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Archive for the ‘Liver & Digestive Diseases Research’ Category

HIV vaccine: Caltech puts us One step further

Posted in Biomarkers & Medical Diagnostics, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Liver & Digestive Diseases Research, Personalized and Precision Medicine & Genomic Research, Systemic Inflammatory Response Related Disorders, Uncategorized, tagged , , , , , , , on August 31, 2012| 1 Comment »

Author and Curator: Chloe Thomas, Manager, Scientific Sessions and Education at Heart Rhythm Society

 

One step further towards an HIV vaccine

Statistics show that approximately 34 million people are infected with the Human Immunodeficiency Virus. Within the last years, important steps have been taken in finding treatments and medications against HIV. The study introduced in this article is a helpful contribution to the development of an HIV vaccine.

Cloning antibodies

Researchers working in the California Institute of Technology have focused more closely on the binding mechanism of the virus to the human cell. Leading a study which was published in the Science Magazine in 2011, they departed from the fact that a passive transfer of HIV neutralizing antibodies can prevent an infection and might therefore even be valuable for the creation of an HIV vaccine. As the number of naturally occurring antibodies is relatively low, the researchers intended to discover whether these antibodies belong to a larger group of molecules which might turn out useful studies of the infection. By cloning more than 500 HIV antibodies taken from four different infected individuals, they discovered that all of them produced a large number of potent HIV antibodies which mimic the binding to CD4. By isolating the potent anti-HIV antibodies of infected people, the scientists have begun to develop ways in order to neutralize subtypes of the infection. The researchers have found a strong version of an anti-HIV antibody, which is named NIH45-46. These antibodies that target the binding site of the host receptor (namely CD4) interact with the protein gp120. This protein sits on the viruses and helps the virus enter the cell, and thus mainly contributes to the infection process. The interaction between antibody and the protein leads to neutralizing the virus and thus may avoid infection. Knowing this, the scientists were able to develop an even stronger type, named NIH45-46G54W, which employs the described mechanism more effectively. The next step the researchers are advocating is a clinical testing period for the newly-created effective antibody. Through that, they hope to gain further information on understanding the neutralization of the virus which might even help in developing a vaccine against HIV.

Scientific research: a long process

Despite the success of the study, it is important to note that an analysis in the laboratories and a clinical testing phase has to be conducted over a long period of time in order to bring about representative results. Methods have to be considered, antibodies suppliers like here have to be contacted, and data have to be evaluated. For that reason, the development of an HIV vaccine cannot happen overnight, but should be furthered patiently.

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Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?

Posted in Bio Instrumentation in Experimental Life Sciences Research, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Health Economics and Outcomes Research, Liver & Digestive Diseases Research, Medical and Population Genetics, Medical Devices R&D Investment, Metabolomics, Pain: Etiology, Genetics & Innovations in Treatment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Systemic Inflammatory Response Related Disorders, tagged , , , , , , , on August 23, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

While a staff nurse at Beth Israel Deaconess Medical Center in Boston, MA in 2008, I provided direct care for Morbid Obese patients, above 400 pounds that were transferred to Farr 9 – the Acute Surgery Unit from the PACU following Bariatric Surgery. The first day after a significant surgical intervention was very tough to the patient and very tough for the nurses, three types of analgesic drugs were used including epidural pumps and PCA. Pain medication diffused in the adipose tissue with just moderate amelioration of pain. Few patients had the operation done 10 years ago and needed a repair. Technology had advanced. More studies are needed to ascertain that in presence of morbid obesity and absence of DM, a Bariatric Surgery is THE Treatment for DM Disease Prevention.

Bariatric Surgery — From Treatment of Disease to Prevention?

Danny O. Jacobs, M.D., M.P.H.

N Engl J Med 2012; 367:764-765  August 23, 2012

Bariatric surgery to treat morbid obesity has improved dramatically over the past 60 years — especially over the past several decades. Today’s methods are far safer than the hazardous intestinal bypass procedures that were introduced in the 1950s. Bariatric-surgery techniques have progressed through various iterations of horizontal and vertical stapling of the stomach with or without banding (e.g., vertical banded gastroplasty) to vertical gastric partitioning or creation of a gastric pouch with proximal bypass into a jejunal loop (i.e., the gastric bypass), which is considered to be a reference standard.

Bariatric Surgery for Morbid Obesity.

Bariatric Surgery for Morbid Obesity.

SOURCE INFORMATION

From the Department of Surgery, Duke University School of Medicine, Durham, NC.

Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects

Lena M.S. Carlsson, M.D., Ph.D., Markku Peltonen, Ph.D., Sofie Ahlin, M.D., Åsa Anveden, M.D., Claude Bouchard, Ph.D., Björn Carlsson, M.D., Ph.D., Peter Jacobson, M.D., Ph.D., Hans Lönroth, M.D., Ph.D., Cristina Maglio, M.D., Ingmar Näslund, M.D., Ph.D., Carlo Pirazzi, M.D., Stefano Romeo, M.D., Ph.D., Kajsa Sjöholm, Ph.D., Elisabeth Sjöström, M.D., Hans Wedel, Ph.D., Per-Arne Svensson, Ph.D., and Lars Sjöström, M.D., Ph.D.

N Engl J Med 2012; 367:695-704  August 23, 2012

BACKGROUND

Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.

METHODS

In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.

RESULTS

During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.

CONCLUSIONS

Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.)

Supported by grants from the Swedish Research Council (K2012-55X-22082-01-3, K2010-55X-11285-13, K2008-65x-20753-01-4), the Swedish Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish federal government under the LUA/ALF agreement concerning research and education of doctors, the VINNOVA-VINNMER program, and the Wenner-Gren Foundations. The SOS study has previously been supported by grants to one of the authors from Hoffmann–La Roche, AstraZeneca, Cederroth, Sanofi-Aventis, and Johnson & Johnson.

Dr. Lena Carlsson reports receiving consulting fees from AstraZeneca and owning stock in Sahltech; Dr. Bouchard, receiving consulting fees from New York Obesity Nutrition Research Center, Pathway Genomics, Weight Watchers, and Nike, payment for manuscript preparation from Elsevier and Wiley-Blackwell, royalties from Human Kinetics and Informa Healthcare, honoraria from NaturALPHA, and reimbursement for travel expenses from European College of Sports Sciences, Nordic Physiotherapy, Wingate Congress, and Euro Sci Open Forum; Dr. Björn Carlsson, being employed by and owning stock in AstraZeneca; Dr. Sjöholm, owning stock in Pfizer; Dr. Wedel, receiving consulting fees from AstraZeneca, Pfizer, Roche, and Novartis; and Dr. Lars Sjöström, serving as a member of the board of Lenimen, receiving lecture fees from AstraZeneca and Johnson & Johnson, and providing an expert statement on drug effects and weight-loss effects on obesity for AstraZeneca. 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.

Drs. Carlsson and Peltonen contributed equally to this article.

We thank the staff members at 480 primary health care centers and 25 surgical departments in Sweden that participated in the study; and Gerd Bergmark, Christina Torefalk and Lisbeth Eriksson for administrative support.

SOURCE INFORMATION

From the Institutes of Medicine (L.M.S.C., M.P., S.A., Å.A., B.C., P.J., C.M., C.P., S.R., K.S., E.S., P.-A.S., L.S.) and Surgery (H.L.), Sahlgrenska Academy at the University of Gothenburg, and the Nordic School of Public Health (H.W.), Gothenburg, and the Department of Surgery, University Hospital, Örebro (I.N.) — all in Sweden; the Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki (M.P.); and Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge (C.B.).

Address reprint requests to Dr. Lars Sjöström at the SOS Secretariat, Vita Stråket 15, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden, or at lars.v.sjostrom@medfak.gu.se.

N Engl J Med 2012; 367:695-704

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Getting Better: Documentary Videos on Medical Progress — in Surgery, Leukemia, and HIV/AIDS.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Immune System in Health and in Disease, Liver & Digestive Diseases Research, Metabolomics, tagged , , , , , on August 23, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

 

NEJM 200th Anniversary Documentary

Getting Better is a 45-minute documentary video that tells three remarkable stories of medical progress — in surgery, leukemia, and HIV/AIDS. Atul Gawande, Vincent DeVita, Tony Fauci, Paul Farmer, and other prominent experts explore research, clinical practice, and patient care, and how health care has continued to get better over the past 200 years. View the film in its entirety, or in segments, now on the 200th anniversary website

http://nejm200.nejm.org/explore/medical-documentary-video/?query=TOC

WATCH THREE VIDEOS – 45 minutes

?query=TOC

The Comments by the Public are an integral part of the video watching experience

From Rough to Refined: The Rise of Surgery (Part 1 of 3)

Targeting Cancer: The Story of Leukemia (Part 2 of 3)

The Plague of Our Time: HIV/AIDS Epidemic (Part 3 of 3)

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Therapeutic Targets for Diabetes and Related Metabolic Disorders

Posted in Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Liver & Digestive Diseases Research, tagged , , , , , , on August 20, 2012| 3 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Diabetes Drug Discovery and Beyond

October 1-3, 2012

Copley Marriott Hotel, Boston, MA

The Diabetes Drug Discovery and Beyond meeting will cover progress on promising pre-clinical and early clinical phase diabetes drug candidates. But this year, we will also highlight emerging therapeutic targets that probe how the underlying defects in metabolic diseases are connected. Some presentations will cover obesity, other metabolic disorders and cardiovascular disease in the context of diabetes and energy homeostasis.

TUESDAY, OCTOBER 2


TARGETS FOR NEW DIABETES THERAPIES

1:30 pm Chairperson’s Remarks

Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer

1:40 FEATURED SPEAKER

Targeting Diabetes via Glucocorticoid Modulation: The Identification of Advanced 11b-HSD-1 Inhibitors

Jeffrey RoblJeffrey A. Robl, Ph.D., Executive Director, Metabolic Diseases R&D, Bristol-Myers Squibb

Preventing excess glucocorticoid tone in metabolically active tissues such as the liver and adipose may be  beneficial in addressing glucose homeostasis and hyperglycemia in patients with type 2 diabetes. We have optimized a series of triazolopyridine based inhibitors resulting in the advancement of BMS-770767 to phase 2 clinical trials. The discovery of BMS-770767 will be presented as well as a description of its development  properties, pharmacokinetics, and pre-clinical pharmacology profile.

2:10 Dyslipidemia Targets and Diabetes

Rebecca Taub, M.D., CEO, Madrigal Pharmaceuticals

This talk will defining diabetic dyslipidemia and discuss how elevated VLDL, triglycerides and fatty liver might contribute to diabetic CV disease. Novel dyslipidemia mechanisms to treat diabetic dyslipidemia including THRbeta agonists will also be covered.

2:40 Effects of PF-04620110, a Novel Diacylglycerol Acyl-Transferase 1 (DGAT1) Inhibitor on Healthy-Obese Volunteers and Type 2 Diabetic Subjects

Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer

Inhibition of DGAT1, the terminal enzyme in the synthesis of triglycerides (TG), has been proposed for the treatment of type 2 diabetes (T2DM). We sought to examine the effects of a potent and selective DGAT1 inhibitor, PF-04620110, on vitamin A absorption, TG, glucose, insulin and total amide glucagon like peptide-1 (GLP-1) levels in both healthy-obese volunteers and Type 2 Diabetic subjects. The results of these studies will be presented.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Pharmacological Manipulation of Diacyl Glycerol Acyl Transferase 1 Using Pre-Clinical Models

Shirly Pinto, Ph.D., CVD – Atherosclerosis Team Lead, Merck Research Laboratories

4:15 Sponsored Presentations (Opportunities Available)

4:45 Beneficial and Adverse Effects of Glucokinase Activators on Glucose Metabolism in Rat Liver Cells

Gabriel Baverel, Ph.D., CEO and CSO, Metabolomics, Metabolys, Inc.

Using a metabolic flux approach, we show the potential beneficial and adverse effects of three gluco-kinase activator drug candidates for type2 diabetes. We report the gluco-kinase activators’ effects on glucose utilization and production, glycogen synthesis and degradation, lactic acid and triglyceride accumulation and on the citric acid cycle during glucose metabolism in rat liver cells. Our work illustrates the advantage of metabolic flux analysis for predicting early during the drug development process, both the efficacy and safety of very small amounts of antidiabetic drug candidates.

5:15 Connecting Mitochondrial Dysfunction and Diabetes

James Dykens, CEO, Eyecyte Therapeutics

Mitochondrial dysfunction contributes via bioenergetic and oxidative mechanisms to a host of degenerative and metabolic diseases, including diabetes. Mitochondrial Ca2+ dynamics alter insulin release, while production of free radicals yields dysregulation of glycolysis. Importantly, xenobiotic therapies for diabetes, e.g., biguanides and thiazolidinediones, directly undermine mitochondrial function thereby lowering blood glucose, albeit via an untoward mechanism. The latter results from cell culture conditions that model diabetes and anaerobic poise, not normal aerobic physiology.

5:45 End of Day

WEDNESDAY, OCTOBER 3

8:00 am Interactive Breakfast Breakout Discussion Groups

Targeting GPCRs

Moderator: Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.

  • Screening strategies for discovery of novel GPCR agonists
  • GPCRs linked to incretin release
  • Targeting GPCRs in the periphery versus CNS

Cardiovascular Challenges

Moderator: Rebecca Taub, CEO, Madrigal Pharmaceuticals

  • Cardiovascular disease in diabetics—why the high incidence
  • History of anti-diabetic therapies effects on diabetic CV disease
  • Update on regulatory requirements to show CV safety with new diabetic therapies

Better Diabetes Models and Markers

Moderator: Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences, University at Buffalo

  • Are there diabetes biomarkers coming forward that offer sufficient advantages to replace our current reliance on glucose and HBA1c?
  • What models and biomarkers are best suited to re-cast our perspective on diabetes as a cardiovascular event with MACE consequences?
  • Should we consider biomarkers of Type 1 diabetes to be different than for Type 2 diabetes from the perspective of CV events and metabolic syndrome?


TARGETING MEMBRANE PROTEINS FOR TYPE2 DIABETES

9:05 Chairperson’s Remarks

Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.

9:10 FEATURED PRESENTATION

Discovery of Ertugliflozin: An Anti-Diabetic Agent from a New Class of SGLT2 Inhibitors

Vincent MascittiVincent Mascitti, Ph.D., Senior Director, Pfizer Global R&D

Inhibition of sodium-dependent glucose co-transporter 2 (SGLT2), located in the kidney, promotes reduction of plasma glucose concentration. The medicinal and synthetic organic chemistry rationale that led to the rapid identification of Ertugliflozin (PF-04971729), an anti-diabetic agent currently in development and belonging to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane bridged ketal motif, will be presented.

9:40 Targeting FGF21 for Type 2 Diabetes

Andrew C. Adams, Ph.D., Post-Doctoral Research Fellow, Diabetes Research, Lilly Research Laboratories

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 Update on the Clinical Candidate ARRY-981: A GPR119 Agonist

Brad Fell, Senior Research Investigator, Medicinal Chemistry, Array BioPharma

GPR119 is a promising new target for the treatment of type 2 diabetes. Agonists of this GPCR, which promote insulin secretion from pancreatic ß-cells and GLP-1 release from enteroendocrine L-cells, provide a unique opportunity for a single drug to elicit insulin secretion via two distinct pathways. However, several GPR119 agonists have recently demonstrated poor clinical efficacy. We will discuss our novel GPR119 clinical candidate, ARRY-981, that has shown meaningful and durable glucose control in preclinical models of diabetes.

11:25 Inflammation, Obesity and Diabetes: Pre-Clinical Investigations of a CCR2 Antagonist

Dana Johnson, Ph.D., Senior Scientific Director, Drug Discovery, Janssen Pharmaceuticals, Johnson & Johnson

With the growing idea of insulin resistance due, in part, to low grade systemic inflammation, mechanistic investigations aimed at altering inflammatory tone have been undertaken by us as well as others. Recruitment of the macrophage and continued activity in the adipose tissue appears to drive insulin resistance, in part, via the secretion of Moncocyte Chemoattractant Protein 1 (MCP-1) and its cognate receptor C-C Chemokine Receptor-2 (CCR2). Our efforts in disrupting the macrophage recruitment via the use of CCR2 antagonists will be presented.

11:55 Monoclonal Antibody Antagonists of the Glucagon Receptor as Therapeutic Agents

Bernard B. Allan, Ph.D., Scientist, Department of Molecular Biology, Genentech, Inc.

Excess glucagon signaling plays a key role in the development of hyperglycemia in type 1 and type 2 diabetic patients. We have generated potent anti-glucagon receptor antagonist antibodies and will present the mechanisms underlying their anti-diabetic activities in pre-clinical models, including their direct effects on hepatic glucose metabolism and indirect effects on beta-cell mass.

12:25 pm Sponsored Presentation (Opportunity Available)

12:40 Luncheon Workshop (Sponsorship Opportunity Available) or Lunch on Your Own


NEW THERAPEUTIC APPROACHES

1:55 Chairperson’s Remarks

Jesper Gromada, Ph.D., Executive Director, Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research

2:00 XMetA, an Allosteric Agonist Antibody to the Insulin Receptor that Selectively Activates Insulin Receptor Metabolic Signaling and Restores Glycemic Control in Mouse Models of Diabetes

John Corbin, Ph.D., Associate Director, Molecular Interactions and Biophysics, Preclinical Research, XOMA

The XMetA antibody represents novel drug class for the treatment of diabetes. XMetA has unique properties including selective partial agonism of insulin receptor metabolic signaling resulting in improvements in the disease state of both hyperinsulinemic insulin resistant and insulinopenic diabetic animals. The in vitro and in vivo data to be presented for XMetA will provide a clear demonstration of how allosteric modulation of the insulin receptor with a monoclonal antibody can translate to improvements in disease.

2:30 Phenotype-Driven Approaches towards Novel Beta-Cell Proliferative and Protective Therapies

Bryan Laffitte, Ph.D., Associate Director, Genomics Institute of the Novartis Research Foundation

Type 1 and type 2 diabetes are characterized by a loss of beta cell mass. However, therapeutic options aimed at preservation or restoration of endogenous beta cell mass, are not currently available. We used phenotypic screening approaches for both small molecule and biologic agents to identify regulators of beta cell survival and beta cell proliferation. We report on several series of small molecules that induce beta cell proliferation and/or protect beta cells from various forms of stress and have potential as therapeutic options for both type 1 and type 2 diabetes.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40 Gastric Bypass in Mice as a Model for Target Identification

Vincent Aguirre, M.D., Ph.D., Assistant Professor, Internal Medicine, University of Texas Southwestern Medical Center

We will discuss a mouse model of gastric bypass, which recapitulates effects of this procedure on body weight, body composition, glucose homeostasis, and stool energy observed in humans. The reproducibility of this model allows high-resolution comparison of effects of gastric bypass across genetic models using advanced methodologies, such as MRS metabolic flux, proteo metabolomics, and deep sequencing. As such, it enables targeted investigation of bypass-induced biological pathways and refined identification of novel pharmaceutical targets capable of mimicking beneficial effects of bariatric surgery.

4:10 Cell-Based Therapies to Treat Diabetes

Norma Kenyon, Ph.D., Professor of Surgery, Microbiology and Immunology and Biomedical Engineering; Executive Director of the Wallace H. Coulter Center for Translational Research; School of Medicine, University of Miami

This presentation will focus on the role of stem cell-based therapies to treat diabetes, highlighting the therapeutic potential of mesenchymal stem cells in diabetes. Our research group’s focus is on ways to transplant islet cells without the need for anti-rejection drugs, including the incorporation of stem cells into transplant protocols.

4:40 Discovery of Lorcaserin: A Selective 5-HT2C Agonist for Weight Management

Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.

Compelling evidence suggests that drugs which activate the 5-HT2C receptor cause weight loss and thus have potential for use as weight management agents. Because serotonin elicits a number of biological responses through modulation of other 5HTrelated proteins, selectivity was a critical challenge particularly with respect to the closely related 5-HT2A and 5-HT2B receptors. This presentation outlines some of events, challenges and achievements that led to the discovery and development of lorcaserin.

SOURCE

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The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Posted in Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Liver & Digestive Diseases Research, Metabolomics, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , on August 20, 2012| 19 Comments »

 

Author: Larry Bernstein, MD

 

Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.  Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

 

Part I.   Basic and downstream effects of inhaled NO

Inhaled nitric oxide (NO), a mediator of vascular tone produces pulmonary vasodilatation with low pulmonary vascular resistance. The route of administration delivers NO selectively improving oxygenation. Developments in our understanding of the cellular and molecular actions of NO may help to explain the results of randomised controlled trials of inhaled NO.

Introduction

Nitric oxide (NO), a determinant of local blood flow is formed by the action of NO synthase (NOS) on L-arginine in the presence of molecular oxygen. Inhaled NO results in preferential pulmonary vasodilatation it lowers pulmonary vascular resistance (PVR), correcting hypoxic pulmonary vasoconstriction (HPV). However, in the therapeutic use of gaseous NO to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and related conditions, evidence of a benefit is disappointing.

Administration of inhaled nitric oxide to adults

The licensed indication of inhaled NO is restricted to persistent pulmonary hypertension in neonates. Pharma-ceutical NO is costly, and raises concerns over potential adverse effects of NO. Therefore, an advisory board under the auspices of the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists published recommendations in 2005 [1]. The sponsor had no authorship or editorial control over the content of the meetings or any subsequent publication.

The NO is administered as a NO/nitrogen mixture to the tubing of ventilated patients, and the NO and NO2 concen-trations are monitored, with methemoglobin levels measured regularly. Even though rapid withdrawal induces rebound pulmonary hypertension, it is avoided by gradual withdrawal [2]. There is variation in vasodilatory response to administered NO between patients [2] and in the same patient, and there is a leftward shift in the dose-response curve with use. Toxicity and loss of the therapeutic effect is a risk of excessive NO administration [3]. A survey of 54 intensive care units in the UK as well as results of a European survey revealed that the most common usage was in treating ARDS, followed by pulmonary hypertension [4], [5]. The only use of therapeutic inhaled NO usage in US adult patients reported from a single medical site (2000 to 2003) reveals that the most common application was in the treatment of RVF in patients after cardiac surgery and then, in surgical and medical patients for refractory hypoxemia[6].

Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome

ALI and ARDS are characterised by hypoxemia despite high inspired oxygen (PaO2/FiO2  [arterial partial pressure of oxygen/fraction of inspired oxygen] ratios of less than 300 mm Hg [40 kPa] and less than 200 mm Hg [27 kPa], respectively) in the context of evidence of pulmonary edema, and the absence of left atrial hypertension suggestive of a cardiogenic mechanism [7]. Pathologically, there is alveolar inflammation and injury leading to increased pulmonary capillary permeability and a serous alveolar fluid with inflammatory infiltrate. This is manifest clinically as hypoxemia, inadequate alveolar perfusion, venous-arterial shunting, atelectasis, and reduced compliance.

Since 1993, when the first investigation on the effects of NO on adult patients with ARDS was published [8], there have been several randomised controlled trials (RCTs) examining the effect in ALI/ARDS  ​(Table 1). The first systematic review and meta-analysis [9] found no beneficial effect on mortality or ventilator-free days. A more recent meta-analysis that considered 12 RCTs with a total of 1,237 patients [10] concluded: [1] no mortality benefit, [2] improved oxygenation at 24 hours (13% improvement in PaO2/FiO2 ratio) at the cost of increased risk of renal dysfunction (relative risk 1.50, 95% confidence interval 1.11 to 2.02). Based on a trend to increased mortality in patients receiving NO, the authors suggested that it not be used in ALI/ARDS.  Why the NO fails to improve patient outcomes requires clarifying the effects of inhaled NO that occur outside the pulmonary vasculature.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 1

Studies of inhaled nitric oxide in adult patients with acute lung injury/acute respiratory distress syndrome

The biological action of inhaled nitric oxide

NO was first identified as an endothelium-derived growth factor (EDGF) and an important determinant of local blood flow [11]. NO reacts very rapidly with free radicals, certain amino acids, and transition metal ions. The action of NOS on the semi-essential amino acid L-arginine in the presence of molecular oxygen and its identity with EDGF was the basis for the Nobel discovery of Furthgott and others [12]. Three isoforms of NO are: neuronal NOS, inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Calcium-independent iNOS generates higher concentrations of NO [13] than the other isoforms and its role has been implicated in the pathogenesis septic shock.

Exogenous NO is administered by controlled inhalation or through intravenous administration of NO donors. It was thought to have no remote or non-pulmonary effects. The effect NO has on circulating targets is shown. (Figure 1).

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 1

New paradigm of inhaled nitric oxide (NO) action. Figure 1 illustrates the interactions between inhaled NO and the contents of the pulmonary capillaries. Although NO was considered to be inactivated by hemoglobin (Hb), proteins including Hb and albumin contain reduced sulphur (thiol) groups that react reversibly with NO causing it to lose its vasodilating properties. A stable derivate, in the presence of oxyhemoglobin, is formed by a reaction resulting in nitrosylation of a cysteine residue of the β subunit of Hb.  The binding of NO to the heme iron predominates in the deoxygenated state [14]. If circulating erythrocytes store and release NO peripherally in areas of low oxygen tension, this augments peripheral blood flow and oxygen delivery via decreased systemic vascular resistance [15]. Thus, NO can act as an autocrine or paracrine mediator but when stabilised may exert endocrine influences [16]. In addition to de novo synthesis, supposedly inert anions nitrate (NO3–) and nitrite (NO2–) can be recycled to form NO, and nitrite might mediate extra-pulmonary effects of inhaled NO [17]. In the hypoxic state, NOS cannot produce NO and deoxy-hemoglobin catalyses NO release from nitrite, potentially providing a hypoxia-specific vasodilatory effect. Given that effects of inhaled NO are mediated in part by S-nitrolysation of circulating proteins, therapies aiming at directly increasing S-nitrosothiols have been developed.

Introduce another effect. When inhaled with high concentrations of oxygen, gaseous NO slowly forms the toxic product NO2, but other potential reactions include nitration (addition of NO2+), nitrosation (addition of NO+), or nitrosylation (addition of NO), and reaction with reactive oxygen species such as superoxide to form reactive nitrogen species (RNS) such as peroxynitrite (ONOO–). These reactions of NO, potentially cytotoxic NO2 , and covalent nitration of tyrosine in proteins by RNS lead to measures of oxidative stress.

In a small observational study, inhaled ethyl nitrite safely reduced PVR without systemic side effects in persistent pulmonary hypertension of the newborn [18]. In animal models, pulmonary vasodilatation was maximal in hypoxia and had prolonged duration of action after cessation of administration [19].

References

  1. Germann P, Braschi A, Della Rocca G, Dinh-Xuan AT, et al. Inhaled nitric oxide therapy in adults: European expert recommendations.  Intensive Care Med. 2005;31:1029–1041. [PubMed]
  2. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353:2683–2695. [PubMed]
  3. Gerlach H, Keh D, Semmerow A, Busch T, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167:1008–1015. [PubMed]
  4. Cuthbertson BH, Stott S, Webster NR. Use of inhaled nitric oxide in British intensive therapy units. Br J Anaesth. 1997;78:696–700.[PubMed]
  5. Beloucif S. A European survey of the use of inhaled nitric oxide in the ICU. Working Group on Inhaled NO in the ICU of the European Society of Intensive Care Medicine. Intensive Care Med. 1998;24:864–877.[PubMed]
  6. George I, Xydas S, Topkara VK, Ferdinando C, et al. Clinical indication for use and outcomes after inhaled nitric oxide therapy. Ann Thorac Surg. 2006;82:2161–2169. [PubMed]
  7. Bernard GR, Artigas A, Brigham KL, Carlet J,et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824. [PubMed]
  8. Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med.1993;328:399–405. [PubMed]
  9. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta-analysis. Anesth Analg. 2003;97:989–998. [PubMed]
  10. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis.  BMJ. 2007;334:779.[PMC free article] [PubMed]
  11. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.  Nature. 1987;327:524–526. [PubMed]
  12. Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad. Leaders in Pharmacutical Intelligence.  A blog specializing in Pharmaceutical Intelligence and Analytics
  13. McCarthy HO, Coulter JA, Robson T, Hirst DG. Gene therapy via inducible nitric oxide synthase: a tool for the treatment of a diverse range of pathological conditions. J Pharm Pharmacol. 2008;60:999–1017. [PubMed]
  14. Coggins MP, Bloch KD. Nitric oxide in the pulmonary vasculature.   Arterioscler Thromb Vasc Biol. 2007;27:1877–1885. [PubMed]
  15. McMahon TJ, Doctor A. Extrapulmonary effects of inhaled nitric oxide: role of reversible S-nitrosylation of erythrocytic hemoglobin. Proc Am Thorac Soc. 2006;3:153–160. [PMC free article] [PubMed]
  16. Cokic VP, Schechter AN. Effects of nitric oxide on red blood cell development and phenotype. Curr Top Dev Biol. 2008;82:169–215. [PubMed]
  17. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008; 7:156–167. [PubMed]
  18. Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet  2002; 360:141–143. [PubMed]

Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.

Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

Part II. Application of inhaled NO and circulatory effects

Cardiovascular effects

NO activates soluble guanylyl cyclase by binding to its heme group to form cyclic guanosine 3’5′-monophosphate (cGMP)   activating a protein kinase. Consequently, myosin sensitivity to calcium-induced contraction is reduced lowering the intracellular calcium concentration as a result of activating calcium-sensitive potassium channels and inhibiting release of calcium. The smooth muscle cell (SMC) relaxation with decrease in pulmonary vascular resistance (PVR) and decreased RV after load could improve cardiac output. However, left ventricular impairment associated with decrease in PVR allows increased RV output to a greater extent than the left ventricle can accommodate and the increase in left atrial pressure reinforces pulmonary edema.

Inhaled NO augments the normal physiological mechanism of hypoxic pulmonary ventilation (HPV) and improves systemic oxygenation ​(Figure 2). The effects of inhaled NO on systemic oxygenation are limited. Experiments show that intravenously administered vasodilators counteract HPV [3]. However, the non-pulmonary effects of inhaled NO include increased renal and hepatic blood flow and oxygenation [14].

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 2

Hypoxic pulmonary vasoconstriction (HPV).       (a) Normal ventilation-perfusion (VQ) matching. (b) HPV results in VQ matching despite variations in ventilation and gas exchange between lung units. (c) Inhaled nitric oxide (NO) augmenting VQ matching by vasodilating.

Non-cardiovascular effects relevant to lung injury

Neutrophils are important cellular mediators of ALI. Limiting neutrophil production of oxidative species and proteolysis reduces lung injury. In neonates, prolonged administration of NO diminished neutrophil-mediated oxidative stress [19]. Neutrophil deformability and CD18 expression were reduced in animal models [20] accomp-anied by decreases in adhesion and migration [21]. These changes limit damage to the alveolar-capillary membrane and the accumulation of protein-rich fluid within the alveoli. Platelet activation and aggregation, intra-alveolar thrombi, contribute to ALI. Inhaled NO attenuates the procoagulant activity in animal models of ALI [22] and a similar effect is seen in patients with ALI [23], but also in healthy volunteers [23,24]. In patients with ALI, decreased surfactant activity in the alveoli and noncompliance, as we recall is hyaline membrane disease accompanied by impaired pulmonary function [25].  The deleterious effects of the NO damages the alveolar wall with loss of surfactant by reactions with RNS [26]. Finally, prolonged exposure to NO in experimental models impairs cellular respiration [27].

The failure of inhaled NO to improve outcome in ALI/ARDS is therefore potentially due to several factors. First, patients with ALI/ARDS die of multi-organ failure, as the actions of NO are not expected to improve the outcome of multi-organ failure, which is a cytokine driven process leading to circulatory collapse. Indeed, the expected beneficial effect of inhaled NO is abrogated by detrimental downstream systemic effects discussed. Second, ALI/ARDS is a heterogeneous condition with diverse causes. Finally, using inhaled NO without frequent dose titration risks unwanted systemic effects without the expected benefits.

Other clinical uses of inhaled nitric oxide

Pulmonary hypertension and acute right ventricular failure

RVF may develop when there is abnormally elevated PVR and/or impaired RV perfusion.  ​Table 2 lists common causes of acute RVF. The RV responds poorly to inotropic agents but is exquisitely sensitive to after load reduction.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 2

Reducing PVR will have beneficial effects on cardiac output and therefore oxygen delivery. In the context of high RV afterload with low systemic pressures or when there is a limitation of flow within the right coronary artery [28], RV failure triggers a backward failure of venous return, as diagrammatically represented in  ​Figure 3.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 3

Pathophysiology of right ventricular failure. CO, cardiac output; LV, left ventricle; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; RV, right ventricle.

Inhaled NO is used when RV failure complicates cardiac surgery, as cardiopulmonary bypass per se causes diminished endogenous NO production [29]. There is marked variation in response to inhaled NO between patients [30] and in the same patient over time. After prolonged use, there is a leftward shift in the dose-response curve.  The risk of excessive NO administration is associated with toxicity and loss of the therapeutic effect without regular titration against a therapeutic goal [31].  Further, cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with NO [32]. Early ischemia-reperfusion injury after lung transplantation manifests clinically as pulmonary edema and is a cause of significant morbidity and mortality [33,34]. Although NO has been administered in this circumstance [35], it hasn’t prevented ischemia-reperfusion injury in clinical lung transplantation [36]. Inhaled NO has been used successfully in patients with cardiogenic shock and RVF associated with acute myocardial infarction [37,38,46], and in patients with acute RVF following acute pulmonary venous thrombo-emboli [39, 47].  An explanation is needed in view of the downstream effects of systemic vasoconstriction and MOF previously identified. No systematic evaluation of inhaled NO and its effect on clinical outcome has been conducted in these conditions.

Acute chest crises of sickle cell disease

Acute chest crises are the second most common cause of hospital admission in patients with sickle cell disease (SCD) and are responsible for 25% of all related deaths [40]. Acute chest crises are manifest by fever, respiratory symptoms or chest pain, and new pulmonary infiltrate on chest  x-ray. The major contributory factors are related to vaso-occlusion. Hemolysis of sickled erythrocytes releasing Hb into the circulation generates reactive oxygen species and reacts with NO [41]. In SCD, the free Hb depletes NO. In addition arginase 1 is released, depleting the arginine needed for NO production, [42]. While secondary PVH is common in adults with SCD the physiological rationale for the use of inhaled NO needs to be considered, except for the complication just referred to. Thus far, iNO has failed to demonstrate either persistent improvements in physiology or beneficial effects on any accepted measure of outcome in clinical trials (other than its licensed indication in neonates). Therefore, inhaled NO is usually reserved for refractory hypoxemia.

Potential problems in designing and conducting RCTs in the efficacy of inhaled NO are numerous. Blinded trials will be difficult to conduct as the effects of inhaled NO are immediately apparent. Recruitment is limited as there is little time for consent/assent or randomization. Finally, industry funding might cast doubt on the independence of the trial results.

Inhaled NO is an unproved tool in the intensivist’s armamentarium of rescue therapies for refractory hypoxemia even though it has an established role in managing complications of cardiac surgery and in heart/lung transplantation. The current place for inhaled NO in the management of ALI/ARDS, acute sickle chest crisis, acute RV failure, and acute pulmonary embolism is a rescue therapy.

Abbreviations

ALI: acute lung injury; ARDS: acute respiratory distress syndrome; Hb: haemoglobin; HPV: hypoxic pulmonary vasoconstriction; iNO: inhaled nitric oxide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; NO2: nitrogen dioxide; NOS: nitric oxide synthase; PaO2/FiO2: arterial partial pressure of oxygen/fraction of inspired oxygen; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RNS: reactive nitrogen species; RV: right ventricle; RVF: right ventricular failure; SCD: sickle cell disease; SMC: smooth muscle cell.

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Engineered Pancreatic Tissues Could Lead to Better Transplants for Diabetics

Posted in Bio Instrumentation in Experimental Life Sciences Research, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Liver & Digestive Diseases Research, tagged , , , , , on August 20, 2012| 1 Comment »

Engineered Pancreatic Tissues Could Lead to Better Transplants for Diabetics

Reporter: Aviva Lev-Ari, PhD, RN

Wednesday, August 15, 2012
By: Kevin Hattori

Technion researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes.

The tissue created by Professor Shulamit Levenberg of the Technion-Israel Institute of Technology and her colleagues has some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

Prof Levenberg
Prof. Shulamit Levenberg

 

The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones, Levenberg and colleagues said. When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice.

Transplantation of islets, the pancreatic tissue that contains hormone-producing cells, is one therapy considered for people with type 1 diabetes, who produce little or no insulin because their islets are destroyed by their own immune systems. But as with many tissue and organ transplants, donors are scarce, and there is a strong possibility that the transplantation will fail.

The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally.

The findings confirm that the blood vessel network “provides key survival signals to pancreatic, hormone-producing cells even in the absence of blood flow,” Levenberg and colleagues concluded in their study published in the journal PLoS One.

One reason transplants fail, Levenberg said, “is that the islets are usually transplanted without any accompanying blood vessels.” Until the islets begin to connect with a person’s own vascular system, they are vulnerable to starvation.

The 3-D system developed by the Technion researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure.

“The advantages provided by this type of environment are really profound,” said Xunrong Luo, an islet transplantation specialist at the Northwestern University Feinberg School of Medicine. She noted that the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant.

Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves, Levenberg and colleagues found.

The technology “is still far from tests in humans,” Levenberg said, but she noted that she and her colleagues are beginning to test the 3-D tissue scaffolds using human instead of mouse islets.

According to Northwestern’s Luo, the 3-D model demonstrated in the study “will have important and rapid clinical implications” if the same results can be replicated with human cells. “This model system also provides a good platform to study the details and mechanisms that underlie successful transplantation.”

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology.

American Technion Society (ATS) donors provide critical support for the Technion—more than $1.7 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.

 

http://www.ats.org/site/News2?page=NewsArticle&id=7567&news_iv_ctrl=1161

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Detecting Potential Toxicity in Mitochondria

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Computational Biology/Systems and Bioinformatics, Liver & Digestive Diseases Research, tagged , , , , , , , , , , , on August 14, 2012| 8 Comments »

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

Mitochondria are responsible for more than 90% of a cell’s energy production via ATP (adenosine triphosphate) generation, in addition to playing a significant role in respiration and many signaling events within most eukaryotic cells. These intracellular powerhouses range in size and quantity within each cell depending on the organism and overall cell function.

Mitochondria consist of a semi-permeable outer membrane, a thin inter-membrane space where oxidative phosphorylation occurs, an impermeable inner membrane that is intricately folded to create layered compartments—or christae—and the matrix that contains ATP-producing enzymes and the organelle’s own independent genome. Each section has a highly specialized function, and any impairment within the organelle can lead to disease or disorders within the overall organism.

Mitochondrial dysfunction may be due to:

1. Hereditary:

Inherited mitochondrial disorders can play a role in prevalent diseases such as cardiac disease and diabetes, and can also result in rare diseases such as Pearson syndrome or Leigh’s disease.

2. Drug Toxicity:

Mitochondrial toxicity as a result of pharmaceutical use may damage key organs, such as the liver and heart. For example:

nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to significantly inhibit mitochondrial respiration in liver cells, leading to liver failure.

Troglitazone, an anti-diabetic and anti-inflammatory, was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.

Drug recalls are costly to a manufacturer’s bottom line and reputation, and more importantly, can be harmful or even fatal to users. As drug discovery continues to evolve, much lead compound research now includes careful review of its interaction and potential toxicity with mitochondria.

Cell-based mitochondrial assays in microplate format may include mitochondrial membrane potential, total energy metabolism, oxygen consumption, and metabolic activity; and offer a truer environment for mitochondrial function in the presence of drug compounds compared to isolated mitochondria-based tests. Combining more than one assay in a multiplex format increases the amount of data per well while decreasing data variability arising from running the assays separately. The aggregated data also provides a more encompassing analysis of the drug’s effect on mitochondria than a single test.

One example, when testing compound effects on mitochondria, would be to measure cell membrane integrity as a function of cytotoxicity and mitochondrial function via ATP production concurrently, thus distinguishing between compounds that exhibit mitochondrial toxicity versus overt cytotoxicity.

General cytotoxicity is characterized by a decrease in ATP production and a loss of membrane integrity whereas mitochondrial toxicity results in decreased ATP production with little to no change in membrane integrity.

The assay’s efficiency is further enhanced via automation.

Robotic instrumentation ensures repeatable operation within the microplate wells when performing tasks such as cell dispensing, serial titration and transfer of compounds, and reagent dispensing. Additionally, by automating tasks within the assay process, researchers are free to attend to other tasks, reducing overall active time spent on the assay. Multi-mode microplate readers are compact instruments that can detect both fluorescent and luminescent signals. In addition, an automated process—including liquid handling and detection—can increase throughput capacity compared to manual methods.

Multiplexed cell-based mitochondrial assays increase sample throughput and decrease variability, costs, and overall time for project completion. Automating the process with robotic instrumentation allows for rapid compound profiling, repeatability, further throughput increase, and decreased per-assay and overall project time.

source:

http://www.dddmag.com/articles/2012/08/detecting-potential-toxicity-mitochondria?et_cid=2794933&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fdetecting-potential-toxicity-mitochondria

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Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)

Posted in 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, Health Economics and Outcomes Research, Liver & Digestive Diseases Research, Metabolomics, Nutrition, Origins of Cardiovascular Disease, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged , , , , , , , on August 1, 2012| 5 Comments »

Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)

Reporter: Aviva Lev-Ari, PhD, RN

Risks of Hypoglycemia in Diabetics with CKD

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 03/13/2012

 http://www.medpagetoday.com/resource-center/diabetes/Risks-Hypoglycemia-Diabetics-CKD/a/31634

According to the National Institutes of Health (NIH), approximately 40% of adults with diabetes have some degree of chronic kidney disease (CKD).1 That’s a lot of patients—perhaps more than one might think.

What should we be doing differently for these patients? Sure, they should be getting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for renoprotection, and blood pressure and lipids should be aggressively managed, but how does (or should) our approach to managing their antidiabetic therapy change?

We might consider taking a more aggressive approach to their glycemic control. In clinical trials, tight glycemic control has been shown to be the primary determinant of decreased microvascular complications.1 However, once we’ve decided how aggressively to manage glycemia, the choice of which antidiabetic to use (and how to dose it) is especially important in these patients.

Unfortunately, when the therapeutic strategy is to maximize glycemic control, the risk of hypoglycemia also increases – in both frequency and severity.2 Patients taking oral antidiabetics that are primarily eliminated by the kidneys are particularly susceptible.1 Furthermore, it should be noted that older patients are also at higher risk.3

Dosing errors are common in CKD patients and can cause poor outcomes.3 Drugs cleared renally should be dose-adjusted based on creatinine clearance or estimated glomerular filtration rate (eGFR). Dose reductions, lengthening of the dosing interval, or both may be required.3

As metformin is nearly 100% renally excreted, it is contraindicated in a number of patients: when serum creatinine is higher than 1.5 mg/dL in men or 1.4 mg/dL in women, in patients older than 80 years, or in patients with chronic heart failure. The primary concern here is that other hypoxic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) may increase the risk of lactic acidosis. Because of this danger, and despite the fact that metformin is usually the recommended first-line treatment for type 2 diabetes, one should use caution when considering metformin in patients with renal impairment.3

Similarly, sulfonylureas should be used with care in diabetics with CKD. The clearance of both sulfonylureas and their metabolites is highly dependent on kidney function. As such, severe and sustained episodes of hypoglycemia due to sulfonylurea use have been described in dialysis patients.2

Regardless of which antidiabetic agent is selected, HbA1c and kidney function should be regularly monitored and the antidiabetic regimen appropriately adjusted. As patients with type 2 diabetes tend to progress over time, most will require a combination of agents to achieve desired glycemic control. These combinations should be chosen carefully in patients with CKD.1

Finally, awareness of and screening for renal impairment in diabetics is a necessary precursor to successful intervention. In these patients, CKD is underdiagnosed and undertreated, and awareness of the disease is low among providers and patients alike.1

Early detection of disease via eGFR or urinary albumin excretion can lead to timely, evidence-based intervention and help prevent or delay progression of CKD. The benefit? Improved kidney and cardiovascular outcomes, and lower associated costs.1

References:

  1. Bakris GL. Recognition, Pathogenesis, and Treatment of Different Stages of Nephropathy in Patients With Type 2 Diabetes Mellitus. Mayo Clin Proc. 2011;86:444-456.
  2. Cavanaugh KL. Diabetes Management Issues for Patients With Chronic Kidney Disease. Clin Diab. 2007;25:90-97.
  3. Munar MY, et al. Drug Dosing Adjustments in Patients With Chronic Kidney Disease. Am Fam Physician. 2007;75:1487-1496.

 

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Mitochondrial Mechanisms of Disease in Diabetes Mellitus

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, Liver & Digestive Diseases Research, Metabolomics, Nutrition, Population Health Management, Genetics & Pharmaceutical, Systemic Inflammatory Response Related Disorders, tagged , , , , , on August 1, 2012| 6 Comments »

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Reporter: Aviva Lev-Ari, PhD, RN

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 03/13/2012

http://www.medpagetoday.com/resource-center/diabetes/Mitochondrial-Mechanisms-Disease-Diabetes-Mellitus/a/31636 

Mitochondria are found in every cell in the human body.1 Known as the “power plant of the cell,” mitochondria are central to the conversion of fatty acids and glucose to usable energy in the form of ATP (adenosine triphosphate).1, 2 A growing body of evidence now demonstrates a link between various disturbances in mitochondrial functioning and type 2 diabetes.1

In patients with type 2 diabetes, the size, number, and efficiency of mitochondria are reduced.3 This can have pathogenic effects in the tissues central to glucose metabolism — the pancreas, liver, and skeletal muscle.

In pancreatic beta cells, mitochondria are central to insulin secretion. As the amount of glucose in the circulation increases, so does the mitochondrial production of ATP inside the cell. When this occurs, ATP-sensitive channels open, leading to membrane depolarization and the secretion of insulin.1

Much data support the concept that mitochondrial function is required for appropriate glucose-induced insulin secretion.4 Studies in beta cell lines have shown that when mitochondrial function is experimentally decreased, insulin secretion shows a similar reduction.4 Supporting studies in humans have shown that individuals with disabling mutations in mitochondrial DNA (i.e., the A32433G mutation) demonstrate impaired pancreatic insulin secretion in response to glucose challenge.

Mitochondrial dysfunction in skeletal muscle and the liver might also contribute to the development of diabetes. As part of its cellular respiratory function, mitochondria utilize (and break down) fatty acids. When mitochondrial function is reduced, intracellular fats may accumulate.2

One hypothesis is that excessive accumulation of intracellular fat may have a central role in insulin resistance. This hypothesis is supported by the observation that excessive lipids lead to reductions in numbers and function of insulin receptors.2

The link between obesity, inactivity, and type 2 diabetes is well established — and weight loss remains a cornerstone of diabetes management.3 The role of mitochondria as cellular “power plant” makes a compelling case for a causative relationship between mitochondrial dysfunction and clinical disease.3

Reduced mitochondrial capacity has been demonstrated in patients with type 2 diabetes.3 In one study, patients who lost weight demonstrated an increase in mitochondrial density and insulin sensitivity. Patients achieved an average weight loss of 7.1% and experienced a decrease in mean HbA1c from 7.9 to 6.5, as well as significant improvements in both fasting and postprandial blood glucose.3

Strategies that focus on increasing mitochondrial function could represent important new approaches in the treatment of diabetes.

One agent under investigation is coenzyme Q10 (CoQ10). In animal studies, CoQ10 significantly reduced fasting and 2-hour postprandial glucose levels. In humans, early, uncontrolled studies of diabetic patients receiving CoQ10 have demonstrated improvements in blood glucose and insulin synthesis and secretion. Furthermore, the clinical benefit of CoQ10 has been evident in a number of therapeutic trials in patients with maternally inherited mitochondrial defects like MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes).1 The therapeutic advantage of supplementary CoQ10 may be especially helpful in patients taking statins, as these patients have been shown to have decreased production of endogenous CoQ10.5

Impaired mitochondrial function in tissues central to glucose metabolism (pancreas, muscle, liver) may be partly responsible for diabetes pathogenesis.2 The failure to appropriately manage cellular energy needs may result in impaired insulin secretion and/or insulin resistance.2 Targeting mitochondrial dysfunction may represent a promising path forward in the development of novel treatments for diabetes.

REFERENCES

  1. Lamson DW, et al. Mitochondrial Factors in the Pathogenesis of Diabetes: A Hypothesis for Treatment. Altern Med Rev. 2002;7:94-111.
  2. Patti ME, et al. The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes. Endocr Rev. 2010;31:364-395.
  3. Toledo FG, et al. Effects of Physical Activity and Weight Loss on Skeletal Muscle Mitochondria and Relationship With Glucose Control in Type 2 Diabetes. Diabetes. 2007;56:2142-2147.
  4. Maassen JA, et al. Mitochondrial Diabetes: Molecular Mechanisms and Clinical Presentation. Diabetes. 2004;53(suppl 1):S103-S109.
  5. Ghirlanda G, et al. Evidence of Plasma CoQ10-Lowering Effect by HMG-CoA Reductase Inhibitors: A Double-Blind, Placebo-Controlled Study. J Clin Pharmacol. 1993;33:226-229.

 

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SAME SCIENTIFIC IMPACT: Scientific Publishing – Open Journals vs. Subscription-based

Posted in Alzheimer's Disease, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, HealthCare IT, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Liver & Digestive Diseases Research, Medical and Population Genetics, Medical Devices R&D Investment, Metabolomics, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Pain: Etiology, Genetics & Innovations in Treatment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Biology & Bio Instrumentation, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, tagged , , , , , , , , , , , , , , on July 23, 2012| 1 Comment »

Reporters: Aviva Lev-Ari, PhD, RN & Pnina G. Abir-Am, PhD

Drastic change in academic education by design: FREE ACCESS to knowledge — Program edX – the  Harvard+MIT collaboration on Online education!! 
FREE ACCESS to Scientific Journals will be the next step. Research to support that by a study carried by Bjork, B. C., and D. Solomon. 2012. Open access versus subscription journals: a comparison of scientific impact. BMC Medicine. 10(1):73+. 
“Following step will be to demonstrated that Scientific Websites like http://pharmaceuticalintelligence.com have SAME Scientific impact as Open Journals!!
“We are well positioned to demonstrate that” said Aviva Lev-Ari, PhD, RN, Director & Founder of Leaders in Pharmaceutical Business Intelligence and the 2/2012 launcher of the initiative called  http://pharmaceuticalintelligence.com  To trace her contributions to Research Methodology, 1976-2005, go to  https://sites.google.com/site/avivasopusmagnum/aviva-s-home-page
The merit of Scientific Website is manifold:
  • Time from Lab/Desk to Publication on the Internet and Search engines is reduced to seconds
  • comments by other scientists are equally valuable to peer review
  • collaboration with other scientist around the globe is fostered on WWW
  • the platform is of collaborative authoring, we have 60 categories of research in one site
  • interdisciplinary work can be published in one site the over arching domain in our case is Life Sciences, Pharmaceutical and Healthcare
In May 2012 MIT and Harvard are collaborating on distribution of course material of all classes on the Internet – a Program called EdX
In the Press Release“EdX represents a unique opportunity to improve education on our own campuses through online learning, while simultaneously creating a bold new educational path for millions of learners worldwide,” MIT President Susan Hockfield said.

Harvard President Drew Faust said, “edX gives Harvard and MIT an unprecedented opportunity to dramatically extend our collective reach by conducting groundbreaking research into effective education and by extending online access to quality higher education.”

“Harvard and MIT will use these new technologies and the research they will make possible to lead the direction of online learning in a way that benefits our students, our peers, and people across the nation and the globe,” Faust continued.

Princeton, Stanford, Michigan and the University of Pennsylvania announced that they would offer free Web-based courses through a for-profit company called Coursera that was founded by two Stanford computer science professors. One of those professors, Andrew Ng, taught a free online course in machine learning this past fall with an enrollment of more than 100,000 students.

There’s also Udacity, co-founded by a former Stanford professor, andKhan Academy, which boasts 3,100 free educational videos across a variety of subjects.

MIT and Harvard said that they hope to eventually partner with other universities to expand the offerings on the edX platform.

Results of the BMC Medicine study are reported, below and they are:  Open Access, But Same Impact
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BioTechniques

http://www.biotechniques.com/news/Open-Access-But-Same-Impact/biotechniques-333012.html#.UA2SsRxueMU 

Open Access, But Same Impact

07/19/2012

Jesse Jenkins
By comparing two-year impact factors for journals, researchers found that open access and subscription-based journals have about the same scientific impact.
Open access (OA) journals are approaching the same scientific impact and quality as traditional subscription journals, according to a new study. In a study published in BMC Medicine on July 17 (1), researchers surveyed the impact factors, the average number of citations per paper published in a journal during the two preceding years, of OA and traditional subscription journals.

By comparing two-year impact factors for journals from the four countries that publish the most scientific literature, researchers have found that OA journals have about the same scientific impact as their subscription-based counterparts. Source: BMC Medicine.

At first, the study’s authors—Bo-Christer Björk from the Hanken School of Economics in Helsinki, Finland, and David Solomon from the College of Human Medicine at Michigan State University—found that there was a 30% higher average citation rate for subscription journals. But after controlling for journal discipline, location of publisher, and age of publication, their results showed that OA and subscription journals had nearly identical scientific impact.

“The newer open access published within the last 10 years, particularly those journals funded by article processing fees, had basically the same impact as subscription journals within the same category,” said Solomon. “I think that that is the key finding.”

The initial higher citation rate for subscription journals was the result of a higher percentage of older OA journals from countries that are not major publishing countries. “A lot of them are from South America or other developing countries, and they tend to have lower impact factors,” said Solomon. “When you compare apples to apples and start looking within subgroups, particularly journals launched after 2000 in biomedicine for example, the differences fall away.”

However, the authors identified a sector of low quality, OA publishers that are looking to capitalize on the article processing charge model rather than contribute to the advancement of science. Solomon said that this could partly be to blame for negative perceptions about the integrity of OA publishing as a whole and its impact on the peer review system. But most researchers are aware of these low-quality publishers and prefer to publish in more reputable OA journals.

In the end, Bjork and Solomon are hopeful that the study’s findings may help dispel some of the misconceptions in the debate over OA publishing. “Open access journals still have the reputation of being second class in the minds of some people. So, we think that this is important because this is objective data verifying that at least the open access journals published in the last 10 years by professional publishers are on par with subscription journals.”

References

  1. Bjork, B. C., and D. Solomon. 2012. Open access versus subscription journals: a comparison of scientific impact. BMC Medicine. 10(1):73+.

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