30 Mayıs 2013 Perşembe
Two GSK Skin Cancer Drugs Approved By FDA
Two GSK Skin Cancer Drugs Approved By FDA30 May 2013-nbsp;-nbsp;-nbsp;
Two new GlaxoSmithKline (GSK) drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), have been approved for the treatment of patients with advanced melanoma by the U.S. Food and Drug Administration (FDA).
Melanoma is the most dangerous form of skin cancer and the number one cause of death from skin disease. According to the National Cancer Institute, about 76,690 people will be diagnosed with melanoma in the U.S. in 2013, and about 9,480 will die from the disease.
Patients with melanoma whose tumors express the BRAF V600E gene mutation can now take the approved drug Tafinlar, a BRAF inhibitor, while patients whose tumors express the BRAF V600E or V600K gene mutations can take Mekinist, a MEK inhibitor.
Experts estimate that 50% of melanomas appearing in the skin have a BRAF gene mutation. The FDA approved these two drugs as single agents, not as a combination treatment.
A genetic test, known as he THxID BRAF test, was also approved by the Agency. The test is a companion diagnostic that will determine whether a person's melanoma cells have the V600E or V600K mutation in the BRAF gene.
Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said:
"Advancements in our understanding of the biological pathways of a disease have allowed for the development of Tafinlar and Mekinist, the third and fourth drugs the FDA has approved for treating metastatic melanoma in the past two years."
In 2011, Zelboraf (vemurafenib) and Yervoy (ipilimumab) were approved by the FDA to treat metastatic or unresectable melanoma - a tumor that is unable to be removed by surgery.
Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Devices and Radiological Health in the FDA's Center for Devices and Radiological Health, said:
"The co-approval of Tafinlar and Mekinist and the second companion diagnostic for BRAF mutation detection demonstrates the commitment of pharmaceutical and diagnostic partners to develop products that detect and target the molecular drivers of cancer."
The approval of the THxID BRAF test is based on data from clinical trials that support the approval of Tafinlar and Mekinist, the experts said. In order to test for the mutation, samples of patients' melanoma tissue were taken.
Tafinlar was analyzed in 250 patients with BRAF V600E gene mutation-positive metastatic or unresectable melanoma. Participants were randomly assigned to two groups: one group received Tafinlar and the other received dacarbazine, a chemotherapy drug.
Results showed that patients who received Tafinlar had a delay in tumor growth that was 2.4 months later than those taking dacarbazine.
The most severe side effects reported in patients taking Tafinlar included a raised risk of skin cancer (cutaneous squamous cell carcinoma), fevers that may be complicated by low blood pressure, dehydration, kidney failure, severe rigors (shaking chills), and elevated blood sugar levels that call for changes in diabetes medication or the need to begin taking drugs to control diabetes.
The most common side effects in patients taking Tafinlar included:
headache
joint pain
hyperkeratosis (thickening of the skin)
ferver
hand-foot syndrome
hair lossnon-cancerous skin tumors
Mekinist was examined in 322 individuals with metastatic or unresectable melanoma with the BRAF V600E or V600K gene mutation. The participants were randomly assigned to receive either Mekinist or chemotherapy.
The scientists found that patients taking Mekinist had a delay in tumor growth that was 3.3 months later than those undergoing chemotherapy.
However, people who took Tafinlar or other inhibitors of BRAF in the past did not seem to benefit from Mekinist.
The most severe side effects reported in patients taking Mekinist included skin infections, loss of vision, lung inflammation, and heart failure.
The most ommon side effects in patients receiving Mekinist included:
diarrhea
rash
peripheral edema (tissue swelling)
skin breakouts that look like acne
Tafinlar and Mekinist - pregnancy and fertility
The experts noted that women of child bearing age should be warned that Tafinlar and Mekinist have the potential to cause fetal harm. Men and women should also be aware that these drugs could cause infertility.
A recent report described simple steps people can take this summer that can help them prevent skin cancer, the most common cancer in the U.S.
Written by Sarah Glynn
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
ADHD Medications Don't Lead To Drug Or Alcohol Abuse
ADHD Medications Don't Lead To Drug Or Alcohol Abuse30 May 2013-nbsp;-nbsp;-nbsp;
Children who are on attention-deficit/hyperactivity disorder (ADHD) medications are not at an increased risk of drug addiction or abuse later on, says a new study published in JAMA Psychiatry.
For a while now, researchers haven not been sure whether medications such as Ritalin or Adderall can increase the risk of children becoming addicted to substances such as alcohol, marijuana, cocaine, tobacco, etc.
Previously, researchers at the Massachusetts General Hospital (MGH) had found that treatment with stimulant drugs does not increase and significantly decreases the risk that girls with ADHD will begin smoking cigarettes or using alcohol or drugs.
However, by thoroughly analyzing 15 long-term studies which tracked drug abuse among a total of 2,565 children diagnosed with ADHD between 1980 and 2012, the authors were able to come to a more concrete conclusion as to its effects on drug/substance abuse.
The results were somewhat surprising. Two of the studies revealed that children on stimulant medication were at a lower the risk of alcohol abuse, while another said they were at a higher risk.
Study author Kathryn Humphreys, a doctoral student in psychology at the University of California, Los Angeles, said that previously "there was evidence for both increased risk and decreased risk for substance problems related to stimulant medication in the treatment of ADHD."
However, this new study indicates that, for the most part, children "who received stimulant medication treatment for ADHD are at no differential risk for these substance outcomes than their counterparts who did not receive medication treatment."
It is important for parents and pediatricians to be aware of all the benefits and risks of treating children with stimulant medication.
Kathryn added:
"Pediatricians and child psychiatrists also must weigh the potential costs and benefits of various treatment options. Our study provides an important update to clinicians.
Particularly for those who are concerned that stimulant medication is a 'gateway' drug or increases the risk for later substance use, there is no evidence at the group level for this hypothesis."
In fact, a previous study suggested that there is a protective effect from stimulants that helps lower the risk of children diagnosed with ADHD taking drugs.
Dr. Andrew Adesman, chief of developmental - behavioral pediatrics at the Steven - Alexandra Cohen Children's Medical Center of New York in New Hyde Park, said the finding "was accepted as gospel, and pediatricians had taken comfort in that there was a secondary benefit to treating patients with stimulant medications."
Analysis of data from two long-term studies of the impact of attention-deficit hyperactivity disorder (ADHD) on the development of psychiatric disorders in young adults confirms that ADHD alone significantly increases the risk of cigarette smoking and substance abuse in both boys and girls, this finding was published in the Journal of the American Academy of Child - Adolescent Psychiatry.
Dr. Adesman added that although children with ADHD are at a higher risk of drug dependency later in life, it is likely due to the nature of the condition itself and not because they took stimulant medications.
There is no evidence to say that ADHD medicines are 'gateway' drugs'.
]
Dr. Rani Gereige, a professor of pediatrics and director of medical education at Miami Children's Hospital, agreed with the other researchers, adding that:
"This is a finding that will reassure families that there is no worry later on of the risk of drug abuse. This worry should not be an issue [for parents] in deciding whether or not to put their child on stimulant medication."
In conclusion, the authors said that ADHD medication doesn't increase the risk of substance abuse.
The researchers said the finding will "provide an important update and suggest that treatment of attention-deficit/hyperactivity disorder with stimulant medication neither protects nor increases the risk of later substance use disorders."
A previous study, published in the American Journal of Psychiatry, similarly found that the use of stimulant drugs to treat children with ADHD has no effect on their future risk of substance abuse.
Written by Joseph Nordqvist
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
Painkillers Linked To Higher Risk Of Heart Attack
Painkillers Linked To Higher Risk Of Heart Attack30 May 2013-nbsp;-nbsp;-nbsp;
High doses of some of the most common painkillers, including ibuprofen and diclofenac, can increase the risk of heart problems by nearly thirty percent, according to a new study published in The Lancet.
The researchers conducted a meta-analysis of clinical trials to analyze the risks associated with taking nonsteroidal anti-inflammatory drugs (NSAIDs) -including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs).
NSAIDs are medications with analgesic (pain reducing) and antipyretic (fever reducing) properties.
High-dose NSAIDs are frequently used to treat and manage pain among patients suffering from inflammatory disorders.
Although many patients are willing to accept the risks associated with the medications, they should be fully informed first by their doctor. The results of this study will help them determine whether they are willing to take the risk.
The cardiovascular risks associated with NSAIDs had been explored by researchers before. One study found that heart attack survivors who were prescribed NSAIDs were 45% more likely to die or have another heart attack within one week of treatment.
In order to fully assess the health impacts of NSAIDs and help patients make an informed choice, the investigators thoroughly analyzed results from a total of 639 different clinical trials (which cover 353,000 patients records).
They identified an increased risk of heart attacks and death among the new generation of NSAIDs "coxibs", which were associated with a thirty percent increase in the risk of major vascular events.
The effects of high dose prescriptions levels of 150mg diclofenac or 2,400mg ibuprofen each day were analyzed.
A previous study published in PLoS Medicine revealed that naproxen and low dose ibuprofen are least likely to increase cardiovascular risk whereas diclofenac, even in doses available without prescription, elevates risk.
Results of the study showed that every year there were three additional heart attacks, four additional cases of heart failure, and one death for every 1,000 people taking the medications.
Ibuprofen a common nonsteroidal anti-inflammatory drug (NSAID)
Lead researcher Prof Colin Baigent, said:
"Three per thousand per year sounds like it is quite a low risk, but the judgement has to be made by patients.
So if you're a patient and you go and sit in front of your doctor and discuss it, you are the one who should be making the judgement about whether three per thousand per year is worth it to allow you, potentially, to go about your daily life."
It's important to note that this finding shouldn't alarm or concern people who only use the painkillers for the occasional headache.
Prof Baigent commented that the finding is particularly relevant to people at high risk of heart disease on high doses of NSAIDs, adding that "the higher your risk of heart disease, the higher your risk of a complication. Roughly speaking, if you've got double the risk of heart disease, then the risk of having a heart attack is roughly doubled."
Of all the NSAIDs analyzed, "Naproxen" didn't appear to increase major vascular events or vascular deaths.
It is crucial that prescribers are aware of the risks associated with these powerful drugs before prescribing them.
Written by Joseph Nordqvist
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
HIV Shell Structure Cracked With Help Of Supercomputer
HIV Shell Structure Cracked With Help Of Supercomputer30 May 2013-nbsp;-nbsp;-nbsp;
A new study that features on the cover of Nature this week describes how researchers in the US have for the
first time cracked the chemical structure of the capsid or protein shell of the human immunodeficiency virus (HIV). The
breakthrough, which likely opens the way to powerful new drugs against the virus that causes AIDS, was made possible with the
help of a new "petascale" supercomputer.
Scientists have been trying for some time to crack the precise chemical structure of HIV's cone-shaped capsid, a protein shell that
protects the virus's genetic material. The capsid is thought to be the key to virulence of HIV and has become an attractive target
for new antiretroviral drug development.
As senior author of this new Nature study, Peijun Zhang, an associate professor of structural biology at the University of
Pittsburgh School of Medicine, says in a statement:
"The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or
prevent the infection."
"This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain
enzymes, but drug resistance is an enormous challenge due to the virus' high mutation rate."
Previous studies have described attempts to chip away at the capsid structure bit by bit. To try and see the atomic-level detail of
the shell, made of over 1,300 identical proteins, researchers have used a range of sophisticated lab tools, from nuclear magnetic
resonance spectroscopy and X-ray crystallography, to cryo-electron microscopy and cryo-EM tomography.
But it was only when they added the processing power of the new petascale Blue Waters supercomputer at the National Center for
Supercomputing Applications at the University of Illinois, to the already impressive array of tools, that Zhang and colleagues were
able to fathom the chemical structure of the entire capsid.
A petascale computer has a number-crunching rate measured in "petaflops", or petas (quadrillions, 1015) of
floating point instructions per second. To put this into context, a petascale computer can perform in one second the same
number of instructions as it would take everyone on Earth doing one calculation per second for 1.5 days.
The simulations that added the missing pieces to the HIV capsid puzzle were conducted during testing of Blue Waters by co-
authors Klaus Schulten, a physics professor, and Juan R. Perilla, a post-doc researcher, both at the University of
Illinois.
Commenting on the HIV capsid challenge, Schulten says:
"This is a big structure, one of the biggest structures ever solved."
"It was very clear that it would require a huge amount of simulation - the largest simulation ever published - involving 64 million
atoms," he adds.
From previous studies that had found the HIV capsid contains a number of identical proteins, the researchers already knew these
proteins are arranged as pentagons and hexagons, and they had a hunch that the pentagons formed the tight round corners of
the cone-shaped capsid they could see under an electron microscope.
But exactly how many of these proteins it takes to make the capsid, or how the pentagons and hexagons fit together, remained a
mystery.
Zhang and the structural biology team at Pittsburgh found that when exposed to high concentrations of salt, the protein building
blocks assemble into tubes made only of hexagons.
From further experiments they found that certain regions of the proteins interact with one another in a way that is "critical for
capsid assembly and stability, and for viral infectivity," they note.
They then managed to get a rough idea of the overall shape of the capsid by taking cryo-electron tomographs of it sliced into
sections.
From these results, and their own simulations of how the hexamers and pentamers might interact, Schulten and Perilla carried out
a series of large-scale computer simulations.
Schulten says that they could only match the 64-million-atom capsid structure to the "diverse" experimental data using a unique
approach they developed themselves that they call "molecular dynamic flexible fitting".
"You basically simulate the physical characteristics and behavior of large biological molecules but you also incorporate the data
into the simulation so that the model actually drives itself toward agreement with the data," he explains.
With these techniques the researchers found that the HIV protein shell comprises 216 hexagons and 12 pentagons arranged in the
way the experimental data suggested.
The proteins in the hexagons and pentagons were identical but the angles through which they attached to each other were
different among different regions of the structure.
Schulten says this is what puzzled them: such a protein would have to be inherently flexible to form such a varied
structure.
By having pentagons as well as hexagons, the capsid can form a closed structure, explain the researchers, describing the property
the pentagons bring as "induced acute surface curvature". (A quick look at the structure of fullerenes, or even soccer balls for
that matter, and you get an idea of what they are talking about).
Schulten says that knowing more about the detailed structure of the HIV capsid will help researchers understand how it functions,
and this helps drug developers work out how to disrupt those functions.
He explains how the HIV capsid has to perform two opposing functions. It has to remain intact to protect its genetic material, but
it also has to be able to release it in a timely manner once inside the host cell so it can replicate.
"That has to happen with really good timing - too quick is not good, too slow is not good. And this is a moment when you can
throw a wrench into the system," says Schulten.
"The timing of the opening of the capsid is essential for the degree of virulence of the virus. This is where we could
perhaps best interfere with HIV infection," he adds.
Funds for the study came from the National Institute of General Medical Sciences at the National Institutes of Health
and the National Science Foundation, which also funds the Blue Waters supercomputer.
Earlier this year, scientists in the UK developed a vaccine
against foot and mouth disease that uses a synthetic virus capsid to provoke an immune response.
To determine the structure of that virus shell, and identify mutations that would improve it, they used Diamond Light Source, the UK's national synchrotron
facility.
Written by Catharine Paddock PhD
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
Stroke Patients Likely Safe To Continue Blood Thinners Before Minor Surgery
Stroke Patients Likely Safe To Continue Blood Thinners Before Minor Surgery30 May 2013-nbsp;-nbsp;-nbsp;
A new guideline from the American Academy of Neurology advises that it is likely safe for patients to continue taking blood thinners like
aspirin or warfarin before minor procedures such as a cataract operation, minor dental surgery or dermatological procedure.
Developed with financial support from the American Academy of Neurology, the guideline appears in the 28 May issue of Neurology, the
Academy's official journal.
One of the co-authors, Jose Biller, chair of the Department of Neurology of Loyola University Medical Center in Maywood, Illinois, says in a
statement:
"This guideline is expected to be useful to neurologists, primary care physicians, surgeons, dentists and other healthcare providers caring for these
patients."
After experiencing a stroke or mini-stroke, many patients are prescribed blood thinners such as aspirin or warfarin (commonly branded as
Coumadin) to reduce the risk of blood clots that could give them another stroke.
The downside of this is that blood thinners increase the risk of bleeding when the patient requires surgery. So patient and doctor are then faced
with a dilemma: how to weigh up the risk of bleeding against the benefits of the surgery (or the future harm that not having the surgery might
pose)?
After systematically reviewing evidence from 133 studies, Biller and colleagues concluded that on the whole, it is likely safe to continue taking them
before minor procedures, but it depends on the blood thinner and type of procedure.
The guideline is set out as a series of "levels" ranging from very unlikely that the procedure increases risk of bleeding, through possibly does not,
to uncertainty about the risk due to lack of research.
For instance:
Taking warfarin or aspirin before dental procedures is very unlikely to increase risk of bleeding.
Taking aspirin before minor procedures like cataract surgery, carpal tunnel syndrome surgery, dermatologic procedures and prostate biopsy
likely does not increase bleeding risk.
Taking warfarin before dermatologic procedures and invasive ocular anesthesia also likely does not increase bleeding risk.
Taking aspirin before procedures such as retinal surgery and ultrasound-guided biopsy possibly does not increase bleeding
risk.
But taking aspirin before orthopaedic hip procedures is likely to increase bleeding risk.
To help healthcare providers apply the guidelines, the authors give three examples of hypothetical cases where patients have had a stroke and are
due to undergo a surgical procedure:
65-year-old man due for routine colonoscopy screening. The patient had a stroke about a year ago. He may or may not need to
have a polyp removed and the risk of bleeding if he does is 2%. His neurologist recommends he continues to take aspirin.
70-year-old woman with breast cancer due to undergo mastectomy. The patient had a stroke before the breast cancer and is taking
aspirin. As there is little published research on the bleeding risk of taking aspirin before such an invasive procedure, the patient and her
neurologist agree she should stop taking the aspirin seven days before the surgery and resume the day after.
60-year-old man due to undergo cataract surgery. The patient is taking warfarin following a stroke. After consulting the guidelines,
his neurologist discovers the risk of bleeding during an eye procedure while taking warfarin is not precisely defined. But the patient says he
would rather risk the bleeding than risk another stroke, so he, the ophthalmologist and neurologist agree he should continue to take warfarin when
he has the cataract surgery.
In the February 2012 issue of Expert Reviews, Loyola University Medical Center physicians report finding that for atrial fibrillation patients at risk for stroke, easy-to-use blood thinners are likely
to replace Coumadin.
Written by Catharine Paddock PhD
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
HIV Shell Structure Cracked With Help Of Supercomputer
HIV Shell Structure Cracked With Help Of Supercomputer30 May 2013-nbsp;-nbsp;-nbsp;
A new study that features on the cover of Nature this week describes how researchers in the US have for the
first time cracked the chemical structure of the capsid or protein shell of the human immunodeficiency virus (HIV). The
breakthrough, which likely opens the way to powerful new drugs against the virus that causes AIDS, was made possible with the
help of a new "petascale" supercomputer.
Scientists have been trying for some time to crack the precise chemical structure of HIV's cone-shaped capsid, a protein shell that
protects the virus's genetic material. The capsid is thought to be the key to virulence of HIV and has become an attractive target
for new antiretroviral drug development.
As senior author of this new Nature study, Peijun Zhang, an associate professor of structural biology at the University of
Pittsburgh School of Medicine, says in a statement:
"The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or
prevent the infection."
"This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain
enzymes, but drug resistance is an enormous challenge due to the virus' high mutation rate."
Previous studies have described attempts to chip away at the capsid structure bit by bit. To try and see the atomic-level detail of
the shell, made of over 1,300 identical proteins, researchers have used a range of sophisticated lab tools, from nuclear magnetic
resonance spectroscopy and X-ray crystallography, to cryo-electron microscopy and cryo-EM tomography.
But it was only when they added the processing power of the new petascale Blue Waters supercomputer at the National Center for
Supercomputing Applications at the University of Illinois, to the already impressive array of tools, that Zhang and colleagues were
able to fathom the chemical structure of the entire capsid.
A petascale computer has a number-crunching rate measured in "petaflops", or petas (quadrillions, 10 to the minus 15) of
floating point instructions per second. To put this into context, a petascale computer can perform in one second the same
number of instructions as it would take everyone on Earth doing one calculation per second for 1.5 days.
The simulations that added the missing pieces to the HIV capsid puzzle were conducted during testing of Blue Waters by co-
authors Klaus Schulten, a physics professor, and Juan R. Perilla, a post-doc researcher, both at the University of
Illinois.
Commenting on the HIV capsid challenge, Schulten says:
"This is a big structure, one of the biggest structures ever solved."
"It was very clear that it would require a huge amount of simulation - the largest simulation ever published - involving 64 million
atoms," he adds.
From previous studies that had found the HIV capsid contains a number of identical proteins, the researchers already knew these
proteins are arranged as pentagons and hexagons, and they had a hunch that the pentagons formed the tight round corners of
the cone-shaped capsid they could see under an electron microscope.
But exactly how many of these proteins it takes to make the capsid, or how the pentagons and hexagons fit together, remained a
mystery.
Zhang and the structural biology team at Pittsburgh found that when exposed to high concentrations of salt, the protein building
blocks assemble into tubes made only of hexagons.
From further experiments they found that certain regions of the proteins interact with one another in a way that is "critical for
capsid assembly and stability, and for viral infectivity," they note.
They then managed to get a rough idea of the overall shape of the capsid by taking cryo-electron tomographs of it sliced into
sections.
From these results, and their own simulations of how the hexamers and pentamers might interact, Schulten and Perilla carried out
a series of large-scale computer simulations.
Schulten says that they could only match the 64-million-atom capsid structure to the "diverse" experimental data using a unique
approach they developed themselves that they call "molecular dynamic flexible fitting".
"You basically simulate the physical characteristics and behavior of large biological molecules but you also incorporate the data
into the simulation so that the model actually drives itself toward agreement with the data," he explains.
With these techniques the researchers found that the HIV protein shell comprises 216 hexagons and 12 pentagons arranged in the
way the experimental data suggested.
The proteins in the hexagons and pentagons were identical but the angles through which they attached to each other were
different among different regions of the structure.
Schulten says this is what puzzled them: such a protein would have to be inherently flexible to form such a varied
structure.
By having pentagons as well as hexagons, the capsid can form a closed structure, explain the researchers, describing the property
the pentagons bring as "induced acute surface curvature". (A quick look at the structure of fullerenes, or even soccer balls for
that matter, and you get an idea of what they are talking about).
Schulten says that knowing more about the detailed structure of the HIV capsid will help researchers understand how it functions,
and this helps drug developers work out how to disrupt those functions.
He explains how the HIV capsid has to perform two opposing functions. It has to remain intact to protect its genetic material, but
it also has to be able to release it in a timely manner once inside the host cell so it can replicate.
"That has to happen with really good timing - too quick is not good, too slow is not good. And this is a moment when you can
throw a wrench into the system," says Schulten.
"The timing of the opening of the capsid is essential for the degree of virulence of the virus. This is where we could
perhaps best interfere with HIV infection," he adds.
Funds for the study came from the National Institute of General Medical Sciences at the National Institutes of Health
and the National Science Foundation, which also funds the Blue Waters supercomputer.
Earlier this year, scientists in the UK developed a vaccine
against foot and mouth disease that uses a synthetic virus capsid to provoke an immune response.
To determine the structure of that virus shell, and identify mutations that would improve it, they used Diamond Light Source, the UK's national synchrotron
facility.
Written by Catharine Paddock PhD
Copyright: Medical News TodayNot to be reproduced without permission of Medical News Today
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