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Nitric Oxide: Chemistry and function

Posted in Biological Networks, Gene Regulation and Evolution, 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, Nitric Oxide in Health and Disease, tagged , , , , , , , on August 10, 2012| 22 Comments »

Curator/Author: Aviral Vatsa PhD, MBBS

Nitric oxide is one of the smallest molecules involved in physiological functions in the body. It is a diatom and thus seeks formation of chemical bonds with its targets rather than structure-function configuration of say protein receptors. Nitric oxide can exert its effects principally by two ways:

  • Direct
  • Indirect

Direct actions, as the name suggests, result from direct chemical interaction of NO with its targets e.g. with metal complexes, radical species. These actions occur at relatively low NO concentrations (<200 nM)

Indirect actions result from the effects of reactive nitrogen species (RNS) such as NO2 and N2O3. These reactive species are formed by the interaction of NO with superoxide or molecular oxygen. RNS are generally formed at relatively high NO concentrations (>400 nM)

Credits: Nitric Oxide: Biology and Pathobiology By Louis J. Ignarro

Credits: Nitric Oxide: Biology and Pathobiology By Louis J. Ignarro

Although it can be tempting for scientists to believe that RNS will always have deleterious effects and NO will have anabolic effects, this is not entirely true as certain RNS mediated actions mediate important signalling steps e.g. thiol oxidation and nitrosation of proteins mediate cell proliferation and survival, and apoptosis respectively. As depicted in the figure above, NO concentration determines the action it exerts on different proteins. This is highlighted in the following examples from different studies:

  • Cells subjected to NO concentration between 10-30 nM were associated with cGMP dependent phosphorylation of ERK
  • Cells subjected to NO concentration between 30-60 nM were associated with Akt phosphorylation
  • Concentration nearing 100 nM resulted in stabilisation of hypoxia inducible factor-1
  • At nearly 400 nM NO, p53 can be modulated
  • >1μM NO, it nhibits mitochondrial respiration

Besides the concentration, duration of NO exposure also determines how proteins respond to NO. Hence proteins can be ‘immediate’ responders or ‘delayed’ responders. The response can be either ‘transient’ (short lived) or ‘sustained’ (prolonged). Different proteins fall into these different categories. These are not rigid categories rather a functional ‘classification’.

Endogenously generated NO concentration ranges from 2 nM as in endothelial cell to >1 μM in a fully activated macrophage. This wide range, along with the unique chemical reactivity of NO offers immense versatility to the physiological effects that it can exert in different cellular milieu in the body.

In addition to the concentration-dependent effects, other factors that determine the local cellular/tissue milieu add to the complexities involved with signal transduction undertaken by NO. These factors are

  • rate of NO production
  • diffusion distance
  • rates of consumption
  • reactivity of RNS with molecular targets.

These kinetic determinants play vital role in physiological functions and disease states.

Although it is not possible to detail the modes of modulation of biological functions by NO in a short post, but I hope the post gives a taste of the intricacies involved with NO functions and that there are various parameters that determine the exact role of NO in a biological milieu.

Sources

http://www.pnas.org/content/101/24/8894.short

http://onlinelibrary.wiley.com/doi/10.1002/ijc.22336/full

http://cancerres.aacrjournals.org/content/67/1/289.short

http://www.sciencedirect.com/science/article/pii/S0005272806000417

http://goo.gl/eVXFh

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Partial Nephrectomy: Similar outcomes for robot-aided vs. conventional surgery

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , , on August 9, 2012| 1 Comment »

 

Reporter: Aviva Lev-Ari, PhD, RN

A Matched Comparison of Perioperative Outcomes of a Single Laparoscopic Surgeon Versus a Multisurgeon Robot-Assisted Cohort for Partial Nephrectomy

The Journal of Urology
Volume 188, Issue 1 , Pages 45-50, July 2012

 

Department of Urology, University of Michigan, Ann Arbor, Michigan

Received 17 October 2011 published online 14 May 2012.

Purpose

Minimally invasive nephron sparing surgery is gaining popularity for small renal masses. Few groups have evaluated robot-assisted partial nephrectomy compared to other approaches using comparable patient populations. We present a matched pair analysis of a heterogeneous group of surgeons who performed robot-assisted partial nephrectomy and a single experienced laparoscopic surgeon who performed conventional laparoscopic partial nephrectomy. Perioperative outcomes and complications were compared.

Materials and Methods

All 249 conventional laparoscopic and robot-assisted partial nephrectomy cases from January 2007 to June 2010 were reviewed from our prospectively maintained institutional database. Groups were matched 1:1 (108 matched pairs) by R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines) nephrometry score, transperitoneal vs retroperitoneal approach, patient age and hilar nature of the tumor. Statistical analysis was done to compare operative outcomes and complications.

Results

Matched analysis revealed that nephrometry score, age, gender, tumor side and American Society of Anesthesia physical status classification were similar. Operative time favored conventional laparoscopic partial nephrectomy. During the study period robot-assisted partial nephrectomy showed significant improvements in estimated blood loss and warm ischemia time compared to those of the experienced conventional laparoscopic group. Postoperative complication rates, and complication distributions by Clavien classification and type were similar for conventional laparoscopic and robot-assisted partial nephrectomy (41.7% and 35.0%, respectively).

Conclusions

Robot-assisted partial nephrectomy has a noticeable but rapid learning curve. After it is overcome the robotic procedure results in perioperative outcomes similar to those achieved with conventional laparoscopic partial nephrectomy done by an experienced surgeon. Robot-assisted partial nephrectomy likely improves surgeon and patient accessibility to minimally invasive nephron sparing surgery.

Key Words:  kidney , kidney neoplasms , nephrectomy , laparoscopy , robotics

Abbreviations and Acronyms:  CLPN, conventional laparoscopic partial nephrectomy, EBL, estimated blood loss, eGFR,estimated glomerular filtration rate, ICU, intensive care unit, LOS, length of stay, RAPN, robot-assisted partial nephrectomy,SRM, small renal mass, WIT, warm ischemia time

 

Similar outcomes for robot-aided, conventional nephrectomy June 22, 2012 in Other Robot-assisted and conventional laparoscopic partial nephrectomies have similar outcomes and complication rates, according to a study published in the July issue of The Journal of Urology. (HealthDay) — Robot-assisted and conventional laparoscopic partial nephrectomies have similar outcomes and complication rates, according to a study published in the July issue of The Journal of Urology. Ads by Google Prostate Cancer Treatment – Expert Prostate Cancer Treatment & Care – View Video to Learn More! – http://www.TuftsMedicalCenter.tv Prostate Cancer Treatment – Learn about Watchful Waiting. Get a Second Opinion at BIDMC. – http://www.BIDMC.org Jonathan S. Ellison, M.D., from the University of Michigan in Ann Arbor, and colleagues compared perioperative outcomes and complications from conventional laparoscopic and robot-assisted partial nephrectomy cases from January 2007 to June 2010. Robot-assisted partial nephrectomies were performed by a heterogeneous group of surgeons, while a single experienced laparoscopic surgeon performed the conventional procedures. One hundred eight pairs of patients were matched by age, hilar nature of the tumor, approach, and R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines) nephrometry score. The researchers found that nephrometry score, age, gender, tumor side, and American Society of Anesthesia physical status classification were similar between the groups. Conventional laparoscopic partial nephrectomy had better operative time. Robot-assisted partial nephrectomy showed significant improvements in estimated blood loss and warm ischemia time compared to the conventional laparoscopic group. The postoperative complication rates and complication distributions by Clavien classification and type were similar for both groups (41.7 percent for the conventional group and 35.0 percent for the robot-assisted group). “Robot-assisted partial nephrectomy has a noticeable but rapid learning curve,” write the authors. “After it is overcome the robotic procedure results in perioperative outcomes similar to those achieved with conventional laparoscopic partial nephrectomy done by an experienced surgeon.” More information: Abstract Full Text (subscription or payment may be required) Journal reference: Journal of Urology

http://medicalxpress.com/news/2012-06-similar-outcomes-robot-aided-conventional-nephrectomy.html

 

Prostate Cancer

What does your PSA score, level, reading, test mean?

By itself, a PSA reading does not mean very much. There are many possible causes of the rise in the PSA reading. The most common of these reasons is an enlarged, inflamed, or infected prostate. So a high PSA score does not necessarily indicate prostate cancer.

Unfortunately there is no failsafe test or methods at this time that can differentiate between a high PSA level caused by inflammation of the prostate or infection of the prostate or prostate cancer. At best doctors use a statistical model, which seeks to predict your chances of having prostate cancer. But that is purely a statistical construct and does not actually predict your specific and personal situation at all.

Nonetheless, an elevated PSA reading should not be ignored. It is a good indicator, certainly the best we have, and you should take precautionary action.

If you have a high PSA reading you need to return your prostate back to good health. You need to make important changes to your diet. You also need to have regular exercise. A third and equally important part of my recommendation is to take appropriate natural supplements.

I provide a roadmap in my guide “All about the Prostate”. Most men who follow my roadmap will see their PSA levels come down. It will return their prostate to good health.

http://www.bensprostate.com/minib/psa-test-and-levels/?utm_source=bing&utm_medium=cpc&utm_campaign=bing-prostate-us-broad&utm_content=psa-2&utm_term=psa

INDICATION

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

IMPORTANT SAFETY INFORMATION

Contraindications – ZYTIGA® (abiraterone acetate) may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess –Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) – AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity – Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect – ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions – The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Drug Interactions – ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations – The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

 

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Use Patents, Carve-Outs, and Incentives — A New Battle in the Drug-Patent Wars

Posted in FDA Regulatory Affairs, Health Economics and Outcomes Research, Medical Devices R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , on August 9, 2012| Leave a Comment »

 

Reporter: Aviva Lev-Ari, PhD, RN

Arti Rai, J.D.

N Engl J Med 2012; 367:491-493  August 9, 2012

The Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch–Waxman Act, aims to strike a balance between the innovation incentives provided by patents and the greater access provided by low-cost generic drugs. The legislation, which relies in part on an explicit link between the Food and Drug Administration (FDA) drug-approval process and the U.S. patent system, has been controversial, particularly because of the ways in which firms producing brand-name drugs have exploited that link to delay market entry of generics as long as possible. Now, the tactical landscape has shifted again, with a recently decided Supreme Court case, Caraco Pharmaceutical Laboratories v. Novo Nordisk.

Under current FDA regulations, the developer of a brand-name drug must submit all patents that it deems to cover the drug to the FDA for publication in the agency’s Approved Drug Products with Therapeutic Equivalence Evaluations — the so-called Orange Book. Before marketing a generic version of a drug, the generics manufacturer must certify that all Orange Book patents for the brand-name product are invalid, are not infringed by the generic product, or have expired. Certifications that patents that are invalid or not infringed, known as Paragraph IV certifications, allow the brand-name drug maker to sue the generics manufacturer to resolve questions of validity and infringement. As a result, FDA approval of the generic drug can be delayed for up to 30 months pending legal resolution.

Orange Book listings can include both product patents on small-molecule chemicals and patents on methods of use for treating particular conditions. FDA regulations require that, in addition to patent numbers and expiration dates, method-of-use patents must have “use codes” that describe their scope.

Frequently, the main product patent on a brand-name drug expires before the use patents do. In that case, FDA regulations based on Hatch–Waxman allow generics firms the option of filing a “section viii statement,” which “carves out” from the generic label those uses on which the brand-name firm still has patents. If the FDA finds this narrower labeling acceptable from the standpoint of safety and efficacy, the generic version has a potential path to market.

Brand-name drug manufacturers have sometimes tried to sue to prevent market entry by generics companies that file section viii statements, typically arguing that although a generics firm may not be directly infringing a use patent, it should be prohibited from marketing its product because such marketing will inevitably “induce” infringement. In other words, the generic-substitution practices of doctors and pharmacists — encouraged by FDA approval of “carved-out” generics as fully substitutable for brand-name drugs and by laws in many states — will inevitably lead to prescription of generic drugs for patented uses. Moreover, brand-name pharmaceutical firms argue that generics firms should be held liable because they are well aware that their products will be prescribed and dispensed in an infringing manner.

The Court of Appeals for the Federal Circuit, the intermediate appellate court for patent cases, has held that as a procedural matter, courts may hear suits brought by brand-name firms in response to a section viii statement filing. However, it has generally rejected the substantive claim of induced infringement, holding that because inducement requires more than mere knowledge that infringement is occurring, the generics firm cannot be held liable unless it specifically promoted the drug for a carved-out use.1

In recent years, carve-out labeling has assumed a prominent role in facilitating market entry of generics. For example, in fiscal year 2010, the FDA approved 11 generic drugs with carve-out labeling. In fact, 3 of the 5 top-selling brand-name drugs that “went generic” that year did so as a consequence of such labeling.2

On occasion, brand-name drug manufacturers have attempted to defeat carve-out attempts by listing use codes that substantially exceed the scope of the use patent. This tactic can be effective, since the FDA does not evaluate representations of patent information in use codes.3

In April 2012, however, the Supreme Court issued a decision enabling generics firms to challenge the submission to the FDA of overly broad use claims. In Caraco, Novo Nordisk’s only unexpired patent covered a relatively narrow use — treating non–insulin-dependent diabetes by combining its diabetes drug repaglinide with another drug, metformin. In the Orange Book, however, Novo Nordisk listed a much broader use code that covered all methods for “improving glycemic control in adults with type 2 diabetes mellitus,” thereby denying generics firms a meaningful carve-out.

The key question in this case was whether amendments to Hatch–Waxman implemented in 2003 allowed generics firms, in the course of a patent-infringement lawsuit brought by the brand-name company, to file a counterclaim to correct overly broad listings of Orange Book use codes. The unanimous opinion of the Court, delivered by Justice Elena Kagan, held that the amendments were indeed intended to correct such overbreadth. As Kagan noted, absent the ability to correct overbreadth, a company could not market a generic drug for noninfringing uses.

As a matter of statutory interpretation, the Supreme Court decision is correct. Both the language and legislative history of the 2003 amendments indicate that Congress intended to control inaccurate Orange Book listing practices with respect to product patents and method-of-use patents. Such misleading practices had been thoroughly documented in a 2002 Federal Trade Commission report. However, as Justice Sonia Sotomayor‘s concurrence points out, the mechanism provided by Congress is far from optimal. A claim to correct overbreadth can be filed only if the generics firm chooses to provoke litigation by filing a Paragraph IV certification and the brand-name firm then sues for infringement. An administrative approach to determining the accuracy of Orange Book listings — an approach in which the FDA might, for example, consult with the Patent and Trademark Office — would clearly be more efficient.

Lurking behind these technical legal disputes over carve-outs, induced infringement, and overly broad Orange Book listings is the broader policy issue of providing incentives to search for new uses. Brand-name pharmaceutical companies argue that the pervasive distribution of generic drugs for patented uses substantially undermines the efficacy of such patents and hence the incentives for finding other uses.4

Strong incentives are probably unnecessary for purposes of generating hypotheses regarding new uses. The heavy prevalence of off-label prescribing — which accounted for more than 20% of prescriptions written by office-based physicians in 2001, according to one study5 — suggests that hypotheses are pervasive. The incentives question is important, however, because the ultimate objective, from the standpoint of both patient welfare and cost, is reliable evidence of efficacy. Such evidence, which is required before the FDA can approve labeling (or allow marketing) for a new use, is generated through investment in well-designed trials.

Such investment need not emerge, however, only from individual firms operating in secrecy and motivated by patents. Indeed, one recent study found that publicly funded research formed the foundation for almost all the new-use FDA approvals that were examined.6 Going forward, the public sector’s role is likely to increase — the new National Center for Advancing Translational Sciences at the National Institutes of Health has explicitly embraced the search for new uses in a number of the programs it is funding.

In many arenas of innovation, proprietary research models supported by intellectual property and publicly funded open research models not only coexist, they play mutually reinforcing, synergistic roles. Brand-name firms could view Caraco‘s partial restriction on their deployment of overly broad use claims as an opportunity to rely less on dubious legal tactics and more on the pursuit of opportunities to leverage public-sector investment.

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

SOURCE INFORMATION

From the Duke University School of Law, Durham, NC.

REFERENCES

    1. 1

      Warner-Lambert Co. v. Apotex, 315 F.3d 1348 (Fed. Cir. 2003).

    1. 2

      Brief for the United States as amicus curiae supporting petitioners, Caraco v. Novo-Nordisk, 2011.

    1. 3

      68 Fed. Reg. 36683 (2003).

    1. 4

      Eisenberg RS. The problem of new uses. Yale J Health Policy Law Ethics 2005;5:717-739

    1. 5

      Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-1026

  1. 6

    Stevens AJ, Jensen JJ, Wyller K, Kilgore PC, Chatterjee S, Rohrbaugh ML. The role of public-sector research in the discovery of drugs and vaccines. N Engl J Med 2011;364:535-541

 

 

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Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Posted in Bio Instrumentation in Experimental Life Sciences Research, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, tagged , , , , , , on August 9, 2012| 4 Comments »

Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Reporter: Aviva Lev-Ari, PhD, RN

 

Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Udo Hoffmann, M.D., M.P.H., Quynh A. Truong, M.D., M.P.H., David A. Schoenfeld, Ph.D., Eric T. Chou, M.D., Pamela K. Woodard, M.D., John T. Nagurney, M.D., M.P.H., J. Hector Pope, M.D., Thomas H. Hauser, M.D., M.P.H., Charles S. White, M.D., Scott G. Weiner, M.D., M.P.H., Shant Kalanjian, M.D., Michael E. Mullins, M.D., Issam Mikati, M.D., W. Frank Peacock, M.D., Pearl Zakroysky, B.A., Douglas Hayden, Ph.D., Alexander Goehler, M.D., Ph.D., Hang Lee, Ph.D., G. Scott Gazelle, M.D., M.P.H., Ph.D., Stephen D. Wiviott, M.D., Jerome L. Fleg, M.D., and James E. Udelson, M.D. for the ROMICAT-II Investigators

N Engl J Med 2012; 367:299-308 July 26, 2012

BACKGROUND

It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes.

METHODS

In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes.

RESULTS

The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65).

CONCLUSIONS

In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.)

Supported by grants from the National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022) and the National Institutes of Health (UL1RR025758, K23HL098370, and L30HL093896, to Dr. Truong).

Dr. Gazelle reports receiving consulting fees from GE Healthcare; Dr. Hauser, receiving consulting fees from Astellas and the Harvard Clinical Research Institute; Dr. Hoffmann, receiving grant support from the American College of Radiology Imaging Network, Bracco Diagnostics, Genentech, and Siemens Healthcare on behalf of his institution; Dr. Nagurney, receiving grant support from Alere (Biosite), Brahms Diagnostica (Fischer), and Nanosphere on behalf of his institution; Dr. Truong, receiving grant support from St. Jude Medical and Qi Imaging on behalf of her institution and travel support from Medconvent and the Society of Cardiac Computed Tomography; Dr. Wiviott, receiving consulting fees from Arena Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, and Ortho-McNeil, grant support from AstraZeneca, Daiichi Sankyo, Eli Lilly, and Merck and Schering-Plough on behalf of his institution, and lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, and Schering-Plough; and Dr. Udelson, being on the scientific advisory board of Lantheus Medical Imaging. No other potential conflict of interest relevant to this article was reported.

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

SOURCE INFORMATION

The authors’ affiliations are listed in the Appendix.

Address reprint requests to Dr. Hoffmann at Massachusetts General Hospital, Cardiac MR PET CT Program, 165 Cambridge St., Suite 400, Boston, MA 02114, or at uhoffmann@partners.org.

 

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Patient Access to Medical Devices — A Comparison of U.S. and European Review Processes

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Massachusetts Niche Suppliers and National Leaders, Medical Devices R&D and Inventions, Mitral Valve: Repair and Replacement, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, Valves & Tools, tagged , , , , , , on August 9, 2012| 1 Comment »

Patient Access to Medical Devices — A Comparison of U.S. and European Review Processes

Reporter: Aviva Lev-Ari, PhD, RN

 

Saptarshi Basu, M.P.A., and John C. Hassenplug, M.Sc.

N Engl J Med 2012; 367:485-488  August 9, 2012

The U.S. process for approving innovative, high-risk medical devices has been criticized for taking longer than the European approval process.1 This contention is often used to support the argument that the Food and Drug Administration (FDA) should lower its standards for approving medical devices, since a slow approval process is delaying Americans’ access to innovative and lifesaving technology. But a review of the data, using appropriate end points, suggests instead that it takes the same amount of time or less for patients to gain access to innovative, high-risk medical devices in the United States as it does in the four largest European markets (Germany, France, Italy, and Britain)2 — largely because patient access is generally delayed until reimbursement decisions are made, which often takes substantially longer in Europe than in the United States.

To compare the United States and Europe fairly on this front, three criteria must be considered: the level of device innovation, equivalent start and end points, and patient access as defined by time to reimbursement. First, we focused on innovative, high-risk devices because in the United States such devices require the strongest evidence of clinical benefit and are the subject of most debates about the relative effectiveness of approval processes in different countries. Furthermore, previous studies have shown that lower-risk devices achieve market access in a similar amount of time in the United States and in Europe.

Second, an accurate comparison of time to market access requires measurement of the total time that elapses between application submission and market access. Previous studies have compared the chronologic dates of application submission and market access, but the date an application is submitted varies from country to country.

Third, patient access should be equated with the availability of reimbursement rather than with device approval, because broad patient access to a new device doesn’t occur until reimbursement by a national or third-party payer is available. Previous comparisons of the U.S. and European systems have used the approval date to measure process duration, but innovative, high-risk devices don’t reach a market where most patients can benefit from them immediately after gaining regulatory approval, though they may be accessible to patients who can afford to pay out of pocket. Rather, there is a second level of review through which public or private insurers decide whether and at what price they will pay for a device. Generally, public systems take longer than private insurers to make reimbursement decisions, and significantly more Europeans than Americans have public insurance. Two thirds of the U.S. population is covered by private health insurance, whereas only a fifth receives publicly funded reimbursement, primarily administered by the Centers for Medicare and Medicaid Services (CMS).

For both private and public systems in the United States, the pathway to patient access to a device starts with the submission of an application to the FDA. The FDA reviews innovative, high-risk devices for safety and effectiveness (clinical benefit) under the premarket approval (PMA) process, and information on the duration of reviews is publicly available. In fiscal year 2011, the FDA approved 40 applications for PMA. The average review time was 13.1 months, with 8.4 months attributed to FDA review time, and 4.7 months to the time the agency waits for the sponsor to address deficiencies in the application (“sponsor time”).3 CMS provides reimbursement for the majority of devices when they earn FDA approval. For a limited number of devices each year, however, CMS conducts a national coverage determination in response to external requests for validation or for devices that have limited or conflicting evidence of clinical benefit. This process averaged 8.6 months over the past 5 fiscal years.4 Although it is difficult to obtain data on how long private insurers take to make coverage decisions, anecdotal information from private insurers suggests that decisions are made within a few weeks to a few months after FDA approval, depending on the amount and quality of evidence of clinical benefit.

In Europe, by contrast, most of the 27 member countries of the European Union (EU) have publicly financed health care systems; such systems cover approximately four fifths of the populations of the four largest device markets. All EU countries require devices to first obtain a Conformité Européenne (CE) marking, which refers to a symbol shown on products that indicates market approval throughout the EU. The CE marking process is conducted by for-profit, third-party “notified bodies” that have been accredited by a member country to assess device safety and performance but do not evaluate effectiveness (which requires more clinical data). Although publicly available data are limited, anecdotal information from notified bodies suggests that the process takes 1 to 3 months, excluding sponsor time.

Most European patients do not have access to innovative, high-risk devices as soon as the devices receive a CE marking. Each country must first make a decision about reimbursement, a process that varies substantially among countries.5 Though a CE marking can be granted on the basis of fewer clinical data than are required for FDA approval, European standards for reimbursement are often similar to or higher than those that the FDA imposes for device approval. European countries may require additional data on the device’s safety and effectiveness, as well as on cost-effectiveness.

In France, a centralized body makes reimbursement decisions after assessing the safety and effectiveness of individual devices. Reimbursement decisions in Italy are devolved to the various regions, and Britain and Germany conduct broader assessments of device types or procedures, rather than of individual devices. Typically, innovative devices not covered under an existing diagnosis-related group (DRG) require review under the lengthier Health Technology Assessment process, which assesses safety, clinical benefit, and cost-effectiveness. Government-provided information on time to reimbursement varies by country. Estimated time frames are an average of 71.3 months in Germany, a range of 36.0 to 48.0 months in France, a range of 16.4 to 26.3 months in Italy, and an estimated 18 months in Britain.

Using this information, we determined that the time it takes to bring innovative, high-risk devices to patients in the United States is similar to or shorter than that in the top four European markets (seefigureComparison of Time to Market in Premarket Approval and Reimbursement Processes.). The public (CMS) process in the United States takes approximately as long as those in Italy and Britain, approximately half as long as that in France, and less than a third as long as that in Germany. The difference in time to market access is even greater when it comes to private insurers (covering the majority of the U.S. population), which often make reimbursement decisions within a few months after FDA approval.

To further illustrate this point, we compared the time to approval for five innovative, high-risk medical devices available in France, Italy, and the United States (see tableComparison of Time to Market Access for Five Innovative Devices in France, Italy, and the United States.). These case studies indicate that the average time to market access for these devices was 26.3 months in France, 30.8 months in Italy, and 15.3 months in the United States.

These numbers may not fully capture the reasons why a device reaches the market more quickly in one country than in another and do not reflect experiences with all innovative, high-risk devices. However, unless one uses equivalent standards in terms of the level of risk, the start and end points of the process, and the key end point of market access, accurate comparisons cannot be made.

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

This article was published on August 1, 2012, at NEJM.org.

SOURCE INFORMATION

From the Office of Planning, Office of the Commissioner, Food and Drug Administration, White Oak, MD.

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On-site nano-Bio-production Unit: To Produce Medicines as per the demand

Posted in Chemical Genetics, Genome Biology, Personalized and Precision Medicine & Genomic Research, tagged , , , on August 8, 2012| Leave a Comment »

On-site nano-Bio-production Unit: To Produce Medicines as per the demand.

via On-site nano-Bio-production Unit: To Produce Medicines as per the demand.

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Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

Posted in Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, tagged , , , , , , on August 8, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Extreme Performance Athletes May Be at Risk for Cardiac Arrhythmias

http://bidmc.org/CentersandDepartments/Departments/CardiovascularInstitute/CVINewsletter/TooMuchGoodThing.aspx

World-class rowing champion Frederick SchochWorld-class rowing champion Frederick Schoch

You probably know that regular, moderate exercise can result in many health benefits. But you may be surprised to learn that prolonged, intensive endurance exercise on an Olympian scale can actually damage your heart.

Scientists and doctors have demonstrated that long-term training and competition in extreme endurance sports such as marathons, iron-man triathlons, competitive rowing and long-distance bicycle races may cause structural changes to the heart and large arteries.

“Athlete’s heart syndrome” was first described more than 100 years ago as an apparently benign condition in which the elite athlete’s heart enlarges and thickens. For many years, doctors noted that abnormal electrocardiograms were common for extreme athletes, but no evidence pointed to an association with serious arrhythmias or sudden cardiac death. However, there is accumulating evidence that chronic extreme athletic activity may lead to potentially harmful changes in the heart in some individuals.

For example, a review published recently in the Mayo Clinic Proceedingsdemonstrated that approximately 12 percent of apparently healthy marathon runners showed microscopic areas of fibrosis, or scarring, in the heart chambers. The significance of these changes is not clear, but they could predispose the heart to abnormal rhythms in some cases.

A two-year follow-up revealed that the rate of coronary heart disease was significantly higher in extreme marathon runners than in moderate runners.

A 2011 Swedish study showed that elite cross-country skiers with long years of endurance training had a 29 percent higher risk of developing a variety of abnormal heart rhythms, some benign as well as some more serious.

Extreme Athletics and Atrial Fibrillation

High-profile professional athletes who are believed to have died of fatal arrhythmias include NFL star Reggie White, who died at 43 in 2004, and legendary ultra-marathoner Micah True, who died at 58 earlier this year.

Researchers believe high-endurance sports may promote the occurrence of atrial fibrillation in susceptible persons. This arrhythmia, which involves uncomfortable episodes of irregular, rapid heartbeat caused by faulty electrical signals in the heart, is usually not life-threatening. However, in about 5 percent of those with the condition, it can lead to heart failure and stroke.

“Physicians are becoming increasingly aware that extreme training regimens and endurance-style competitions can, in rare instances, lead to potentially dangerous abnormal cardiac rhythms,” says Alfred E. Buxton, MD, Director of the Clinical Electrophysiology Laboratory at Beth Israel Deaconess Medical Center’sCardioVascular Institute.

Physicians need to take into account the current research, follow new developments and be prepared to advise certain patients to make lifestyle changes based on the new data, he says.

One Athlete’s Story

Mark E. Josephson, MDMark E. Josephson, MD

Mark E. Josephson, MD, Chief of Cardiovascular Medicine at the CardioVascular Institute — and an internationally recognized expert in electrophysiology and catheter ablation — has treated numerous rowers and other high-performance athletes who have suffered from atrial fibrillation. One example is Frederick Schoch, a world-class rowing champion and executive director of Boston’s celebrated annual Head of the Charles Regatta.

Schoch was diagnosed with paroxysmal atrial fibrillation in 2009 after he experienced heavy breathing and lightheadness following his crew’s fifth consecutive first-place finish in the Regatta’s 50 and older category. Schoch learned that atrial fibrillation can cause blood clots in the left atrium (upper chamber) and can lead to heart failure and stroke. Treatments may include medications (such as beta-blockers or anti-arrhythmic drugs), interventions (such as catheter ablation) and/or surgery.

To regulate his heart rate, Schoch’s primary care physician prescribed the drug diltiazem, but his episodes persisted and he feared he would never be able to compete again.

“Rowing is in my DNA,” says Schoch, whose father was an Olympic rower. “But with afib, I couldn’t even walk up the stairs.”

In 2010, a fellow rower referred Schoch to Dr. Josephson, who has treated more than 1,000 cardiac arrhythmia patients.

Back in the Boat

After hearing Schoch’s story, Dr. Josephson performed a catheter ablation, an interventional procedure that reduces the frequency of paroxysmal atrial fibrillation symptoms about 70 percent of the time. The procedure typically lasts two hours and involves inserting a catheter through the groin and puncturing the membrane between the heart’s right and left atria. Catheters are placed at the pulmonary veins (which are the source of atrial fibrillation triggers in 90 percent of paroxysmal afib cases), while the cardiologist delivers a high-frequency, low-voltage current to the site. This burns the tissue to isolate the pulmonary vein from the atrius so that triggers can’t initiate atrial fibrillation.

Schoch spent one night at BIDMC and returned to work two days later. He resumed his training, and in 2011, just one year after his procedure, he led his team to their sixth first-place finish in the Regatta’s senior division. Currently, he is serving as a television analyst, commenting on rowing at the 2012 Summer Olympics. He is also training for the next Head of the Charles Regatta in October.

“I am eternally grateful to Dr. Josephson,” says Schoch. “I hope that my experience can be helpful to others.”

Do Not Stop Exercising!

While the findings cited here are unsettling, they shouldn’t discourage anyone from being physically active. For most adults, the American Heart Associationrecommends 150 minutes of moderate exercise a week (30 minutes a day on five days), or 75 minutes per week of vigorous exercise. Exercise is almost as effective when divided into several shorter periods during the day for convenience.

The result will be increased physical capacity and mental well-being, and a significant reduction in cardiovascular disease risk factors such as high blood pressure, excess weight and unhealthy cholesterol levels. Regular exercise helps fend off not only heart disease and stroke, but also many cancers, osteoporosis, diabetes, arthritis and depression.

“Moderate exercise is certainly good for your heart and your overall health,” says Dr. Buxton. “However, as is usually the case in life, moderation should be the guideline. Beyond 30 to 60 minutes per day, you may reach a point of diminishing returns. So don’t overdo it, but take comfort in knowing that with the right diagnosis and treatment, atrial fibrillation can be managed successfully.”

Above content provided by the CardioVascular Institute at Beth Israel Deaconess Medical Center. For advice about your medical care, consult your doctor.

Posted August 2012

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$20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy

Posted in Pharmaceutical R&D Investment, tagged , , , , , , , , , , , , , on August 8, 2012| 2 Comments »

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

Last August, UPenn scientists announced the dramatic results of a tiny clinical trial of their immunotherapy approach, describing long-lasting remissions in leukaemia patients for whom standard therapies had stopped working. Trials are also underway for other leukaemias and for lymphoma, mesothelioma, myeloma and neuroblastoma, according to the university.

The therapy developed by UPenn’s Carl June is complicated. Vaccines prompt a patient’s immune system to attack dangerous cells through an approach, called chimeric-antigen-receptor immunotherapy – a genetically redesigned immune cells for a more powerful attack. In this therapy first, blood is collected from leukaemia patients and exposed to substances that activate T cells, powerful cells that launch and coordinate immune attacks. Next, the T cells are genetically modified to recognize and attack leukaemia cells. Finally, the altered cells are returned to the patient, where they are expected to proliferate until the cancer cells are gone.

Drug giant Novartis is making a multimillion dollar bet that a patient’s immune system can be cancer’s worst enemy. It is teaming up with scientists at the University of Pennsylvania (UPenn) in Philadelphia to develop and manufacture cancer immunotherapies.

In the US$20-million collaboration, announced today, Novartis, which is based in Basel, Switzerland, will get exclusive worldwide rights to these technologies.

source

http://blogs.nature.com/news/2012/08/novartis-gives-upenn-20-million-for-cancer-vaccine.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+news%2Frss%2Fnewsblog+%28News+Blog+-+Blog+Posts%29&WT.ec_id=NEWS-20120807

 

 

 

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Human embryonic pluripotent stem cells and healing post-myocardial infarction

Posted in Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Resident-cell-based, tagged , , , , , , , , , , , , , on August 7, 2012| 7 Comments »

Human embryonic pluripotent stem cells and healing post-myocardial infarction

Curator: Larry H. Bernstein, MD, FCAP
I present a followup based on several recent posts related to the promise of using induced human pluripotent stem cells for repair of ischemia damaged myocardium postinfarct and related effect of heart failure (HF).  There has been a change in the concept of cardiovascular risk related to the emergent knowledge of the biology underlying oxidative stress.  The more recent discovery of the relationship between ongoing inflammation and clinical outcomes has led to a variety of blood-based assays which may impart additional knowledge about an individual’s propensity for future cardiovascular events (1). Vascular injury and repair are significantly mediated by circulating endothelial progenitor cells (1).  Circulating progenitor endothelial cells are defined by co-expression of the markers CD34, CD309 (VEGFR-2/KDR) which are measured by pre-enrichment flow cytometry with specific identification of cell markers (CD34, CD133) and endothelial cell antigens (KDR/VEGFR-2, CD31) (2), used in the assessment of various diseases and physiological states.  Improvements in flow cytometry include the Attune® cytometer, which enables the collection of more than 4,000,000 live white blood cell (WBC) events in just 35 minutes (3). Using these methods of analyses, it became evident that circulating endothelial progenitor cells have angiogenic potential.

Activators and inhibitors have been tested for their ability to modulate angiogenesis in early phase clinical trials, and in the case of anti-Flk1 antibodies clinical utility has been demonstrated for anti-tumor strategies (4). Extending this concept further, we pose that just as the progenitor role invoked for angiogenesis, transcriptional networks and interactions are involved in the morphogenesis of the developing vertebrate heart. The identities of crucial regulators involved in defined events in cardio-genesis are being uncovered at a rapid rate. Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. (4, 5, 6). However, our ability to cross the divide between knowledge and change has not been easy, as reported by Aviva Lev-Ari (7).  In a two-day-old mouse, a heart attack causes active stem cells to grow new heart cells; a few months later, the heart is mostly repaired. But in an adult mouse, recovery from such an attack leads to classic after-effects: scar tissue, permanent loss of function and life-threatening arrhythmias (7, 8).

Myocardial cell replacement therapies are hampered by a paucity of sources for human cardiomyocytes and by the expected immune rejection of allogeneic cell grafts. The success using dermal fibroblasts from HF patients reprogrammed by retroviral delivery of Oct4, Sox2, and Klf4 or by using an excisable polycistronic lentiviral vector resulted in HF-hiPSCs induced to differentiate into cardiomyocytes (HF-hiPSC-CMs)(9). Multi-electrode array recordings revealed adequate responses to stimulation.  Further study with in vivo transplantation in the rat heart revealed the ability of the HF-hiPSC-CMs to engraft, survive, and structurally integrate with host cardiomyocytes and within 48 hours the tissues were beating together. Human-induced pluripotent stem cells thus can be established from patients with advanced heart failure and coaxed to differentiate into cardiomyocytes, which can integrate with host cardiac tissue (10).  The success of the approach rests on modifying the myocardial electro-physiological substrate using cell grafts genetically engineered to express specific ionic channels (11). The expressed potassium channels alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.  The key feature involves reprogramming a patient’s own skin cells by delivering three genes followed by a small molecule called valproic acid to the cell nucleus (12).

An alternative approach avoiding the caveats of limited graft survival, is to stimulate a resident source, restricted homing to the site of injury and host immune rejection (13). Thymosin β4 restores vascular potential to adult epicardial-derived progenitor cells with injury.  Specifically, it activates adult progenitors to re-express a key embryonic epicardial gene, Wilm’s tumour 1 (Wt1).  It was inferred that embryonic reprogramming would mobilize this cell population and differentiation would give rise to de novo cardiomyocytes. Delivery of Tβ4, in conjunction with GMT (an acronym for three genes that normally guide embryonic heart development), into the damaged region resulted in reduction of scar area and improvement in cardiac function compared to GMT or Tβ4 alone. Thymosin-beta4 facilitates cardiac repair after infarction by promoting cell migration and myocyte survival. Additionally, the tetra peptide Ac-SDKP was reported to reduce left ventricular fibrosis in hypertensive rats, reverse fibrosis and inflammation in rats with MI, and stimulate both in vitro and in vivo angiogenesis. Effects of Ac-SDKP, such as the enhancement of angiogenesis and the decrease in inflammation and collagenase activity, are similar to those described for thymosin-beta4. However, there are conflicting reports (14-18).

There are other studies that show promise.  There has been the first infusion of stem cells into the coronary artery (19). This result was at least as effective as intramyocardial injection in limiting LV remodeling and improving both regional and global LV function. The intracoronary route appears to be superior in terms of uniformity of cell distribution, myocyte regeneration, and amount of viable tissue in the risk region. Another finds that down regulation of leukocyte HIF-1? Expression resulted in decreased recruitment of WBC to the sites of inflammation and improvement in cardiac function following MI (20).  Irradiated 6-to 8-week-old C57/BL6J mice received 50 000 GFP HIF-1? or scramble siRNA transfected hematopoietic stem cells. Down regulation of HIF-1? suppressed WBC cytokine receptors CCR1,-2, and-4, which are necessary for WBC mobilization and recruitment to inflammatory cytokines following MI.  There also have been cited limitations to success in older patients (21). The findings suggest that coronary artery disease and cardiac remodeling in chronic ischemia has a significant negative correlation between the age of the patient and the number of migrated ckit-positive cells.

Lymphocytes infiltrate and react with ischemia damaged heart tissue, which can impair proper tissue healing.  In a study with isoproterenol induced myocardial necrosis TNF-α, IFN-γ and CCL-5, but not FOXP3 + expression, was increased in draining lymph nodes, indicating that the observed lymphocyte population that proliferated in response to cardiac components presented a pro-inflammatory and pro-fibrotic profile.  The group was rendered tolerant by myocardial gavage and expressed cardiac FOXP3 + earlier than did the control group, and showed a milder inflammatory infiltrate, lower MMP-9 expression, less collagen deposition, and improved cardiac performance when compared to animals that received only isoproterenol administration (22).  Patients with acute myocardial infarction show high circulating levels of neuropeptide Substance P (SP) and NK1-positive cells that co express Progenitor Cell (PC) antigen, such as CD34, KDR, and CXCR4. Moreover, NK1-expressing PC is abundant in infarcted hearts, highlighting the role of SP in reparative neovascularization (23). Do CD4 + T cells become activated and influence wound healing after experimental MI?   To study the role of CD4 + T cells in wound healing and remodeling, CD4 + T-cell- deficient mice (CD4 knockout [KO], MHCII) and T-cell receptor-transgenic OT-II. Within the infarcted myocardium, CD4 KO mice displayed higher total numbers of leukocytes and proinflammatory monocytes (18.3±3.0 104/mg WT versus 75.7±17.0 10 4/mg CD4 KO, P<0.05), and MHCII and OT-II mice displayed significantly greater mortality. Collagen matrix formation in the infarct zone was severely disturbed in CD4 KO and MHCII mice, as well as in OT-II mice (24).

Thus, it appears that CD4T cells become activated after MI and facilitate wound healing of the myocardium. Inflammation and immune responses are integral components in he healing process after myocardial infarction. Importantly, dendritic cell (DC) infiltration occurs in the infarcted heart.  In concert with the previous two studies, DC-ablated infarcts had enhanced monocyte/ macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6C high monocytes and F4/80 + CD206 – M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6C low monocytes and F4/80 + CD206 + M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group (25). Thus, the DC is a potent immunoprotective regulator during the post-infarction healing process via its control of monocyte/macrophage homeostasis.  Despite the recent successes, there are a number of interlocking and possibly explanatory processes to control in the mix.

What about medical therapies?  Here too there is a factor in engaging eNOS or iNOS activity as detailed in the presentation by Aviva Lev-Ari (26).  60–70% of major cardiovascular events cannot be prevented with current approaches focused on LDL, such as statin therapy, and low HDL levels are particularly common in males with early-onset atherosclerosis.  She makes the point that there is compelling evidence that HDL is not solely a marker of lower risk of cardiovascular disease but instead is a mediator of vascular health.

Aviva Lev-Ari examines the phytoestrogen, Genistein, and other drugs. Genistein acutely stimulates Nitric Oxide synthesis in vascular Endothelial cells by a cyclic adenosine 5′-monophosphate-dependent mechanism (Liu et al., 2004). The intracellular signaling pathways for activation of eNOS by genistein were shown independent of PI3K/Akt or ERK/MAPK but depended on the cAMP/PKA cascade. In addition, the genistein action on eNOS was not inhibited by an ER antagonist and was unrelated to tyrosine kinase inhibition. Furthermore, genistein has antiatherogenic effects and inhibits proliferation of vascular endothelial and smooth muscle cells, and in vitro studies suggest a protective role of genistein in the vasculature.  In Liu et al., (2004) study, genistein acted directly on BAECs and HUVECs to activate eNOS and NO production through nongenomic mechanisms in whole vascular endothelial cells.  In addition, 5-hydroxytryptamine evokes endothelial nitric oxide synthase activation.  In this example, eNOS co-localizes with PECAM-1, but not with VE-cadherin and plakoglobin at the intercellular junctions of the endothelium.

Finally, activation of endothelial nitric oxide synthase (eNOS) resulted in the production of nitric oxide (NO) that mediates the vasorelaxing properties of endothelial cells.  The responses were effectively blocked by a 5-HT1B receptor antagonist, a 5-HT1B/5-HT2 receptor antagonist, and eNOS selective antagonists, L-Nomega -monomethyl-L-arginine (L-NMMA) and L-N omega-iminoethyl-L-ornithine (L-NIO). This lends credence to a 5-HT1B receptor/eNOS pathway, accounting in part for the activation of eNOS by 5-HT.  Finally, a third-generation ß-blocker augments vascular Nitric Oxide release. Nebivolol increases vascular NO productionby causing a rise in endothelial free [Ca2+]i and endothelial NO synthase–dependent NO production. It is a ß1-selective adrenergic receptor antagonist with proposed nitric oxide (NO)–mediated vasodilating properties. Nevertheless, it appears that not nebivolol, but its metabolites augment NO production (Broeders et al., 2000).  These findings reveal new insights into interaction with eNOS in vascular therapy: [1] new indications for TDZs as stimulators of eNOS; [2] new indications for beta blockers as NO stimulant. Nebivolol is a vasodilator, thus functions as an antihypertensive.

References:

1.  Saha S. Innovations in Bio-instrumentation for Measurement of Circulating Progenitor Endothelial Cells in Human Blood.  Pharma Intell. July 8, 2012. http://pharmaceuticalintelligence.com/2012/07/08/innovations-in-bio-instrumentation-for-measurement-of-circulating-progenitor-endothelial-cells-in-human-blood/

(http://www.ncbi.nlm.nih.gov/pubmed/19124422)

2.  Ibid (http://www.ncbi.nlm.nih.gov/pubmed/20381496).

3.  Ibid (http://zh.invitrogen.com/etc/medialib/files/Cell-Analysis/PDFs.Par.54318.File.tmp/CO24210-Human-CEC_cancer.pdf)

4. Saha S. Endothelial Differentiation and Morphogenesis of Cardiac Precursors. Pharma Intelligence. July 17, 2012.

5. Ibid (http://circres.ahajournals.org/content/90/5/509.full).

6. Ibid (http://www.ncbi.nlm.nih.gov/pubmed/22669846).

7.  Aviva-Lev-Ari.  Stem cells create new heart cells in baby mice, but not in adults, study shows.Aug 3, 2012. Pharma Intelligence.

8.  Krishna Ramanujan http://www.news.cornell.edu/stories/July12/HeartStemCells.html

9. Saha S. Human Embryonic-Derived Cardiac Progenitor Cells for Myocardial Repair.  Pharma Intelligence. Aug 1, 2012.

10.  Zwi-Dantsis L, Huber I, Habib M, Winterstern A, (..), Gepstein L. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. Eur Heart J. 2012 May 22. [Epub ahead of print]  (VBL RX, Inc. Tel Aviv, http://www.vblrx.com).

11.  Yankelson L, Feld Y, Bressler-Stramer T, Itzhaki I,(..), Gepstein L. Cell therapy for modification of the myocardial electrophysiological substrate. Circulation. 2008 Feb 12; 117(6):720-31. Epub 2008 Jan 22.

12.  Huber I, Itzhaki I, Caspi O, Arbel G, (..), Gepstein L. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 2007 Aug; 21(10):2551-63. Epub 2007 Apr 13.

13.  Aviva Lev-Ari. Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair. Pharma Intelligence. April 30, 2012.

14.  Ibid. Shrivastava S, Srivastava D, Olson EN, DiMaio JM, Bock-Marquette I.

Ann N Y Acad Sci. 2010 Apr; 1194:87-96.

15.  Ibid.  Smart N, Risebro CA, Clark JE, Ehler E, (..), Riley PR, Thymosin beta4 facilitates epicardial neovascularization of the injured adult heart.  Ann N Y Acad Sci. 2010 Apr;1194:97-104

16.   Ibid. Smart N, Bollini S, Dubé KN, Vieira JM, (..) Riley PR. Nature. 2011 Jun 8; 474(7353):640-4 

17.   Ibid. Zhou B, Honor LB, Ma Q, Oh JH, (..), Pu WT. Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes.  J Mol Cell Cardiol. 2012 Jan; 52(1):43-7. Epub 2011 Aug 26.

18.   Ibid. Scientists Report that Process of Converting Non-Beating Heart Cells into Functional, Beating Heart Cells is Enhanced Using Thymosin Beta 4 in Conjunction with Gene Therapy.  Regenerx Biopharmaceuticals, Inc. Nature. Apr. 18, 2012

19.  Li, Q., Guo, Y., Ou, Q., Chen, N., (…), Bolli, R. Intracoronary administration of cardiac stem cells in mice: A new, improved technique for cell therapy in murine models.  Basic Research in Cardiology 2011; 106 (5), pp. 849-864.

20. Dong, F., Khalil, M.,Kiedrowski, M.,O’Connor, C.,(..) ,Penn, M.S. Critical role for leukocyte hypoxia inducible factor-1α expression in post-myocardial infarction left ventricular remodeling.  Circulation Research   2010; 106 (3) , pp. 601-610

21. Aghila Rani, K.G.,Jayakumar, K.,Sarma, P.S., Kartha, C.C. Clinical determinants of ckit-positive cardiac cell yield in coronary disease. Asian Cardiovascular and Thoracic Annals 2009; 17 (2), pp. 139-142.

22. Ramos, G.C., Dalbó, S., Leite, D.P.,Goldfeder, E. ,(..), Assreuy, J. The autoimmune nature of post-infarct myocardial healing: Oral tolerance to cardiac antigens as a novel strategy to improve cardiac healing. Autoimmunity 2012; 45 (3), pp. 233-244.

23.  Amadesi, S., Reni, C., Katare, R., Meloni, M., (…),Madeddu, P. Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. Circulation 2012; 125 (14) , pp. 1774-1786.

24. Hofmann, U.,Beyersdorf, N.,Weirather, J.,Podolskaya, A.(..), Frantz, S. Activation of CD4 + T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 2012; 125 (13) , pp. 1652-1663.

25. Anzai, A., Anzai, T.,Nagai, S., Maekawa, Y., (…), Fukuda, K. Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling. Circulation 2012; 125 (10), pp. 1234-1245

26. Lev-Ari A. Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production. Pharma Intelligence. July 19, 2012.

27.  Ibid. Li AC, Binder CJ, Gutierrez A, Brown KK, (..), Glass CK. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPAR-alpha, Beta/delta, and gamma.  J Clin Invest 2004; 114:1564-1576.

28.  Ibid. Broeders MAW, Doevendans PA, Bekkers BCAM, (…), van der Zee R. Nebivolol: A Third-Generation ß-Blocker That Augments Vascular Nitric Oxide Release, Endothelial ß2-Adrenergic Receptor–Mediated Nitric Oxide Production. Circulation 2000; 102:677.

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Updated Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Bio Instrumentation in Experimental Life Sciences Research, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Valves & Tools, tagged , , , , , on August 7, 2012| 8 Comments »

Updated Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

Reporter: Aviva Lev-Ari, PhD,RN

 

UPDATED on 5/27/2014

Survival After TAVI: Longest Follow-up Data Yet Yield Some Surprises

May 23, 2014

PARIS, FRANCE — Some of the longest follow-up for the first transcatheter aortic-valve implantations (TAVI) ever performed confirm earlier observations that the biggest threat to survival in TAVI-implanted patients remains their comorbidities and not problems related to their valves, regardless of valve type. More surprising, some of the procedural issues that preoccupy interventionalists and surgeons today did not emerge as important in this longer-term follow-up.

Presenting three- and five-year data from the UK TAVI registry in a press conference here at EuroPCR 2014 , Dr Neil Moat (Royal Brompton Hospital, London, UK) pointed to what he called “biphasic” survival curves. In the first few months after valve implantation, there is a steep drop in survival, he noted. Thereafter, the curve becomes significantly less steep, mirroring the survival curves typically seen in older patients who have undergone surgical valve replacement.

“In the first six months, you have quite a dramatic attrition of patients, then mortality falls to about 6% of patients per year,” he said. “What this is telling us is that patients undergoing TAVI are not dying of TAVI-related factors.”

The UK TAVI registry contains prospectively collected data from 100% of all consecutive transcatheter aortic-valve replacement (TAVR) patients treated since January 1, 2007. The current analysis includes 870 early patients whose mortality status was ascertained in July 2013.

In all, 62% of TAVR-treated patients were alive at three years, while just under half—48.4%—were still alive at five years.
Dr Neil Moat [Source: EuroPCR]

In multivariable analyses, the strongest baseline predictor of mortality at three years was

  • creatinine >200 µg/mmol, followed by
  • presence of atrial fibrillation,
  • chronic obstructive pulmonary disease (COPD), or a
  • high EuroSCORE (>18.5).

Of note, device- or procedure-related characteristics that typically get a lot of attention at interventional meetings were not significant predictors of late survival. For example,

  • 12.7% of patients still alive at three years had had moderate/severe aortic regurgitation at the time of their procedure, compared with
  • 14.9% of patients who’d died, but the difference was not statistically significant. Likewise,
  • permanent pacemaker implantation had been performed in 16.2% of patients still alive at follow-up and in
  • 19.3% of patients who died, again a nonsignificant difference.

Not surprisingly,

  • more transfemorally treated patients were alive at three years than
  • patients treated via a nontransfemoral procedure (64.3% vs 55.7%, p=0.017).

Roughly the same number of patients received the

  • Edwards Sapien device in the early days of the TAVI registry (410) as received the
  • Medtronic CoreValve (452).

By three years,

  • 40.7% of Sapien-treated patients had died, compared with
  • 35.4% of CoreValve-treated patients (p=0.078).
“CoreValve had a trend toward better survival, but I wouldn’t want to overinterpret that,” Moat cautioned. These are preliminary data, he stressed, but added, “There is a trend there that needs looking at” when the registry has more patients, with more follow-up.

One of the theories put forward in other sessions at EuroPCR is that the higher pacemaker-implantation rate with CoreValve might, in fact, help bump up survival rates with this device.

“It’s an interesting hypothesis,” Moat said. “But I don’t think we have any data to support that hypothesis, either here or in any other study. I think if there were an effect of early pacemaker implantation it would be in this first [six-month] phase. Some people are concerned that the early attrition is sudden death because of late heart block occurring two, three, or four months after the procedure. So if you are having pacemakers implanted more frequently, you are being protected from that, but I think our data strongly suggest that pacemaker implant does not affect long-term survival.”

Moat disclosed being a consultant for Medtronic.

 

UPDATED on 2/9/2014

Transcatheter Technologies Completes Durability Testing of Its Prosthetic Aortic Heart Valve, Intrinsic to World’s First ‘Truly Repositionable’ TAVI Device, TRINITY

January 28, 2014 6:29 AM 

Business Wire

“This 3rd-generation TRINITY technology could be a game-changer for TAVI.” Prof. Dr. Christian Hengstenberg, MD, German Heart Center, Munich (Note: Prof. Dr. med Hengstenberg has no financial ties to Transcatheter Technologies.)

REGENSBURG, Germany–(BUSINESS WIRE)–January 28, 2014–

Transcatheter Technologies GmbH, an emerging medical device company that is developing a third-generation transcatheter aortic valve implantation (TAVI) system-TRINITY-announced today that an independent laboratory has completed ‘advanced wear testing’ (AWT) of the company’s TRINITY valve prosthesis, far exceeding minimum testing standards. Indeed, AWT of the TRINITY heart valve has already completed 600 million cycles, or an estimated 15 years of durability testing.

Transcatheter Technologies has previously announced the successful 30-day follow-up results of a pilot study of its TRINITY TAVI system that is designed to be the world’s first ‘truly repositionable’ and, therefore, best TAVI system.

“Unlike second-generation TAVI systems, the Trinity aortic valve is designed to be positioned precisely or repositioned, even after full implantation, in a safe and simple manner,” said principal investigator Prof. Dr. Christian Hengstenberg, a cardiologist at the German Heart Center, Munich, Germany, with no financial interest or arrangement or affiliation with Transcatheter Technologies. “In our study, Trinity’s novel sealing cuff continues to provide outstanding follow-up results without PVL (paravalvular leak), a frequent complication of TAVI. Equally important, the TRINITY aortic valve is designed to reduce the risk of atrio-ventricular (AV) block significantly through supra-annular positioning of the TRINITY valve.”

“We are extremely pleased that our TRINITY valve has already demonstrated three times the minimum standard for advanced wear testing of a tissue heart valve,” said Wolfgang Goetz, M.D., Ph.D., CEO, a cardiac surgeon by training. We also are extremely pleased with the continuing excellent results of our third-generation TRINITY System in the follow-up of our first patient.

“The big issue with the second-generation TAVI systems is that they cannot be truly repositioned once fully implanted. TRINITY, however, is designed to solve this critically important issue and thereby potentially reduce the undesirable side consequences of PVL,” added Dr. Goetz. “With TRINITY, once our valve is completely expanded and anchored above the annulus, a cardiologist can fully evaluate the valve’s function to determine whether it needs to be repositioned, retrieved, or kept in the same position. This feature and its supra-annular anchoring are absolutely unique to TRINITY, which is why we have positioned TRINITY as a Third-Generation TAVI System.”

CAUTION: TRINITY is not approved for use in the United States

Ronald Trahan Associates Inc.
Ronald Trahan, APR, +1-508-359-4005, x108

SOURCE

Transcatheter aortic valve implantation (TAVI): risk for stroke and suitability for surgery

For additional discussion go to 

Transcatheter Aortic Valve Implantation (TAVI): Risky and Costly

http://pharmaceuticalintelligence.com/2012/08/02/transcatheter-aortic-valve-implantation-tavi-risky-and-costly/

BMJ 2012; 345 doi: 10.1136/bmj.e4710 (Published 31 July 2012) Cite this as: BMJ 2012;345:e4710

Evidence for TAVI Questioned

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: July 31, 2012

The tens of thousands of transcatheter aortic valve implantations (TAVI) performed worldwide may not have solid evidence behind them, European researchers suggested.

To begin with, a health technology assessment commissioned by the Belgian government suggested that only patients who are “deemed inoperable for technical reasons such as a series of previous operations or irradiation of the chest wall” be reimbursed for TAVI, according to Mattias Neyt, PhD, of the Belgian Health Care Knowledge Centre in Brussels, and colleagues.

That’s about 10% of patients currently being considered for the procedure, they wrote online in an analysis article in BMJ.

Why is there such a big disconnect between the growing number of patients undergoing TAVI and the findings of the Belgian technology assessment? Neyt and colleagues said there are several factors that have resulted in more enthusiasm than evidence for TAVI.

One of those factors is the process by which medical devices receive marketing approval in the E.U., which, they said, puts medical devices “on the same footing as domestic appliances such as toasters.”

As a consequence of what the authors referred to as “Europe’s lax licensing laws,” the two TAVI devices in common use today – Medtronic’s CoreValve and Edward Lifescience’s Sapien – were approved in 2007, “long before any substantial clinical trial evidence was available.”

Even the U.K.’s National Institute for Health and Clinical Excellence (NICE) concluded that the evidence was “adequate from a clinical point of view” for the use of TAVI in those unsuitable for surgery, but when surgery is an option — even a high-risk one — the evidence for TAVI was inadequate.

However, the British analysis did not consider costs associated with the procedure, Neyt and colleagues pointed out.

In the U.S., the FDA approval process is more rigorous than that of the E.U., but Neyt and colleagues were “far from convinced” that the results from the PARTNER trials (Cohort A andCohort B) were adequate to justify approval of the Sapien valve.

Although the cost-effectiveness of TAVI for inoperable patients (cohort B) is “equivocal,” they wrote, the clinical evidence seems to suggest that TAVI can be justified. However, they pointed out some problems that they said were not considered within the overall evidence, such as a higher rate of comorbidities and a higher rate of previous MIs among the inoperable control patients.

In PARTNER cohort A, where TAVI was compared with high-risk surgical patients, the authors noted a concern for a higher rate of stroke or transient ischemic attack among the TAVI patients.

Nevertheless, an FDA panel in June recommended expanding the indication for the Sapien valve to include high-risk surgical candidates. One of the panelists said that stroke is “just an accepted risk of the procedure.”

But Neyt and colleagues don’t accept that. They concluded that based on the evidence, as well as the concern for efficient use of limited resources, “it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI.”

Another issue that could undermine the integrity of the evidence, Neyt and colleagues said, was the absence of full disclosure on the part of principal investigator Martin B. Leon, MD, from Columbia University.

According to the Belgian researchers, part of the deal involving the sale of Leon’s valve company to Edwards included future payments from Edwards “on the achievement of three milestones: successful treatment of 50 patients, regulatory approval in Europe, and limited approval in the U.S.”

These three milestones were not disclosed in the original paper published in the New England Journal of Medicine, they said.

Neyt and colleagues also complained that the FDA and Edwards Lifesciences are holding on to negative findings from an FDA-authorized follow-on study of 90 inoperable patients. Some of the data released at an FDA meeting in 2011 showed a higher 1-year mortality rate among those receiving TAVI (34.3% versus 21.6%), they said, but efforts to obtain any of those data have been rebuffed by both the FDA and Edwards.

They brought this concern to the editors of the NEJM, but the editors didn’t think the concern invalidated the overall PARTNER findings.

Tying all this together, Neyt and colleagues called for “a major improvement in transparency of information” that would “allow clinicians to practice evidence-based medicine, patients to make informed decisions, and health technology assessment agencies to make the right judgments.”

The authors reported they had no relationships to disclose.

Primary source: BMJ

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