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Posts Tagged ‘Conditions and Diseases’

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nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to significantly inhibit mitochondrial respiration in liver cells, leading to liver failure.

Troglitazone, an anti-diabetic and anti-inflammatory, was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.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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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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Bio-marker guided prognostic and functional evaluations of “Stroke”

Posted in Alzheimer's Disease, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Exec Compensation in the Cardiac & Vascular Repair Tools Subsegment, Frontiers in Cardiology and Cardiovascular Disorders, Pharmacotherapy of Cardiovascular Disease, tagged , , , , , , , , , , , , , on August 3, 2012| 1 Comment »

 

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

A new proof-of-concept study shows that plasma concentrations of precursor fragments of the neuropeptide enkephalin (proenkephalin A, or PENK-A) are elevated in patients with acute stroke compared with those with TIA and nonischemic events.

Researchers are making efforts to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease.

Although the mature neuropeptides are degraded within minutes, their precursor fragments are much more stable and represent neuropeptide synthesis in stoichiometric relations. “They are therefore well suited as biomarkers and may be suitable for measurement in clinical settings,” said Dr. Doehner.

The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders.

{Ernst  A., Kohrle  J., Bergmann  A.;  Proenkephalin A 119—159, a stable proenkephalin. A precursor fragment identified in human circulation, Peptides 27 2006 1835-1840
Ernst  A., Suhr  J., Kohrle  J., Bergmann  A.;  Detection of stable N-terminal protachykinin A immunoreactivity in human plasma and cerebrospinal fluid, Peptides 29 2008 1201-1206}

Researchers are making efforts to use these precursor fragments as markers to distinguish an ischemic stroke from a transient ischemic attack (TIA) or an intracerebral hemorrhage.

The authors strongly hope that it may help to advance the use of biomarkers in the clinical evaluation of stroke patients.

Despite the limitations, elevated PENK-A levels correlated with stroke severity and with brain lesion size, and they predicted mortality and more functional disability.

“There is clearly an unmet need to establish biomarker-guided prognostic and functional evaluations for patients with stroke, said the lead author Wolfram Doehner, MD, PhD, from the Center for Stroke Research, in Berlin, Germany

The new report was published in Journal of the American College of Cardiology.

http://content.onlinejacc.org/article.aspx?articleid=1217869

http://www.medscape.com/viewarticle/768457?src=nldne

 

 

 

 

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Amyloidosis

Posted in Bone Disease and Musculoskeletal Disease, Cell Biology, Signaling & Cell Circuits, Genome Biology, Infectious Disease & New Antibiotic Targets, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Uncategorized, tagged , , , , , , , , , , , , on June 4, 2012| 4 Comments »

β-amyloid fibrils.

β-amyloid fibrils. (Photo credit: Wikipedia)

Extracellular deposition of insoluble fibrillar proteins in tissues and organs lead to a condition known as amyloidosis which is thought to be caused by misfolding of proteins. There are several types of amyloidosis, but the unifying feature of the amyloidoses is that the deposits share a common ß-pleated sheet structural conformation that confers unique staining properties.

There are several types of amyloidosis and the most common form is the primary amyloidosis (AL) for amyloid of light chain composition. Symptoms can occur in any organ of the body and the organs most often involved include the heart, kidneys, nervous system, and gastrointestinal tract.

Amyloid deposits in these organs can cause

shortness of breath,

fatigue,

edema (swelling of ankles and legs),

dizziness upon standing,

a feeling of fullness in the stomach (especially after eating),

diarrhea,

weight loss,

enlarged tongue,

numbness of the legs and arms,

protein in the urine (proteinurea) and

enlarged liver (hepatomegaly).

Primary amyloidosis (AL) is an acquired plasma cell disorder in which a monoclonal immunoglobulin light chain is produced in the bone marrow and usually found in the blood or urine. AL amyloidosis occasionally occurs with multiple myeloma. The amyloid fibrils in this type of amyloidosis are made up of immunoglobulin light chain proteins (kappa or lambda).

Amyloidosis caused by infection or inflammation is known as Secondary Amyloidosis (also known as AA amyloidosis) in which elevation of an acute phase protein, SAA, a portion of which (AA protein) deposits as amyloid fibrils. AA amyloidosis usually begins as disease in the kidneys, but other organs can be affected, and may cause protein in the urine, edema, and fatigue.

Medical or surgical treatment of the underlying chronic infection or inflammatory disease can slow down or stop the progression of this type of amyloid where as in case of AL chemotherapy is the standard practice.

Other forms of amyloidosis are familial amyloidosis (ATTR) a most common form of inherited amyloidoses caused by a mutation in the transthyretin (TTR) gene that produces abnormal transthyretin protein which deposits as amyloid fibrils. Symptoms of disease are usually neuropathy (numbness and tingling in the arms and legs, dizziness upon standing, and diarrhea) and cardiomyopathy and occur in mid to late life. The standard treatment is liver transplantation since the transthyretin protein which causes familial amyloidosis is made in the liver, replacing this organ removes the source of mutant protein production. A new liver will make only normal transthyretin. Each family has its own pattern of organ involvement and associated symptoms and the mode of transmission is autosomal dominant.

Other rare forms of inherited amyloidosis include apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII) gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys).

Beta-2 microglobulin amyloidosis is caused by chronic renal failure and often occurs in patients who are on dialysis for many years. Amyloid deposits are made of the beta-2 microglobulin protein that accumulated in tissues, particularly around joints, when it cannot be excreted by the kidney because of renal failure.

There are many types of localized amyloidoses. The most common and best known is Alzheimer’s disease.

Localized amyloid deposits in the airway (trachea or bronchus), eye, or urinary bladder are made up of light chain proteins, similar to those in AL amyloidosis. However, in localized amyloidosis the abnormal plasma cells producing the amyloid light chains are in the tissues, not in the bone marrow. Other localized types of amyloidosis are associated with hormone proteins, aging, or specific areas of the body, and have not been found to develop into systemic amyloidosis

Diagnosis of this disease is sometimes difficult as many of the sysmptoms are general and can occur in other diseases. Symptoms in each patient depend on the type of amyloidosis and on the type of involved organ systems.

Amyloidosis can only be diagnosed by a positive biopsy (i.e., an identification of the amyloid deposits in a piece of tissue). Initial biopsies are most commonly obtained from the abdominal fat. image from BMCIf amyloid is suspected in other organs, however, a biopsy may be needed from these specific areas. Tissue biopsies must be stained properly with Congo red, a dye which will color the amyloid if it is present and cause it to have a unique appearance when viewed under a special microscope. If amyloid is present in a tissue biopsy, further tests can be done to determine the type of the amyloid.

The Amyloid Treatment & Research Program (ATRP) at Boston Medical Center (BMC) is an international referral center that treats amyloidosis with stem cell transplantation. The Program offers a multi-disciplinary approach to diagnosis and treatment of this multi-organ disorder. Amyloid doctors specializing in cardiology, pulmonary, nephrology, gastroenterology, neurology, and other systems participate in patient evaluation and care.

The ATRP at BMC studies the systemic types of amyloidoses defined under amyloid types. Other forms of amyloidosis include Alzheimer’s and other neurodegenerative diseases, prion diseases, serpinopathies, some of the cystic fibroses, and others.

They have developed Amyloid Light Chain Database, called ALBase, with the support of an NHLBI P01 award, HL68705. ALBase is a curated database and collection of analytical and graphical tools designed to facilitate the analysis of amyloidogenic immunoglobulin (Ig) light chains (LC) occurring in patients with AL amyloidosis. ALBase is designed to compile and analyze Ig LC sequences from patients with AL amyloidosis, to compare their predicted protein sequence and structure to non-amyloidogenic LC sequences from patients with multiple myeloma or health controls. The hypothesis underlying this is that the primary sequence of the LC is likely to be a major determinant of secondary structure and of propensity to unfold, oligomerize, and form fibrils.

“ALBase is available to the scientific community for research purposes. Please reference the site if you make use of it.”

Two patients of Dr. David Seldin are diagnosed with systemic amyloidosis and they shared their experiences from diagnosis to treatment and recovery (You can listen to an audio of this broadcast by clicking here: Rare Disease Feature (WAER 88.3 FM)).

Both patients credit their physicians for investigating abnormal tests and nonspecific symptoms, and for referring them to amyloid specialists early in the disease course.

http://www.bu.edu/amyloid/david-c-seldin-m-d-ph-d/

http://www.bu.edu/amyloid/2012/03/08/npr-interview/

http://www.bmc.org/amyloid.htm#2012gala

Curated by: Dr. Venkat S. Karra, Ph.D

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Insight into how cholesterol promotes amyloidogenesis

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, tagged , , , , , , , on June 1, 2012| 2 Comments »

Enzymes act on the APP (Amyloid precursor prot...

Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid and its crucial in the formation of senile plaques in Alzheimer (Photo credit: Wikipedia)

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release  the amyloid-β polypeptides, which are associated with Alzheimer’s disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded “N-helix” followed by a short “N-loop” connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer’s therapeutics.

Source

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

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What the Cardiologist Needs to Know

Posted in Cardiovascular Pharmacogenomics, Infectious Disease & New Antibiotic Targets, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , , , , , on May 29, 2012| Leave a Comment »

Guidelines for the Diagnosis and Treatment of Endocarditis

from

British Society of Antimicrobial Chemotherapy (BSAC)

Clinicians who care for patients diagnosed with infective endocarditis (IE) are (un)fortunate to be able to refer to several guidelines about its diagnosis and treatment. The guidelines vary considerably, especially with regards to antibiotic prescribing recommendations, which generally reflect local practice and expert opinion in light of largely observational data. All guidelines recommend a multidisciplinary approach to the management of IE.

Infective endocarditis

Infective endocarditis (Photo credit: Wikipedia)

Echocardiography remains a cornerstone of IE diagnosis but is neither 100% sensitive nor specific and multiple scans may be needed to identify vegetations. Echocardiography should also be used in all patients with Staphylococcus aureus bacteraemia. The prevalence of IE among patients with S aureus bacteraemia is variable but was reported as 13% in one large prospective US study and 22% in a recent European study. Clinical assessment is unreliable in diagnosing IE in patients with S aureus bacteraemia and without echocardiography the diagnosis may be missed. Transoesophageal echocardiography is now recommended in most cases of suspected or confirmed IE but may be unnecessary in patients with right-sided valve involvement.

Establishing a microbiological diagnosis in an era of increasingly complex infections with unpredictable resistance patterns is important. However, traditional recommendations for blood culture sampling have been amended for patients with suspected IE and severe sepsis or septic shock. In this situation, two (rather than three) sets of blood cultures, taken at different times within an hour before the start of empirical treatment, are now advised. This is a pragmatic recommendation to avoid undue delay in starting empirical antimicrobial treatment. In other patients, the usual need for three sets of blood cultures is recommended but with at least 6 h between sampling times; an important aim of multiple sampling is to demonstrate the presence of a sustained or persistent bacteraemia, which is characteristic of IE. Identification of atypical micro-organisms using serology in culture-negative cases should be limited to Coxiella and Bartonella in the first instance—a reflection of the extremely small numbers of reported cases of IE caused by Mycoplasma, Brucella and Legionella.

Fungal causes of IE should be considered in culture-negative IE if serology is non-diagnostic and the patient is immunocompromised, has a prosthetic valve, is an intravenous drug user or is not responding to empirical antibacterial treatment. The application of broad-range (16S ribosomal RNA gene) PCR on surgically resected valves or embolic material should be used when culture has failed. False-negative 16S ribosomal RNA gene PCR reactions can occur in the presence of inhibitors of the DNA polymerase within clinical samples or as a result of the vagaries of sampling (ie, processing a piece of tissue that does not contain any bacteria). Bacterial DNA has been shown to be present within cardiac tissue several years after successful treatment of IE, so results should be interpreted with caution in a patient with a previous diagnosis of IE. Application of 16S ribosomal gene PCR to blood in patients with IE is problematic owing to the low levels of bacteria present (1–10 fu/ml) and subsequent difficulty in DNA extraction; as a result it is not currently available for routine clinical use.

Empirical treatment (that started before obtaining a microbiological diagnosis) is generally discouraged, except in those who are acutely unwell or shocked. There is no clear evidence that speeding up the diagnosis, and instigation of treatment, improves outcomes, although this would seem intuitive. Early treatment (started within days of onset of symptoms rather than weeks) is a laudable aim, but the few days delay in hospital while appropriate echocardiographic and microbiological tests are undertaken on a stable patient are unlikely to have a negative impact on outcome. Conversely, the administration of broad-spectrum antibiotics when the diagnosis of IE has not been considered (and often when inadequate samples have been obtained) may have considerable impact on the ability to establish the diagnosis and subsequently deliver effective treatment.

Outpatient antibiotic treatment (OPAT) for IE is included in the BSAC guidelines in response to increasing efforts to expand these services and manage more patients outside hospital. Patients who might be considered for OPAT include those who are stable and responding well to treatment, are without signs of heart failure and without any indications for surgery or uncontrolled extracardiac foci of infection. Delivery of OPAT requires appropriate funding, support and infrastructure, coupled with the ability to rapidly access inpatient services and obtain urgent expert advice if needed. This has been proved to be feasible and safe in the UK, even in high-risk IE cases.

Although the guidelines include recommendations for most causes of IE, the predominant pathogens remain staphylococci, streptococci and enterococci. Routine addition of gentamicin to flucloxacillin for the treatment of native valve staphylococcal IE is no longer recommended (see Table 1). This recommendation is unchanged from previous BSAC guidelines but the ESC continue to include gentamicin as an optional addition. Further evidence of the toxicity of gentamicin has been published, based on findings from a randomised controlled trial comparing daptomycin with either vancomycin or cloxacillin plus gentamicin for the treatment of S aureus bloodstream infection or IE Recommendations for meticillin-resistant staphylococci also differ from those of the ESC; although vancomycin is the primary agent in both sets of guidelines, rifampicin is recommended by BSAC in place of gentamicin because of concerns about efficacy and toxicity. Daptomycin, a recently licensed lipopeptide, is also recommended as an alternative agent for patients who are intolerant to vancomycin or have infection caused by vancomycin-resistant isolates.

Previous recommendations for treatment of streptococcal IE have been simplified, with greater emphasis placed on benzylpenicillin rather than amoxicillin as the primary agent to reduce risk of Clostridium difficile infection. Enterococcal treatment regimens are largely consistent with the ESC guidelines, though a low threshold for withdrawing gentamicin in patients with deteriorating renal function or other signs of toxicity is advised, based on observational data that shorter gentamicin courses are not associated with worse outcomes.

The timing of cardiac surgery in IE should be evaluated by the multidisciplinary team on a case by case basis. Attempts to advise whether cardiac surgery should be emergent, urgent or elective can seem artificial. The traditional indications for surgery in IE are well established but it is becoming apparent that patients with IE caused by S aureus, or patients with evidence of systemic embolisation, should also be considered for early surgery, which may confer a mortality benefit.

Device-related infections have been deliberately omitted from the current BSAC guidance as the challenges in preventing, diagnosing and treating cases of intracardiac device IE are different from ‘traditional’ native or prosthetic valve IE. Further specific device-related guidance is likely to be published in the future and a joint working party involving the BSAC, BCS and Heart Rhythm UK has been established. IE guidelines are always imperfect owing to the difficulties in studying this relatively uncommon condition and the scarcity of randomised trials. At present, we are uncertain of the incidence, risk factors, causative micro-organisms (and their antimicrobial sensitivities), and patient outcomes in IE affecting the UK population. A recently established national endocarditis database may help to answer some of these questions, but its success will be crucially determined by the degree of support and national participation. See http://www.neemo.leedsth.nhs.uk/ (only via the N3 network) for details.

see source for more

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

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Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Posted in Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , , on May 29, 2012| 15 Comments »

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Curator: Aviva Lev-Ari, PhD, RN

 

Excellent review of Hypertension Medications is provided in the following two short videos:

VIEW VIDEOS

Hypertension Explained Clearly! 1 of 2

Hypertension Explained Clearly! 2 of 2

 

http://www.drugs.com/clinical_trials/new-data-shows-investigational-triple-antihypertensive-combination-therapy-significantly-lowers-9712.html

Hypertension Treatment in the Last Decade

 The need for combination drug therapy was recognized in 2000, In Combination Antihypertensive Drugs: Recommendations for Use

NEIL S. SKOLNIK, M.D., JONATHAN D. BECK, M.D., MATHEW CLARK, M.D., Abington Memorial Hospital, Jenkintown, Pennsylvania

Am Fam Physician. 2000 May 15;61(10):3049-3056

Combination Medication: Impact on Compliance

Increased Compliance with fewer pills a favorable outcome of combination medication for Hypertension.

More medications, fewer pills: Combination medications for the treatment of hypertension Richard Lewanczuk, MD PhD1 and Sheldon W Tobe, MD2

Can J Cardiol. 2007 May 15; 23(7): 573–576.

Classification of Blood Pressure

Category SBP mmHg DBP mmHg

Normal <120 and <80

Prehypertension 120–139 or 80–89

Hypertension, Stage 1 140–159 or 90–99

Hypertension, Stage 2 ≥160 or ≥100

Principles of Hypertension Treatment

• Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients

with diabetes or chronic kidney disease.

• Majority of patients will require two medications to reach goal.

Without Compelling Indications

Stage 1

Hypertension

(SBP 140–159 or DBP

90–99 mmHg)

Thiazide-type diuretics

for most. May consider

ACEI, ARB, BB, CCB,

or combination.

 Stage 2

Hypertension

(SBP ≥160 or DBP

≥100 mmHg)

2-drug combination for

most (usually thiazidetype

diuretic and ACEI,

or ARB, or BB, or CCB).

Causes of Resistant Hypertension

• Improper BP measurement

• Excess sodium intake

• Inadequate diuretic therapy

• Medication

– Inadequate doses

– Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs

(NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)

– Over-the-counter (OTC) drugs and herbal supplements

• Excess alcohol intake

• Identifiable causes of hypertension (see reverse side)

Compelling Indications for Individual Drug Classes

 Compelling Indication  and Initial Therapy Options

• Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT

• Post myocardial infarction BB, ACEI, ALDO ANT

• High CVD risk THIAZ, BB, ACEI, CCB

• Diabetes THIAZ, BB, ACEI, ARB, CCB

• Chronic kidney disease ACEI, ARB

• Recurrent stroke prevention THIAZ, ACEI

Key: THIAZ = thiazide diuretic, ACEI= angiotensin converting enzyme inhibitor, ARB = angiotensin receptor

blocker, BB = beta blocker, CCB = calcium channel blocker, ALDO ANT = aldosterone antagonist

http://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf

JNC-7 on Treatment for Hypertension

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, or JNC-7, most people require more than one medication to achieve treatment goals. Some medications are being manufactured in combinations, which reduces the number of pills a patient must take and may reduce costs.

http://www.livestrong.com/article/217562-combination-drugs-for-hypertension/#ixzz1wD1wneZg

All combination drugs for Hypertension are presented in

http://www.livestrong.com/article/217562-combination-drugs-for-hypertension/#ixzz1wD3dqnrl

JNC-7 lists the following Combinations of Drugs for Hypertension:

ACE Inhibitors and Calcium Channel Blockers

The angiotensin converting enzyme inhibitors, or ACEIs, are a group of drugs that work in the kidneys to block a reaction that leads to tightening of the blood vessels and retention of sodium and water. They lower blood pressure by counteracting these effects.

Calcium channel blockers, or CCBs, work by relaxing smooth muscle in the heart and blood vessels. One common side effect of this group of drugs is leg swelling. This can be lessened when they are used in combination with the ACEIs.
Amlodipine-benazepril, enalapril-felodipine and trandolapril-verapamil are examples of these medicines that have been combined into a single pill. Multiple dosing variations are available.

ACE Inhibitors and Diuretics

Diuretics are commonly known as “water pills” because they work by increasing urine output and lowering blood volume, and therefore blood pressure. Diuretics are generally inexpensive, work well to enhance the effects of other medicines and have a proven track record in preventing cardiovascular complications of hypertension, as discussed in JNC-7.

Many ACE inhibitors are available packaged with hydrochlorothiazide, or HCTZ. Benazepril, enalapril, lisinopril and others are commonly seen in this combination.

ARBs and Diuretics

The angiotensin receptor blockers, or ARBs, are related to the ACEIs, in that they work on the same renal pathway. However, the ARBs work farther down the process and often have fewer side effects. The beneficial effects on blood pressure are similar between the two groups.

Candesartan, losartan, telmesartan, valsartan and others are available as combination drugs with HCTZ.

Beta-blockers and Diuretics

Beta-blocking medications work in the peripheral nervous system to slow the heart rate and decrease adrenalin-type effects on the blood vessels. JNC-7 notes that the beta-blockers are especially useful in those with hypertension and heart disease or angina.

Atenolol is available with the diuretic chlorthalidone, which is similar to HCTZ. Bisoprolol, metroprolol, propranolol LA and timolol come in combination with HCTZ.

Centrally Acting Drugs and Diuretics

Methyldopa and reserpine affect the central nervous system to produce a lowering of blood pressure. They are not used often, but can be effective in the appropriate situation. Each come in a combination drug with HCTZ, while reserpine is also produced with chlorthalidone and chlorothiazide.

Diuretic Combinations

Various diuretics work in different locations of the kidneys to affect their anti-hypertensive properties. HCTZ tends to lower blood potassium, so is available in combination with spironolactone or triamterene, which are known to elevate potassium. The combination tends to be potassium neutral.

ARB and Calcium Channel Blocker and Diuretic

In July 2010, a triple combination drug for hypertension was approved by the US Food and Drug Administration. Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide, according to Monthly Prescribing Reference.

Three Combination Drug Therapy for Antihypertension from Daiichi Sankyo’s Portfolio of Products

Daiichi Sankyo has a
comprehensive portfolio of drugs offering a wide range of treatments for patients in a number of disease
categories including hypertension, heart disease and hyperlipidemia/atherosclerosis.

The discovery of epinephrine (also known as adrenaline) in 1889, to the development of the statin class of lipid-lowering agents and the development of the first glitazone, which revolutionized long-term control of type 2 diabetes.

New ideas and pairing of existing information with novel concepts, led to the  creation of  medicines as well as new methods of drug discovery and delivery.

Daiichi Sankyo products for hypertension, heart disease and hyperlipidemia/atherosclerosis which are currently marketed in the U.S. include several drug combinations for Cardiovascular disease.

http://dsi.com/c/document_library/get_file?uuid=5b356194-9d74-47ba-94a6-a82a7ea694cb&groupId=12065

TRIBENZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker and Diuretic

How TRIBENZOR work

Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. TRIBENZOR can help your blood vessels relax and reduce the amount of fluid in your blood. This can make your blood pressure lower. Medicines that lower blood pressure may lower your chance of having a stroke or a heart attack.

Some people may need more than 1—or even more than 2—medicines to help control their blood pressure. TRIBENZOR combines 3 effective medicines in 1 convenient pill. Read the following chart to learn how each medicine works in its own way to help lower blood pressure.

TRIBENZOR: 3 effective medicines in 1 pill

The medicine in TRIBENZOR How it works What it does
Angiotensin II receptor blocker Blocks a natural chemical in your body that causes blood vessels to narrow.

Lowers

Yours

blood

pressure
Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.
Diuretic (water pill) Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.

http://www.tribenzor.com/how_works.html

            Effectively lower blood pressure. People taking the 3 medicines in TRIBENZOR had greater reductions in blood pressure than did people taking any 2 of the medicines combined

            Start to work quickly. People taking TRIBENZOR saw results in as little as 2 weeks

AZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker

How AZOR work

AZOR relaxes and widens blood vessels to help lower blood pressure.

You may have already tried another blood pressure medicine that works a certain way to lower blood pressure. But 1 blood pressure medicine may not be enough for you. You may find the help you need with the 2 effective medicines in AZOR.

AZOR combines 2 effective medicines in 1 convenient pill.

Learn how each medicine in AZOR works in its own way to help lower blood pressure.

The medicine in AZOR How it works What it does
Angiotensin II receptor blocker (ARB) Blocks a natural chemical in your body that causes blood vessels to narrow. This helps your blood vessels relax and widen.

Lowers

Your

Blood

pressure
Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.

http://www.AZOR.com/how_works.html

 

Benicar and Benicar HCT are Daiichi Sankyo’s products an ARBs and Diuretics

How Benicar and Benicar HCT work

Benicar and Benicar HCT are prescription medicines used to lower high blood pressure (hypertension). They may be used alone or with other medicines used to treat high blood pressure. Benicar HCT is not for use as the first medicine to treat your high blood pressure.

 Lowering blood pressure with Benicar or Benicar HCT

There are many different choices to treat high blood pressure. You may have started with some lifestyle changes or different medicines to find what works for you. You and your doctor can talk about whether Benicar or Benicar HCT is a good choice for you.

The medicine in Benicar How it works

What it does
Angiotensin II receptor blocker (ARB) Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen.

Lowers

your

blood

pressure

Some people may need more than 1 medicine to help manage high blood pressure. So doctors may choose to prescribe Benicar HCT. The 2 medicines in Benicar HCT help to lower blood pressure more than taking either medicine alone. You and your doctor can talk about what’s right for you.

The medicines in Benicar HCT How it works

What it does
Angiotensin II receptor blocker (ARB) Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen.

Lowers

your

blood

pressure
Diuretic(a water pill) Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.

Benicar and Benicar HCT are medicines that both

Block calcium

Block a chemical called angiotensin II

Block water and salt

There are no generic forms of Benicar or Benicar HCT

http://www.benicar.com/how_work.html

Risk of Antihypertensive drugs

Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study

BMJ 2012;344:d8190

Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.

http://www.bmj.com/content/344/bmj.d8190

Affordability of the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio is supported by a Manufacturer Program to 2016.

There are no generic drugs for the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio. Daiichi Sankyo, Inc., will cover up to $140 of the co-pay for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR after the patient pays the first $25. Offer applies to patients with commercial insurance; $25 initial savings available for patients without insurance; offer expires 2016. If a retail or mail-order pharmacy does not accept the Savings That Last card, patients may obtain a Direct Member Reimbursement form by calling the number on the back of the card to receive instructions on how to obtain the savings benefit. Offer not valid for patients enrolled in a state or federal healthcare program including but not limited to Medicaid, Medicare, Veterans Administration, or TRICARE/CHAMPUS. Offer valid in the United States and Puerto Rico. Void where taxed, restricted, or prohibited by law. Void in Massachusetts, except for patients without insurance. Daiichi Sankyo, Inc., reserves the right to rescind, revoke, or amend this program, at any time, without notice.

 TRIBENZOR is preferred on some of the largest Medicare Part D plans.

http://www.tribenzorhcp.com/savings_that_last.html

Cost Savings Associated with Filling a 3-Month Supply of Prescription Medicines

http://ideas.repec.org/a/wkh/aheahp/v7y2009i4p255-264.html

 Out-of-pocket and Total Costs of Fixed-dose Combination Antihypertensives and Their Components

Atonu Rabbani1 and G. Caleb Alexander1,2,3,4

American Journal of Hypertension (2008); 21, 5, 509–513. doi:10.1038/ajh.2008.31

Given patient burden and non-adherence from out-of-pocket prescription costs, the clinical benefits of brand-named fixed-dose combination antihypertensive therapy should be balanced with their greater out-of-pocket costs.

http://www.nature.com/ajh/journal/v21/n5/abs/ajh200831a.html

 

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HDL Itself Does Not Prevent Heart Attacks

Posted in Cardiovascular Pharmacogenomics, Genome Biology, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , , , , on May 24, 2012| 1 Comment »

First Lady Laura Bush sits with Lois Ingland, ...

First Lady Laura Bush sits with Lois Ingland, a heart disease survivor, during an event at the Carolinas Medical Center Wednesday, Feb. 15, 2006, in Charlotte, NC. Despite having none of the risk factors of heart disease, Lois, a mother of four, suffered a heart attack when she was 36 years old. (Photo credit: Wikipedia)

If you are hoping to lower your risk of a heart attack simply by raising your levels of “good” cholesterol—high-density lipoproteins (HDLs)—you may be disappointed. Although epidemiological studies point to HDLs as protective against heart disease, a new genetic analysis presented at the meeting shows that while high HDL might correlate with a healthier heart, it’s not itself responsible for lowering heart attack risks.

Source

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

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