Day: 09/18/2015

Bacteria research set to bolster antibiotic-resistant drug development.

Posted by

0


ANSTO has collaborated on research with the University of Newcastle upon Tyne and ISIS that has produced the first in vitro model of the outer membrane of the bacteria Escherichia coli (E.coli), which is expected to be used as a robust tool for developing antibiotics and other drugs. Single-cell gram negative bacteria, such as E.coli, are increasingly a source of antibiotic-resistant infections.
Instrument Scientist Stephen Holt is a co-author of the research, which has just been published as a ‘Hot Paper’ by the prestigious journal Angewandte Chemie. Lead author is Prof Jeremy Lakey of the University of Newcastle, with whom Holt has collaborated for a decade on the study of bacterial outer membranes.  Dr Luke Clifton from the ISIS neutron spallation source was also a lead author.
Ecoli_membrane_model
A stable in vitro model of E.coli is important because the structure and dynamics of the membrane in vivo is poorly understood. The outer membrane, or envelope, is only 20 nanometres thick.
“We’ve demonstrated in different ways using neutron scattering that the model behaves in a way that you would expect if you were to do things to a living bacteria,” said Holt.
Gram negative bacteria, such as E.coli, have a protective outer surface that unusually is composed of two layers — the so-called inner cell membrane and an outer membrane. This double membrane which is unique in biology is highly impermeable to incoming molecules; it acts as a highly selective filter.
E.coli is a highly successful organism. In evolutionary terms, it is believed to have descended from a common ancestor of cyanobacteria, which emerged 3.6 billion years ago.  E.coli bacteria live in the digestive tract of people and animals and most are harmless. However, some forms of E.coli cause illness.
The inner and outer membranes are very different.  The outer membrane is a complex, asymmetrical structure composed of lipopolysaccharides (LPS) that are attached to a lipid bilayer by varying lengths and types of phosphorylated sugar chains. The lipid bilayer is made up of two types of phospholipids. Calcium and magnesium ions link the core polysaccharides of adjacent LPSs in the upper strand of the bilayer.
It is the physical properties of the membrane barrier that limits the effectiveness of antimicrobials and mutations to outer membrane proteins are thought to contribute to the development of antibiotic resistant strains.
The researchers started construction of the synthetic model with a flat gold layer that chemically adheres to silicon substrate through a nickel-iron magnetic alloy. Gold is coated with a monolayer of the phospholipid (the inner membrane), which is covered in a layer of water.  The water layer in the model is thinner than the periplasm in the bacteria.
The deposition of the free floating outer bilayer was more challenging as the system is not self-assembling. To create it, they needed to use laboratory methods (Langmuir-Blodgett/Langmuir Schaeffer) to compress and stack monolayers of molecules horizontally and vertically.
In this case, they needed a phospholipid layer with hydrophilic (like water) heads pointing down joined to a phospholipid layer with hydrophobic (doesn’t like water) tails pointing up.
“Although we have used a truncated version of LPS, the structure replicates the crucial elements of a bacterial membrane using much more complex lipids than have typically been used,” said Holt.
The lipopolysaccharide core is attached to the phospholipid layer by phosphorylated sugar chains cross linked by magnesium and sodium ions with a positive charge.
They tested the stability of the model by removing the calcium and magnesium ions with a solution of EDTA (edetic acid). “If you take the calcium or magnesium out, the whole thing is destabilised because the charges in the outer leaflet repel each other.”
The structure of the model was confirmed using neutron reflectometry. They had to deuterate the lipids (replacing hydrogen with deuterium) to make them more readily detectable by neutrons.
“In a simplistic view, we treat each of the different components as a layer and the technique allows us to look at the position of the layers relative to the substrate.”
The reflectometry, which was undertaken at ISIS  (Oxford, UK), confirmed that the floating, supported bilayer (FSB) mimicked the unusual asymmetric structure of the membrane.
Adding the antimicrobial proteins, lysozyme and lactoferrin caused the disruption of the outer membrane bilayer. This was confirmed with neutron reflectometry.
“We’ve explained how these agents interact with the model system on a molecular basis,” said Holt. “And the explanation agrees really well with the way those two proteins behaved when introduced to a solution of E.coli.”
The next challenge for the researchers is to begin incorporating membrane proteins into the bilayer.

– See more at: http://www.ansto.gov.au/AboutANSTO/MediaCentre/News/ACS075808#sthash.aCXtVjW6.dpuf

Four Things You May Not Know About Palliative Care

Posted by

0


Palliative care is a medical specialty that focuses on providing patients with relief from the symptoms and stress of a serious illness. The goal is to improve quality of life for both the patient and the family.

But many Americans still aren’t clear on what palliative care really is or how it can benefit them. Here are four things you may not know about palliative care and how it can help patients and families live well with serious illness:

  1. Palliative care is available at any age and at any stage of your illness

Palliative care provides an extra layer of support for people living with serious illness, and it can be brought in from the point of diagnosis. In fact, the earlier palliative care is brought in, the better. It is not dependent on prognosis, so unlike hospice care, palliative care can be provided along with curative treatment. Receiving palliative care simply means that you want an extra layer of support to help improve your quality of life. Palliative care is about living with a serious illness.

Palliative care is available for both children and adults with serious illness, regardless of age or stage of illness. You don’t have to be elderly to receive palliative care; you just have to want to live better with serious illness.

  1. Palliative care can provide support to caregivers as well as seriously ill patients

Dealing with a serious illness is stressful not only to the patient, but to their families. Caregivers often experience lost work hours or lost jobs, high stress and serious declines in physical and mental health. Palliative care doesn’t just treat the patient; it treats the entire family. According to a 2014 study, caregivers who received palliative care had an improved quality of life and lower levels of depression and feelings of being overwhelmed.

  1. Palliative care is available to children with serious illnesses and their families

Children with serious illness face unique challenges. Pediatric palliative care is specialized medical care tailored to the needs of seriously ill children and their families. It helps to manage symptoms of the child’s disease, and it also helps with communication and coordination of care. With the close communication that palliative care provides, families are better able to choose options that are in line with their values, traditions and culture. This improves the well-being of the entire family.

  1. You can have palliative care along with curative treatment

Palliative care is appropriate at any stage in a disease, and many patients receive palliative care alongside curative treatment. In fact, the curative treatment itself can often bring on symptoms that negatively impact a patient’s quality of life. Cancer patients like Christine Buehlmann struggle with the symptoms that accompany chemotherapy. Palliative care was provided as a complement to chemotherapy, helping to restore Christine’s energy and physical strength. Palliative care is about improving the quality of life of both the patient and their families.

FDA approves cariprazine to treat schizophrenia and bipolar disorder.

Posted by

0


The U.S. Food and Drug Administration approved Vraylar (cariprazine) capsules to treat schizophrenia and bipolar disorder in adults.

Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia. Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. . Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors.

512px-Cariprazine.svg

Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors

cariprazine cut

Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.

The most common side effects for schizophrenia were extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements. The most common side effects for bipolar disorder were extrapyramidal symptoms, the urge to move (akathisia), indigestion (dyspepsia), vomiting, drowsiness (somnolence) and restlessness.

Are Engineered Small Proteins the Next-generation Immune Checkpoint Inhibitors?

Posted by

0


The inaugural International Cancer Immunotherapy Conference, hosted jointly by the Cancer Research Institute (CRI), the Association for Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology (EATI), and the American Association for Cancer Research (AACR), began Wednesday, September 16, at the Sheraton New York Times Square Hotel. This year’s conference theme is “Translating Science Into Survival.”

The audience at this week's CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The audience at this week’s CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

A study presented by Stanford researchers at the conference may take immunotherapy to the next level.

Anyone who follows the progress made with cancer immunotherapy will have gleaned the success the cancer research community has had in developing, testing, and getting FDA-approved immune checkpoint inhibitors to the clinic.

Cancer cells often evade immune recognition by engaging the PD-1/PD-L1 pathway, a mechanism by which they apply “brakes” on immune cells called T cells, preventing the T cells from attacking cancer cells. Immune checkpoint inhibitors, such as pembrolizumab (Keytruda), the immunotherapy former U.S. President Jimmy Carter is being treated with, block the PD1/PD-L1 pathway and release the brakes on T cells so that they can recognize and attack cancer cells. Owing to successful outcomes from clinical trials, the FDA has approved three immune checkpoint inhibitors so far—pembrolizumab and nivolumab (which block PD-1), and ipilimumab (which blocks another checkpoint, CTLA4)—to treat certain metastatic melanomas and advanced lung cancers. All current FDA-approved immune checkpoint inhibitors are antibodies.

But are antibodies truly the best immune checkpoint inhibitors?

Aaron Ring, an MD/PhD student at Stanford University.
Aaron Ring, an MD/PhD student at Stanford University.

That’s a question raised by scientists in thelaboratory of Irving Weissman, MD, at theLudwig Center at Stanford University School of Medicine in California. “This question, at this point, remains unanswered and even unaddressed,” says Aaron Ring, an MD/PhD student from Weissman’s lab. In addition to being scientifically intriguing, this question holds the very exciting potential to create even better therapeutics for patients, adds Ring, who will shortly be taking up a position as assistant professor in the Department of Immunobiology at Yale University School of Medicine.

Sydney Gordon, a graduate student in Weissman’s lab, explained that their team is now addressing this question because they recognize that the immune checkpoint-inhibiting antibodies have some overlooked limitations. “First, it would be ideal if drugs that target PD-L1 could get inside the tumors. However, antibodies, because of their large size, cannot get there effectively, which prevents them from working to their full potential. Second, antibodies against PD-1 and PD-L1 can result in counterproductive collateral damage, depleting some of the very antitumor immune cells they are supposed to activate,” she said.

The hypothesis

Gordon, Ring, and colleagues hypothesized that an engineered protein that is much smaller in size than a conventional antibody and targets PD-L1 to block the PD-1/PD-L1 signaling pathway could potentially overcome these limitations and function as a superior immune checkpoint inhibitor. The team indeed developed such a small protein and presented their findings at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Engineering the high-affinity PD-1 protein

The Stanford researchers engineered the high-affinity PD-1 protein by a process called directed evolution, Ring explained. “Our goal was to enhance the ability of the natural PD-1 receptor to bind extremely tightly to PD-L1 as a small competitive “decoy” that is about one tenth the size of an antibody,” he said. The researchers generated more than 100 million variants of PD-1 that contained mutations at the PD-L1 binding interface and within the core of the protein. “By selecting for tight binders through increasingly more difficult conditions, we let the principles of natural selection do the hard work and guide us to the strongest binders. In the end, our best variants bound to PD-L1 about 50,000-times stronger than the natural PD-1 protein,” said Ring.

Testing the small protein’s efficacy

Sydney Gordon, a PhD student at Stanford University, presented the team's findings at the immunotherapy conference this week.
Sydney Gordon, a PhD student at Stanford University, presented the team’s findings at the immunotherapy conference this week.

The next step in their research was to test if the high-affinity PD-1 protein they engineered lived up to expectations.

Through a series of experiments in mice, the researchers first demonstrated that the small protein was more efficient in penetrating the tumors than were anti-PD-L1 antibodies, which went as far as gathering around the blood vessels outside the tumors. Next, they showed that the high-affinity PD-1 protein did not impact T-cell numbers in the blood and lymph nodes collected from mice whose tumors were treated with the protein, as opposed to anti-PD-L1 antibodies, which caused significant depletion of T cells that worsened when they combined the antibody with other immunotherapies.

“This may have important implications when considering how to optimize immunotherapeutic combinations for patients,” Gordon said.

Further studies by the team showed that while both high-affinity PD-1 protein and anti-PD-L1 antibodies were effective in shrinking small tumors, only the high-affinity PD-1 protein was able to slow the growth of large tumors. It was also more effective at shrinking large tumors when combined with an anti-CTLA4-antibody. The anti-PD-L1 antibodies, on the other hand, were ineffective at eliminating large tumors, either alone or in combination with an anti-CTLA4-antibody.

“This was the key study for us that best highlighted a situation where small protein therapeutics could produce a better outcome than conventional antibodies,” Gordon said.

“Given how well anti-PD-1 and anti-PD-L1 antibodies are working for cancer patients, it may seem like a reasonable assumption that we have adequately targeted the pathway at this point. However, our results show that significantly more antitumor activity is possible using a small-protein therapeutic compared with a conventional antibody,” Ring said.

There are, however, some limitations to using the high-affinity PD-1 proteins in patients in their current form, the researchers note. Because of their small size, the high-affinity PD-1 proteins may get excreted from the body more quickly, which means that they would have to be administered more frequently than antibodies. Further, they may be “immunogenic,” meaning patients could develop an immune response to the drug itself. “Both issues would need to be addressed for high-affinity PD-1 or a similar small-protein therapeutic to be developed for clinical use,” Gordon elaborated.

Beyond therapeutic application

The researchers went a step further and evaluated the utility of the high-affinity PD-1 protein in identifying the right patients for this type of therapy.

PD-L1, the target of the high-affinity PD-1 protein, is considered a potential biomarker, in that its presence in a tumor may tell whether or not the patient’s cancer is suitable for immunotherapy targeted toward the PD-1/PD-L1 pathway. However, currently this can only be determined by performing a biopsy of the tumor and studying the tissue under a microscope. There are a couple of problems with this: First, biopsy is an invasive surgical procedure that comes with some risk and discomfort. Second, PD-L1 is not uniformly distributed in a tumor, so there is a possibility of not finding it in the biopsy sample.

So the researchers wondered whether they could measure PD-L1 levels in a noninvasive manner by radiolabeling the high-affinity PD-1 protein, which when injected in a patient will bind to PD-L1 present in the tumor and in metastatic tissues. This could then be imaged using PET. “Together with our collaborators in the Gambhir laboratory we were able to perform in living mice some proof-of-principle studies and demonstrate that it is possible to locate PD-L1 using radiolabeled high-affinity PD-1 protein,” Ring said.

“I would anticipate that many of the advantages that we saw for our engineered PD-1 proteins would extend to other small proteins being developed by other research groups and biotechnology companies,” he added.

What Happens to Your Body When You Don’t Get Enough Sleep

Posted by

0


If you eat well and exercise regularly but don’t get at least seven hours of sleep every night, you may undermine all your other efforts.

Sleep disorders expert Harneet Walia, MD, says it’s important to focus on getting enough sleep, something many of us lack. “First and foremost, we need to make sleep a priority,” she says. “We always recommend a good diet and exercise to everyone. Along the same lines, we need to focus on sleep as well.”

What Happens to Your Body When You Don't Get Enough Sleep

How much sleep do you actually need?

Everyone feels better after a good night’s rest.  But now, thanks to a report from the National Sleep Foundation, you can aim for a targeted sleep number tailored to your age.

The foundation based its report on two years of research. Published in a recent issue of the foundation’s journal Sleep Health, the report updates previous sleep recommendations. It breaks them into nine age-specific categories with a range for each, which allows for individual differences:

  • Older adults, 65+ years: 7-8 hours
  • Adults, 26-64 years: 7-9 hours
  • Young adults, 18-25 years: 7-9 hours
  • Teenagers, 14-17 years: 8-10 hours
  • School-age children, 6-13 years: 9-11 hours
  • Preschool children, 3-5 years: 10-13 hours
  • Toddlers, 1-2 years: 11-14 hours
  • Infants, 4-11 months: 12-15 hours
  • Newborns, 0-3 months: 14-17 hours

Dr. Walia says there’s evidence that genetic, behavioral and environmental factors help determine how much sleep an individual needs for the best health and daily performance.

But a minimum of seven hours of sleep is a step in the right direction to improve your health, she says.

What happens when you don’t get enough sleep?

Your doctor urges you to get enough sleep for good reason, Dr. Walia says.  Shorting yourself on shut-eye has a negative impact on your health in many ways:

Short-term problems can include:

  • Lack of alertness: Even missing as little as 1.5 hours can have an impact, research shows.
  • Impaired memory: Lack of sleep can affect your ability to think and to remember and process information.
  • Relationship stress: It can make you feel moody, and you can become more likely to have conflicts with others.
  • Quality of life: You may become less likely to participate in normal daily activities or to exercise.
  • Greater likelihood for car accidents: Drowsy driving accounts for thousands of crashes, injuries and fatalities each year, according to the National Highway Traffic Safety Administration.

If you continue to operate without enough sleep, you may see more long-term and serious health problems. Some of the most serious potential problems associated with chronic sleep deprivation are high blood pressure, diabetes, heart attack, heart failure or stroke. Other potential problems include obesity, depression and lower sex drive.

Chronic sleep deprivation can even affect your appearance.  Over time, it can lead to premature wrinkling and dark circles under the eyes. Also, research links a lack of sleep to an increase of the stress hormone cortisol in the body. Cortisol can break down collagen, the protein that keeps skin smooth.

Make time for downtime

“In our society, nowadays, people aren’t getting enough sleep. They put sleep so far down on their priority list because there are so many other things to do – family, personal and work life,” Dr. Walia says. “These are challenges, but if people understand how important adequate sleep is, it makes a huge difference.”

10 unusual genetic disorders in humans you won’t believe are real

Posted by

0


A birth defect in which a human being has more than usual number of limbs, or a disease in which the feet of the patient face backwards. In India, such people are either considered a little embodiment of God himself or just evil. Heard of ghost with feet turned backwards? Well, these are nothing but some really serious genetic disorders. Some people with these disorders live a normal life and some die within a half hour of their birth.

Human beings shape their lives from the moment they are born until their last breath and in between they are diagnosed with a lot of diseases. But, these are some disorders which generally starts even before they are born.

Here is a list of some really horrifying genetic abnormalities and reasons behind them:

Ectrodactyly
Famously known as ‘lobster claw hand’ or ‘split hand malformation’, individuals with this disorder have a cleft where the middle finger or toe should be. This genetic malfunction generally happens when there are some deletions, translocation, and inversions in chromosome 7.

Image Source: Wikipedia

Proteus Syndrome
Proteus Syndrome is a rare genetic disorder in which bones, skin, and other tissues are overgrown. The disorder results from a mutation in a gene called AKT1 which controls cell growth. In this disorder, some of the cells grow and some don’t. This difference in the sizes of cells causes the overgrowth.

Image Source: Wikipedia

Polymelia
Polymelia is a birth defect in which the affected individual has more than the usual number of limbs. This deformity is generally said to be the result of a partially absorbed conjoined twin. The defect can also be found in animals.

Image Source: Wikipedia

Neurofibromatosis
The exact cause of this genetic disorder is not known. In this disease, the skin of the patient starts getting thick and lumpy and a bony lump grows on the patient’s forehead. The doctors suggested that the disorder is a combination of several diseases such as neurofibromatosis type I and Proteus syndrome.

Image Source: Gudhealth

Diprosopus
Also known as craniofacial duplication, Diprosopus is an extremely rare hereditary disorder in which parts (or all of the face) are duplicated. This anomaly is the result of abnormal activity by the protein named SHH (sonic hedgehog).

Image Source: Tumblr

Anencephaly
Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. However, it is widely accepted fact that children born with this disorder only lack the largest part of the brain consisting mainly of the cerebral hemispheres.

Image Source: Wikipedia

Feet facing backwards
Wang Fang, a young woman from China, was born with this rare disorder which caused her feet to grow backwards. When she was born, it was feared that she wouldn’t be able to walk properly but she has been as normal as any other human being.



Cutaneous horn
The disorder is also known as cornu cutaneum. The cutaneous horn is an unusual skin tumor in which a horn appears on the body parts of the patient. The horn could be of wood or coral. They are small but in very rare cases, they can get really large. A French woman, Madame Dimanche’s horn measured 10 inches.

Image 

 

 

Harlequin ichthyosis
Harlequin ichthyosis is a very rare and often fatal genetic skin disorder. Babies affected with Harlequin ichthyosis are born with extremely thick plates of skin separated with deep red cracks over their entire bodies.

Image

Cyclopia
This rare disorder is generally characterized by the failure of the embryo to properly divide the tracks of the eye into two hollows. The disease is very common in animals and very rare in human beings.

Image 

Beware! Smoking can make you diabetic.

Posted by

0


Smoking cigarettes or breathing in second-hand tobacco smoke significantly increases the risk of Type-2 diabetes, warns a new study. DH File Photo

Smoking cigarettes or breathing in second-hand tobacco smoke significantly increases the risk of Type-2 diabetes, warns a new study.

While current smokers are at around 37 percent increased risk of developing Type-2 diabetes, passive smoking or breathing in second-hand smoke could raise the odds by as much as 22 percent, the findings showed.

The researchers estimated that 11.7 percent of cases of Type-2 diabetes in men and 2.4 percent in women (about 27.8 million cases in total worldwide) may be attributable to active smoking.

They also found that risk decreases as time elapses after smokers quit.

“Cigarette smoking should be considered as a key modifiable risk factor for diabetes. Public health efforts to reduce smoking will have a substantial impact on the global burden of type 2 diabetes,” said study co-author Frank Hu, professor of nutrition and epidemiology at Harvard T.H. Chan School of Public Health in Boston, US.

In this study, the researchers conducted an analysis of 88 previous studies on the association between smoking and Type-2 diabetes risk, looking at health data from nearly six million study participants.

They found that when compared with people who never smoked, current smoking increased the risk of Type-2 diabetes by 37 percent, former smoking by 14 percent and passive smoking (breathing in second-hand smoke) by 22 percent.

Among current smokers, the amount smoked made a difference. The increased risk of developing Type-2 diabetes was 21 percent, 34 percent, and 57 percent for light, moderate, and heavy smokers, respectively.

Pulmonary Arterial Hypertension: Targeting Prostacyclin and Endothelin

Posted by

0


Pulmonary arterial hypertension (PAH) affects between 15 and 50 million individuals.1 Remodeling of the pulmonary vasculature, thrombi, and increased vascular resistance and pulmonary arterial pressure (over 25 mm Hg) lead to right heart failure and death if not treated.1-4 PAH may be idiopathic or genetic, or caused by drugs and/or disease.1 The 3-year survival rate for idiopathic or heritable PAH is 74%.2

World Health Organization (WHO) functional classes range from least (class I) to most affected (class IV) based on functional compromise (including shortness of breath, fatigue, chest pain, and dizziness); 75% of patients are WHO functional class III/IV at diagnosis.3 Clinical presentation is usually related to right heart failure symptoms.4 Medications developed specifically for PAH include prostanoids (epoprostenol, treprostinil, and iloprost) and endothelin receptor antagonists (ERAs) (bosentan and ambrisentan).4

Prostanoids (Prostacyclin Vasodilators) Prostacyclin promotes vasodilation, but is decreased with PAH.2 Prostanoids are direct vasodilators that inhibit platelet aggregation, cause smooth muscle relaxation, and may affect pulmonary remodeling and reduce inflammation.2,4,5 Adverse effects (AEs) common to all prostanoids include headache, gastrointestinal disturbances, jaw pain, and flushing.2 Consider using inhaled formulations to reduce systemic AEs.2

Epoprostenol was the first prostanoid.4 This drug improves symptoms, exercise capacity, hemodynamics, and survival (possibly), but it is complex to administer.2,4,6 Because its short half-life (less than 6 minutes) necessitates an indwelling catheter for continuous infusion (increasing infection and thrombosis risk), pump failure could lead to deadly rebound pulmonary hypertension.2,4,6 Close observation is needed during initiation/ titration because of potentially fatal acute pulmonary edema.2 Flu-like symptoms are common.2,4

Dosing starts at 2 ng/kg/min and increases to 10 to 16 ng/kg/min if tolerated.4 There are 2 formulations: the more stable (24 to 72 hours) arginine-mannitol excipient (Veletri) or the glycine-mannitol excipient (Flolan), which is only stable at room temperature for 8 hours (24 hours using cold packs).2,5,6

Iloprost (Ventavis) is an inhaled prostanoid that improves exercise tolerance and symptoms, and slows deterioration.4 Although monotherapy works for about 17% of patients, over half lose efficacy within 1 year.2,4 Iloprost is dosed at 2.5 to 5 mcg inhaled 6 to 9 times a day (every 2 hours while awake).2,4,7 Hepatic impairment slows elimination, so dosing intervals may increase (eg, 3-4 hours) depending on response.7 Cough and insomnia are common AEs, and iloprost may interact with warfarin.4,7 Transitioning between inhaled iloprost and inhaled treprostinil appears safe and well tolerated.2 Treprostinil increases quality of life and improves pulmonary function, with a 68% survival rate at 4 years.2,4 It is available as an infusion, inhalation, or oral tablet.4 A half-life of about 4 hours reduces the dosing frequency.4,11

Parenteral treprostinil (Remodulin) is given subcutaneously (SC) or intravenously (IV) with a pump.2 At room temperature, SC fluid is stable for 72 hours and the IV fluid for 48 hours.2 Dosing is started at 1.25 ng/kg/min (IV) or 2.5 ng/kg/min (SC). The average long-term doses are 26 and 42 ng/kg/min, respectively.2 Pump/tubing problems (30%), and edema are common AEs.2 Local pain and inflammation (SC infusion site pain 85%; not a problem with IV) is doselimiting or leads to discontinuation.2,4 Use of the same site for 4 or more weeks reduces pain peaks brought on by injection site changes.2 Bloodstream infections are less frequent with treprostinil than with epoprostenol (0.36 vs 0.12 infections/1000 treatment days).2

Inhaled treprostinil (Tyvaso) is dosed 4 times a day, at least 4 hours apart.2 Dosing starts at 18 mcg (3 breaths/dose); full dose is 54 mcg (9 breaths/dose).2 Cough is very common (54%), as is dizziness and throat irritation.2 Triple therapy with sildenafil, bosentan, and inhaled treprostinil is associated with a 91% survival rate at 24 months.2

Oral treprostinil (Orenitram) is a sustained- release (2 times/day) tablet.2 Oral bioavailability is low (17%). It is dosed with food to increase area under the concentration time curve, Cmax, and Tmax. Dosing starts at 0.25 mg, increasing to an average of 3.4 mg. Consider recommending 0.25 mg every 8 hours for tolerability, which limits the maximum oral dose. Severe hepatic impairment is a contraindication due to hepatic metabolism of the oral tablet and because the tablet shell does not dissolve. Use with caution in patients with diverticulitis because the tablet may lodge in the diverticulum.2
Endothelin Receptor Antagonists
ERAs mediate vasoconstriction, fibrosis, proliferation, inflammation, vascular hypertrophy, and organ damage.8 They counteract endothelin-mediated vasoconstriction and decrease smooth muscle proliferation and remodeling. Endothelin and its receptors are overactive in PAH, however,4 which signals poor prognosis.9

Bosentan (Tracleer) is an oral medication that improves exercise capacity and functional status, delays clinical worsening, and maintains safety and efficacy up to 5 years.3,4,10 It is only available through a restricted access program due to its hepatotoxicity and teratogenicity risk; monthly monitoring is mandatory; pregnancy is contraindicated.4,10 Abnormal liver function tests occur in about 17% of patients, and most events resolve with discontinuation.3,4 Dosing starts at 62.5 mg twice daily, with or without food, increasing to 125 mg twice daily after 1 month.4,10 About 30% will need concomitant PAH medications (sildenafil, tadalafil, or prostanoids).3

Ambrisentan (Letairis) is an oral, highly selective ERA that decreases pulmonary arterial pressure, improves lung function and hemodynamics, delays time to clinical worsening, and has a dose-dependent increase in exercise tolerance.4,9 AEs include peripheral edema, headache, and dose-dependent nasal congestion, but ambrisentan is well tolerated long term.9 Dosing starts at 5 mg daily, increasing to 10 mg daily if tolerated; monitor monthly for increased liver function and bilirubin.4,9 Hemoglobin and hematocrit reductions are possible: recommend baseline levels and periodic monitoring.9 Pregnancy is contraindicated.9

Macitentan (Opsumit) is an extendedrelease tablet (set dosing: 10 mg once daily) and has a high affinity for, and prolonged binding at, endothelin receptors.1 It is the first ERA with significantly decreased morbidity and mortality. The drug also causes dose-dependent decreases in mean arterial pressure, but does not affect heart rate or QTc, even at triple the approved dose. It has a black box warning regarding reproductive effects and hemoglobin decreases. Because of possible liver injury, it is not recommended for use in patients with severe hepatic impairment. Macitentan does not interact with warfarin or cyclosporine, it increases sildenafil exposure; ketoconazole doubles to triples macitentan exposure (but is still well tolerated); rifampin decreases macitentan concentrations 4-fold. Pharmacokinetics are not affected by age, sex, meals, ethnicity, or hepatic or renal impairment.1

Treatment Recommendations
Currently, the preferred treatments for mild (WHO class II) PAH include phosphodiesterase inhibitors (sildenafil and tadalafil), riociguat, and ERAs (bosentan, ambrisentan, and macitentan).2 Moderate to severe PAH (WHO classes III and IV) usually require prostacyclin analogs (epoprostenol, iloprost, and treprostinil), which improve mortality, clinical worsening, exercise capacity, and hemodynamics.2 Combination therapy with medications with different mechanisms of action is an option; however, studies to date have shown limited improvement in efficacy with combinations tried.4 Several more therapeutic approaches are still under study for PAH.4 Nonpharmacologic treatments include balloon septostomy or lung transplantation (the treatment of choice when pharmacologic agents are insufficient).4,9

Debra Freiheit has been a practicing pharmacist and human services professional for more than 25 years. Specializing in medical information, she has compiled a broad spectrum of experience obtained through research for companies including Cerner and PPD Inc. With an emphasis on clear and concise information transfer, Debra has built a career communicating data with medical professionals and patients. Education and knowledge have been the motivation of a rich career of caregiving through research. Debra’s current project involves the creation of a multinational database of drug information.

References

  1. Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015;54(5):457-471. doi: 10.1007/s40262-015-0255-5.
  2. LeVarge BL. Prostanoid therapies in the management of pulmonary arterial hypertension. Ther Clin Risk Manag. 2015;11:535-547. doi: 10.2147/TCRM.S75122.
  3. Simonneau G, Galie N, Jansa P, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014;172(2):332-339. doi: 10.1016/j.ijcard.2013.12.179.
  4. Goudie AR, Lipworth BJ, Hopkinson PJ, Wei L, Struthers AD. Tadalafil in patients with chronic obstructive pulmonary disease: a randomized, double-blind, parallel-group, placebo controlled trial. Lancet Respir Med. 2014;2(4):293-300. doi: 10.1016/S2213-2600(14)70013-X.
  5. Veletri [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2012.
  6. Chin KM, Badesch DB, Robbins IM, et al Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study. Am Heart J. 2014:167(2);218-225.e1. doi: 10.1016/j.ahj.2013.08.008.
  7. Ventavis [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2013.
  8. Opsumit [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2015.
  9. Croxtall JD, Keam SJ. Ambrisentan. Drugs. 2008;68(15):2195-2204.
  10. Tracleer [package insert]. South San Francisco, CA. Actelion Pharmaceuticals; 2012.
  11. Remodulin [package insert]. Research Triangle Park, NC . United Therapeutics Corp; 2014.

– See more at: http://www.pharmacytimes.com/publications/issue/2015/september2015/pulmonary-arterial-hypertension-targeting-prostacyclin-and-endothelin/P-2#sthash.DBm2ALHf.dpuf

People are getting Matrix-style brain implants to boost their memory

Posted by

0


Like something out of the Matrix, we’re entering an era where it may be possible to boost your memory with a few zaps to the brain.

A few dozen people who were given brain implants that delivered targeted shocks to their mind’s memory center scored better on memory tests, DARPA announced at a conference in St. Louis last week.

These implants could someday be used to restore memory to people suffering from traumatic brain injury or other neurological problems, agency representatives said.

“As the technology of these fully implantable devices improves, and as we learn more about how to stimulate the brain ever more precisely to achieve the most therapeutic effects, I believe we are going to gain a critical capacity to help our wounded warriors and others who today suffer from intractable neurological problems,” program manager Justin Sanchez said in a statement.

Total recall?

The goal of the study, which is part of DARPA’s Restoring Active Memory (RAM) program, was to allow scientists to read and interpret the brain activity involved in forming and recalling memories and predict when a person is about to remember something incorrectly. The electrodes can then be used to deliver targeted electrical shocks to specific groups of brain cells that store a memory, making it more easily accessible, according to DARPA.

A team of USC scientists that is not part of the DARPA effort has also been working for several years on developing brain implants to boost and enhance memory in rats and other animals, but this is the first time this kind of technology has been tested in humans.

The people who received the implants volunteered to test them while they were having brain surgery for neurological problems unrelated to memory loss.

During the surgery, scientists implanted small electrode arrays in brain regions involved in forming declarative memories – the kind of memory used to remember events, times, places, or lists of objects – as well as in areas involved in spatial memory and navigation.

In preliminary findings, the researchers were able to not only record and interpret the signals that store memories in the brain and retrieve them later, but also activate memory areas to improve the patients’ recall for lists of objects.

Scientists are still figuring out the best way to deliver the stimulation, i.e., when the lists are first being memorized, or when the person is trying to recall the items.

DARPA is withholding some details of the study because they haven’t been published in a scientific journal yet.

Other brainy boosts

The RAM program is just one of several efforts aimed at boosting memory or cognition.

While we’re nowhere near the ability to download skills into our brains like Neo in the Matrix, another DARPA program launching in October, called RAM Replay, aims to improve people’s memory of physical skills, by mimicking the brain’s natural process of replaying these skills – something our brains do naturally while we sleep.

Meanwhile, DARPA’s Systems-Based Neurotechnology for Emerging Therapies (SUBNETS) program is developing implants to provide relief to people suffering from PTSD and other neurological disorders.

Frozen Giant Virus Still Infectious After 30,000 Years

Posted by

0


It’s 30,000 years old and still ticking: A giant virus recently discovered deep in the Siberian permafrost reveals that huge ancient viruses are much more diverse than scientists had ever known.

They’re also potentially infectious if thawed from their Siberian deep freeze, though they pose no danger to humans, said Chantal Abergel, a scientist at the National Center for Scientific Research at Aix-Marseille University in France and co-author of a new study announcing the discovery of the new virus. As the globe warms and the region thaws, mining and drilling will likely penetrate previously inaccessible areas, Abergel said.

scanning electron microscopy images of giant viruses.

“Safety precautions should be taken when moving that amount of frozen earth,” she told Live Science. (Though viruses can’t be said to be “alive,” the Siberian virus is functional and capable of infecting its host.)

The new virus isn’t a threat to humans; it infected single-celled amoebas during the Upper Paleolithic, or late Stone Age. Dubbed Mollivirus sibericum, the virus was found in a soil sample from about 98 feet (30 meters) below the surface. [The 9 Deadliest Viruses on Earth]

M. sibericum is a member of a new viral family, the fourth such family ever found. Until about a decade ago, viruses were thought of as universally tiny, Abergel said, and they were isolated by filtration techniques that strained out larger particles. But after the discovery of an amoeba-infecting giant viruscalled Mimivirus, first reported in the journal Science in 2003, researchers widened their search for bigger viruses. Mimivirus and its ilk are so large that they can be seen under an ordinary light microscope. The largest of this group, Megavirus chilensis, has a diameter of about 500 nanometers. Typical viruses range in size from 20 nanometers up to a few hundred nanometers.

Since the discovery of the Mimivirus family, researchers have discovered the Pandoraviridae and Pithoviridae families — the latter discovered in thesame soil sample as M. sibericum and reported by Abergel and her colleague Jean-Michel Claverie, the head of the Structural and Genomic Information Laboratory at the National Center for Scientific Research at Aix-Marseille University, in 2014.

Unusual evolution

M. sibericum is wider in diameter than the other giant viruses discovered, at 600 nanometers versus 500. It has a genome of 600,000 base pairs (picture the “rungs” on the DNA “ladder”), which hold the genetic instructions to create 500 proteins. Viruses are snippets of RNA or DNA that work by hijacking a cell’s machinery to carry out these instructions. [Tiny Grandeur: Stunning Images of the Very Small]

Abergel and her team are interested in studying resurrected giant viruses to understand how this group evolved and how viral genetics could have influenced the evolution of cells. Viruses are incorporated into cells, and viral DNA sometimes becomes a permanent part of a cell’s genome.

“Viruses played a role in making the cell evolve in a very good way,” Abergel said. The researchers don’t know when giant viruses emerged on Earth, but they probably have roots in the very origins of DNA and RNA, she said.

“We are now at the stage where there are four families of giant viruses, and we can say that they are much more diverse [than previously known],” Abergel said.

The researchers’ technique to isolate and study these viruses doesn’t pose a threat to humans or animals, Abergel said, but it’s possible that dangerous viruses do lurk in suspended animation deep belowground, she said. These viruses are buried deep, so it’s likely that only human activities — such as mining and drilling for minerals, oil and natural gas — would disturb them. The discoveries of the giant viruses reveal that they can remain infectious for at least tens of thousands of years, Abergel said. So far, however, scientists have yet to discovery any ancient human-infecting giant viruses.

Deeper study of the viruses will help clarify the risk, Abergel and Claverie wrote in a statement in 2014. But the research has the potential to answer basic questions as well, Abergel said.

“We do think that these giant viruses will help us understand how life appeared on Earth,” she said. “We think there are so many genes which are unique to those genomes, and there are many things to learn from the study of those genes.”