with the reduction in vaginal dryness although not the lack of improvement in sex drive seen in prior studies.

“KEEPS also highlights the need for individualized decision making about hormone therapy, given that oral conjugated equine estrogen and transdermal estradiol may have different profiles of effects, and different women have different symptom profiles and priorities for treatment,” the researchers noted in the press release.

KEEPS Sponsor Biased?

Kronos has long had an openly declared interest in countering the 2002 WHI findings of increased health risks from postmenopausal hormone therapy. In 2007, it issued a series of press releases attacking the WHI conclusions and touting KEEPS — one of which included a synopsis describing the nascent trial as “one of the studies to refute the WHI.”

The money behind Kronos comes from the Aurora Foundation. The latter was established by John Sperling, the billionaire founder of the University of Phoenix and other for-profit education ventures.

About 90% of Kronos’ $5.3 million in funding in 2010, the last year for which public records are available, came from Aurora. The $4.8 million given to Kronos that year was more than half of Aurora’s total giving.

Sperling, who is the foundation’s sole trustee, has a long history of involvement in sometimes controversial biological research involving life extension. He funded a successful, multimillion-dollar effort to clone his girlfriend’s dog in 2007, and later a similar cloning project for house cats.

Previously, he had bankrolled a medical clinic in a Phoenix suburb called the Kronos Group — not related to the Kronos Longevity Research Institute — that offered anti-aging remedies to older patients. It has since morphed into Kronos Optimal Health, which markets relatively conventional health and wellness programs to employers and individuals.

A 2004 article in Wired magazine reported that Sperling had also invested in a group of biotechnology companies seeking to develop anti-aging technologies based on cloning and stem cells.

The study was sponsored by the Kronos Longevity Research Institute with funding from the National Institutes of Health for the ancillary cognitive and affective portion.

The presentation was supported by grant funding from Noven Pharmaceuticals.

This article was developed in collaboration with ABC News.

Primary source: North American Menopause Society
Source reference:
Manson JE, et al “New findings from the Kronos early estrogen prevention study (keeps) Randomized trial” NAMS2012.

Crystal Phend

Staff Writer

Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctorâ€™s Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.

SOURCE:

http://www.medpagetoday.com/MeetingCoverage/NAMS/35106?utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news

http://www.medpagetoday.com/OBGYN/HRT/32952

http://www.medpagetoday.com/OBGYN/HRT/31394

Read Full Post »

Commentary on Dr. Baker’s post “Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes”

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, tagged Apoptosis, Baker, Cancer - General, cell survival, Craig Mello, ENCODE, junk DNA, Messenger RNA, MicroRNA, miR, miR-1, miR-155, miR-223, miR-380, miRNA, mRNA destabilization, neuroblastoma, non-coding, Noncoding DNA, p53, RNA on October 3, 2012| 6 Comments »

Author and Curator: Ritu Saxena, Ph.D.

A recent post by Dr. Margaret Baker entitled “Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes” talks about how the ENCODE project is revealing new insights into the functions of non-coding region of the human genome previously labeled as “junk DNA”. MicroRNA or miRNA, which as stated by Dr. Baker, “are among the non-gene encoding sequences in the genome and have been shown to play a major post-transcriptional role in expression of multiple genes.”

The post has touched upon several aspects of miRNA including origin, function, and mechanism of action. This commentary is an extension of Dr. Baker’s post, expanding upon the mechanism of action of miRNAs along with their role in potential disease therapy.

microRNA: Revisiting the past

MicroRNA were not discovered long back, infact, it was in 1998 when the presence of the non-coding RNAs that could be involved in switching ‘on’ and ‘off’ of certain genes. In the last decade, 2006 Nobel Prize for medicine or physiology was awarded to scientists Andrew Fire and Craig Mello for their discovery of this new role of RNA molecules.

A breakthrough research was published in the September 2010 issue of Nature journal, stating that mammalian microRNAs predominantly act by decreasing the levels of target mRNA. Mammalian microRNAs predominantly act to decrease target mRNA levels. miRNAs were initially thought to repress protein output without changes in the corresponding mRNA levels. Guo et al challenged the previous notion of ‘translational repression’ and concluded on the basis of their experimental results that ‘mRNA-destabilization’ scenario for the major part is responsible for the repression in protein expression via miRNAs. Authors utilized the method of ‘ribosome profiling’ to measure the overall effects of miRNA on protein production and then compared these to simultaneously measured effects on mRNA levels. Ribosome profiling prepares maps that exact positions of ribosomes on transcripts after nucleases chew upon the exposed part of transcripts that are not covered by ribosomes. MiR-1 and miR-155 were introduced into the HeLa-cell line. Both of these miRNAs are not normally expressed in HeLa cells. Another miRNA used was mir-223 which is expressed in significant amounts in neutrophils. The reason for choosing the set of these miRNAs was that they had already been shown to repress protein levels via proteomics research. It was deciphered that miRNA-mediated repression was similar regardless of target expression level and further stated that “for both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for lowered mRNA levels accounted for most for most (>/=84%) of the decreased protein production.” These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.

Authors concluded that the discovery “will apply broadly to the vast majority of miRNA targeting interactions. If indeed general, this conclusion will be welcome news to biologists wanting to measure the ultimate impact of miRNAs on their direct regulatory targets.”

Since then and even before the paper was published, several other miRNAs and their roles have been discovered. Information on miRNAs has been consolidated in a database that can be accessed online at http://www.mirbase.org/

microRNA: From bench to bedside

Scientific community had speculated the role of non-coding RNAs in disease treatment right after their discovery. One such study demonstrating the utilization of microRNA for Cancer treatment was published in the September 2010 issue of the journal Nature Medicine. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome inMYCN-amplified neuroblastoma

The p53 gene is known as a tumor suppressor gene and its inactivation has been associated in some cancers such as neuroblastoma. The study reported that microRNA-380 (miR-380) was able to repress the expression of p53 gene in cancer patients causing uninhibited cell survival and proliferation. The research group was able to decrease the tumor size in vivo in a mouse model of the neuroblastoma by delivering miR-380 antagonist. The researchers also observed that the inhibition of endogenous miR-380 in embryonic stem or neuroblastoma cells resulted in induction of p53, and extensive apoptotic cell death.

Thus, the success of miR antagonist for decreasing tumor size speaks of the effectiveness of miR as a potential therapeutic target for cancer treatment.

In conclusion, as stated by Dr. Baker in her post, “the miRNA data for tissues and specific cell types involved in disease pathology form a new approach to either detecting or possibly correcting gene (coding or non-coding) dysregulation. miRNA mimics and anti-miRNA agents are being developed as new therapeutic modalities.”

Reference:

Pharmaceutical Intelligence post, Author, Dr. Margaret Baker: Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes

http://pharmaceuticalintelligence.com/2012/09/24/junk-dna-codes-for-valuable-mirnas/

Research articles: Mammalian microRNAs predominantly act to decrease target mRNA levels

miR-380-5p represses p53 to control cellular survival and is associated with poor outcome inMYCN-amplified neuroblastoma

Expert reviews- miRNA and Cancer treatment

News briefs: http://ygoy.com/2010/10/02/new-treatment-for-junk-dna-induced-cancers-discovered/

http://www.evolutionnews.org/2010/10/micrornas–once_dismissed_as_j038861.html

Read Full Post »

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Nitric Oxide in Health and Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Biology & Bio Instrumentation, Technology Transfer: Biotech and Pharmaceutical, tagged Calcium, Endothelium, Estradiol, Estrogen, Isozyme, Messenger RNA, nitric oxide, Nitric oxide synthase, NO, sex hormones on October 3, 2012| 5 Comments »

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Reporter and Curator: Sudipta Saha, Ph.D.

Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium, NO synthesis has subsequently been shown to play important roles in:

the regulation of vascular and gastrointestinal tone,
in cell-mediated cytotoxicity against bacteria and tumors, and
in a variety of central and peripheral nervous system activities.

NOSs can be divided into three functional classes based on their sensitivity to calcium.

The cytokine- or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations.
The constitutive forms, isozymes eNOS (originally described in endothelial cells) and
nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion.

The mechanisms by which their synthesis is controlled are unknown. The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced. The three human isozymes characterized to date are distinct, with their deduced protein sequences showing only 50-60%o amino acid identity. nNOS, which in rats and humans localizes to neurons in the central and peripheral nervous system and colocalizes with NADPHdiaphorase activity, has also been shown to be widely distributed in several non-neuronal tissues including human skeletal muscle.

It had been thought that both nNOS and eNOS were purely constitutive enzymes, although studies suggest eNOS may be induced by shear stress. Studies demonstrate that these NOSs can be induced in several tissues during pregnancy and in nonpregnant female and male animals by estradiol and that in skeletal muscle it is accompanied by an increase in NOS-specific mRNA.

Evidences emerging from various laboratories showed that there is an increase in the release of NO from the vasculature during pregnancy. Furthermore, treatment of pregnant animals at the end of gestation with tamoxifen reduced NOS activity in the cerebellum, an organ where tamoxifen acts as a pure estrogen-receptor antagonist. Thus, the increase in calcium-dependent NOS activity during pregnancy is mediated by estrogen. This conclusion is supported by the fact that treatment of nonpregnant females and male animals with estradiol also increased calcium-dependent NOS activity in all tissues studied.

Interestingly, testosterone treatment also increased cerebellar NOS activity without affecting other tissues. However, testosterone may increase brain NOS by directly binding estrogen receptors as has been reported. Furthermore, the cerebellum was the only tissue in the male to respond to a 5-day course of estradiol, suggesting that it may have a larger number and/or a greater availability of estrogen receptors than other tissues. In addition, the brain is rich in aromatase, which converts testosterone into estradiol. This, together with the observation that progesterone does not induce NOS, indicates that the induction of both nNOS and eNOS is specific for estrogen and not a characteristic of all sex steroids. These experiments do not exclude the possibility that the addition of progesterone might modify the estradiol effect.

The increases in NOS activity are the result of augmented enzyme synthesis (enzyme induction) since they are accompanied by increases in the specific mRNAs for both eNOS and nNOS. It is not, however, possible to tell whether the increases in mRNA are caused by an upregulation of mRNA synthesis (transcriptional induction) or decreased mRNA breakdown.

Although calcium-dependent NOS activity was increased by estradiol in tissues obtained from both female and male guinea pigs, a longer duration of treatment was necessary in the male. The most likely explanation for this observation is that the number or availability of estrogen receptors is initially too low in most tissues of the male and requires a period of estrogen priming. Although other factors may play a role, the duration of exposure may well explain the observation that the effect of pregnancy on NOS-specific mRNA is greater than estradiol alone.

The observation that estradiol induces calcium-dependent NOSs has several important implications:

An increase in release of NO from the endothelium would decrease vascular tone and contractility, events that are characteristic in pregnancy.
Heterogeneity among tissue endothelium regarding the effects of estrogen on basal NO release could explain the selective redistribution of maternal cardiac output to organs important for a successful pregnancy.
Consistent with this possibility is the observation that the effect of pregnancy on endothelium-derived NO is greatest in the uterine artery, followed by the mesenteric artery and then renal arteries.
An alternative hypothesis to explain the adaptation of smooth muscle to pregnancy is that it is caused by prostacyclin. Prostacyclin is increased during pregnancy and contributes to the observed reduced contractility of the ovine uterine artery to angiotensin II.

However, estradiol does not increase the synthesis of prostacyclin by the endothelium, nor does inhibition of prostacyclin synthesis prevent the effects of pregnancy on smooth muscle. In addition, both the incidence of esophageal reflux and the gastrointestinal transit time are increased during pregnancy. Although this phenomenon has previously been attributed to a direct effect of progesterone, NO is a powerful dilator of the gastrointestinal smooth muscle. If the increase in NOS activity observed in the esophagus applies to the bowel, enhanced NO might be the mechanism underlying both increased esophageal reflux and transit time.

The biological signifcance of an estradiol-dependent increase in the NOS in the central nervous system is of great interest and deserves further investigation. Furthermore, an estradiol-mediated increase in NOS in the vasculature could be the mechanism whereby premenopausal women are protected from coronary artery disease since increased NOS may slow the development of atherosclerosis and reduce the contractile response to acute thrombosis. Finally, the induction of calcium-dependent NOS enzymes by estradiol suggests that the present classification of this family of enzymes into constitutive and inducible types needs to be revised, since eNOS and nNOS enzymes at least are both constitutive and inducible.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed?term=Calcium%20dependent%20NOS%20induction%20by%20sex%20hormones

Other research published on Nitric Oxide on this Scientific Web Site include the following:

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/

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

Curator: Aviva Lev-Ari, PhD, RN, July 12, 2012

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 1

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

Read Full Post »

« Newer Posts - Older Posts »

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

Archive for October, 2012

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Further observations

Summary of Key Points

Relevant observations

Most favorable and unexpected findings were:

References

Related articles

Like this:

Genes involved in Male Fertility and Sperm-egg Binding

Like this:

A new treatment for depression and epilepsy – Approval of external Trigeminal Nerve Stimulation (eTNS) in Europe

Like this:

NO Nutritional remedies for hypertension and atherosclerosis. It’s 12 am: do you know where your electrons are?

Additional References

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

Like this:

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

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

Like this:

Building a Drug-Delivery System(DDS): choice of polymers and drugs

Like this:

Commentary on Dr. Baker’s post “Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes”

microRNA: From bench to bedside

Like this:

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Other research published on Nitric Oxide on this Scientific Web Site include the following:

Like this:

Follow Blog via Email

Recent Posts

Archives

Categories

Meta

Archive for October, 2012

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Further observations

Summary of Key Points

Relevant observations

Most favorable and unexpected findings were:

References

Related articles

Share this:

Like this:

Share this:

Like this:

Share this:

Like this:

Additional References

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

Share this:

Like this:

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

Share this:

Like this:

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

Share this:

Like this:

Share this:

Like this:

Share this:

Like this:

microRNA: From bench to bedside

Share this:

Like this:

Calcium Dependent NOS Induction by Sex Hormones: Estrogen

Other research published on Nitric Oxide on this Scientific Web Site include the following:

Share this:

Like this:

Follow Blog via Email

Recent Posts

Archives

Categories

Meta

Inhibition of ET-1, ET_A and ET_A-ET_B

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

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