ICUS Weekly News Monitor 11-12-2015

1.  Science Ticker,  Nov 11, 2015,  Blood-brain barrier jiggled loose to deliver medicine
By Laura Sanders
2.  The Globe and Mail,  Nov 9, 2015.  Sunnybrook doctor first to perform blood-brain barrier procedure using focused ultrasound waves     By  Wency Leung
3.  Focused Ultrasound Foundation,  Nov 9, 2015,  Blood-Brain Barrier Opened Non-Invasively With Focused Ultrasound for the First Time
4.  Drug Safety,  Nov 2015,  Safety of Perflutren Ultrasound Contrast Agents: A Disproportionality Analysis of the US FAERS Database     Authors: Manfred Hauben, et al
Science Ticker
Nov 11, 2015
Blood-brain barrier jiggled loose to deliver medicine
By Laura Sanders
In its job protecting the brain from would-be invaders, the blood-brain barrier also blocks medicines from reaching the brain.  But on November 5, ultrasound zaps shook loose that tight barrier in a woman who has a brain tumor, potentially granting entry to a chemotherapy drug. The technique, which relies on tiny bubbles set jiggling by ultrasound beams, has shown promise in animal models (SN: 9/27/08, p. 20). This is the first time it has been tried on a person, says neurosurgeon Todd Mainprize of Sunnybrook Health Sciences Centre in Toronto, who led the procedure.
Mainprize and colleagues injected microbubbles, a chemotherapy drug and an imaging agent that could be visualized by a scanner into the blood of the woman. Then, targeted ultrasound beams passed through her brain, where they made the microbubbles in her blood vessels contract and expand. This jostling temporarily opened the blood-brain barrier, allowing the imaging agent — and presumably the drug — to enter the brain tissue near her tumor, Mainprize reported in a November 10 media briefing.
The unpublished results are preliminary; the researchers don’t how much of the drug made it into the tumor, or how the patient will fare long-term. Mainprize and colleagues plan to perform the procedure on other patients to test whether the procedure is safe and feasible. If so, the method might ultimately be used to deliver medicine to treat a wide range of brain maladies such as tumors and Alzheimer’s disease.
The Globe and Mail
Nov 9, 2015
Sunnybrook doctor first to perform blood-brain barrier procedure using focused ultrasound waves
By  Wency Leung
Dr. Todd Mainprize leaned over and peered through his wire-rim glasses at a computer screen showing the brain scan of his brain cancer patient, Bonny Hall, who lay in a magnetic resonance imaging machine (MRI) in the adjacent room.
“This has gone exactly the way we hoped,” the neurosurgeon said, crossing his arms.
He smiled and nodded. His experimental procedure had been a success.
Here in the S-wing of Toronto’s Sunnybrook Hospital, Mainprize and his research team accomplished on Thursday what no one in the world has ever done before: Using focused ultrasound waves, they have opened the human blood-brain barrier, paving the way for future treatment of an array of currently impossible or hard-to cure-illnesses – from brain cancer to certain forms of depression, stroke, Parkinson’s disease and Alzheimer’s disease.
The blood-brain barrier is an extremely selective filter that Mainprize likens to cling film, which coats the blood vessels in the brain, preventing harmful substances in the bloodstream from passing through. Though its function is to protect the brain, this barrier has limited doctors’ ability to treat diseases, such as tumours, using drugs like chemotherapy to target specific areas of the brain.
By successfully opening the blood-brain barrier, “that will allow us to use many, many more medications in the brain than we can currently use,” said Dr. Kullervo Hynynen, director of physical sciences at Sunnybrook Health Sciences Centre, who developed the technology used in the experimental procedure.
Hynynen said about 98 per cent of molecules that could potentially be used for brain treatments cannot currently be used because they cannot get through the blood-brain barrier. This includes antibodies, which in animal studies have been shown to remove brain plaques involved in Alzheimer’s disease, or stem cells, which could be used to treat stroke patients. Thus, he says, the ability to penetrate the blood-brain barrier will “revolutionize” brain medicine.
Previous methods of circumventing this cling film-like coating have been inconsistent and difficult to control, or invasive, such as inserting microcatheters through the skull to inject drugs directly into the brain. But by using focused ultrasound, the Toronto researchers have demonstrated a way of breaching the blood-brain barrier that is non-invasive, selective (or contained within a specific area), reversible and, the researchers believe, safe.
Here’s how it works: Medication is first introduced into a patient’s bloodstream – in this case, a chemotherapy drug called liposomal doxorubicin. Next, microbubbles, or tiny air bubbles, which are typically used as a contrast medium to enhance visibility in ultrasound imaging, are intravenously delivered into the bloodstream. Using MRI to locate their target area, doctors then send focused ultrasound waves, causing the microbubbles in the brain’s capillaries to expand and contract. This expansion and contraction creates little tears in the cling film-like layer of endothelial cells of the blood-brain barrier, allowing the drug molecules to pass through into the brain to the targeted areas.
The microbubbles themselves do not cross the barrier and disappear within minutes, passing through the lungs. Meanwhile, the tiny tears in the blood-brain barrier close up again between an estimated eight to 12 hours.
The appearance of bright spots, the size of pinkie fingerprints, on the MRI images of Bonny Hall’s brain allowed Mainprize to immediately see that he had accomplished what he set out to do.
“This white spot and this white spot is where we opened the blood-brain barrier,” he said, pointing to the computer screen.
In the days previous, Hall, 56, of Tiny, Ont., was anxious yet eager to be the first patient to undergo the procedure.
“I think that someone has to go first,” Hall said, noting she empathized with the first patient to be treated with penicillin. “I kind of feel that way.”
Hall discovered her brain tumour eight years ago, though doctors at the time found it was benign. About five months ago, however, they found it had become cancerous and had grown to about five centimetres by three centimetres – about the size of a miniature candy bar – on the right side of her head, just above her ear.
Although the tumour caused no pain, Hall experienced what she described as “little blips,” or small 10– to 20-second seizures during which she would feel “spaced out.”
On the morning of the procedure, as the chemotherapy drug dripped into her arm, Hall said she was looking forward to getting her life back to normal.
“Seeing people here really suffer,” she said of the other patients at the hospital’s cancer centre, “I really do hope this will work for them some day.”
The following morning, after determining it possible to open the blood-brain barrier, Mainprize performed traditional surgery to remove Hall’s tumour. He carefully cut open a hand-sized flap of skin and muscle and removed part of her skull, extracting a white mass of tissue. The tumour will be analyzed over the next week to determine how much of the chemotherapy effectively passed through the blood-brain barrier.
The next step for the research team will be to repeat the focused ultrasound procedure on nine additional patients to show it can be replicated safely.
The possibilities for future research, Mainprize said, are enormous. “With ... this technique, you can selectively open almost anywhere in the brain and deliver whatever you want,” he said. “Essentially, whatever you can think of is a potential study that may help in the future.”
Focused Ultrasound Foundation
Nov 9, 2015
Blood-Brain Barrier Opened Non-Invasively With Focused Ultrasound for the First Time
Charlottesville, VA – November 9, 2015 – The blood-brain barrier has been non-invasively opened in a patient for the first time. A team at Sunnybrook Health Sciences Centre in Toronto used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB), allowing the more effective delivery of chemotherapy into a patient’s malignant brain tumor.
BBB Team_PhotoThe team, led by neurosurgeon Todd Mainprize, MD, and physicist Kullervo Hynynen, PhD, infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.
“The blood-brain barrier has been a persistent impediment to delivering valuable therapies to treat tumors,” said Dr. Mainprize. “We are encouraged that we were able to open this barrier to deliver chemotherapy directly into the brain, and we look forward to more opportunities to apply this revolutionary approach.”
Read Sunnybrooks ReleaseThis patient treatment is part of a pilot study of up to 10 patients to establish the feasibility, safety and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. The Focused Ultrasound Foundation is currently funding this trial through their Cornelia Flagg Keller Memorial Fund for Brain Research.
“Breaching this barrier opens up a new frontier in treating brain disorders,” said Neal Kassell, MD, Chairman of the Focused Ultrasound Foundation. “We are encouraged by the momentum building for the use of focused ultrasound to non-invasively deliver therapies for a number of brain disorders.”
Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.
The procedure was conducted using Insightec’s ExAblate Neuro system. “This first patient treatment is a technological breakthrough that may lead to many clinical applications,” said Eyal Zadicario, Vice President for R&D and Director of Neuro Programs, Insightec.
While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.
A recent study by Gerhard Leinenga and Jürgen Götz from the Queensland Brain Institute in Australia further corroborated Hynynen’s research, demonstrating opening the blood-brain barrier with focused ultrasound reduced brain plaques and improved memory in a mouse model of Alzheimer’s disease.
Based on these two pre-clinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s is being organized.
About The Blood-Brain Barrier
The blood-brain barrier (BBB) is a protective layer of tightly joined cells that lines the blood vessels of the brain and keeps harmful substances, such as toxins and infectious agents, from entering the surrounding tissue. Unfortunately, this barrier also prevents certain drugs from reaching their targets within the brain in adequate concentrations. Safely and temporarily opening the barrier in a well-defined area to deliver drugs at therapeutic levels is a long-sought goal for treatment of a wide variety of neurological conditions including brain tumors, Alzheimer's disease, Parkinson's disease and epilepsy.
Currently, there are limited options to circumvent the blood-brain barrier and deliver drugs. Drugs can be directly injected into the brain, with the risk of hemorrhage, infection or damage to normal brain tissue from the needle or catheter. The pharmacological agent mannitol has been used to disrupt the barrier when injected into the blood supply, but this approach is uncontrolled and non-selective and can further be associated with significant effects on blood pressure and the body’s fluid balance.
About Focused Ultrasound
Focused ultrasound uses ultrasonic energy guided by magnetic resonance or ultrasound imaging to treat tissue deep in the body without incisions or radiation. Multiple intersecting beams of ultrasound are directed and concentrated on a target, much like a magnifying glass can focus multiple beams of light on a single point. Where each individual beam passes through the tissue, there is no effect. But, at the focal point, the convergence of the multiple beams of focused ultrasound energy results in many important biological effects depending on the nature of the tissue and the ultrasound parameters.
There are currently 18 known mechanisms of focused ultrasound, including several methods of drug delivery, such as disrupting the blood-brain barrier.
There are focused ultrasound systems currently approved in the U.S. to treat uterine fibroids, ablate prostate tissue and alleviate pain from bone metastases. There are a growing number of clinical applications in various stages of research and development around the world, including Parkinson’s disease, essential tremor, breast cancer, liver cancer and hypertension.
About the Focused Ultrasound Foundation
The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of focused ultrasound. Since its establishment in 2006, the Foundation has become the largest non-governmental source of funding for focused ultrasound research. More information can be found at
Drug Safety
Drug Saf (2015) 38:1127–1139
DOI 10.1007/s40264-015-0332-6
Nov 2015
Safety of Perflutren Ultrasound Contrast Agents: A Disproportionality Analysis of the US FAERS Database
Manfred Hauben1,3; Eric Y. Hung3; Kelly C. Hanretta2; Sripal Bangalore1; Vincenza Snow3
Email:  Eric Y. Hung, This email address is being protected from spambots. You need JavaScript enabled to view it.
1 New York University Medical Center, New York, NY, USA
2 Mount Sinai School of Medicine, New York, NY, USA
3 Pfizer, Incorporated, 219 East 42nd Street, New York, NY 10017, USA
Perflutren microbubble/microsphere ultrasound contrast agents have a black-box warning based on case reports of serious cardiopulmonary events. There have been several subsequent observational safety studies. Large spontaneous reporting databases may help detect/refine signals of rare adverse events that elude other data sources/study designs.
The objective of this study was to supplement existing knowledge of the reported safety of perflutren using statistical analysis of spontaneous reports.
We analyzed information from the US Food and Drug Administration Adverse Event Reporting System using a disproportionality analysis. Analysis of overall reporting for perflutren was supplemented by subset (age, indication) analysis. A signal of disproportionate reporting
(SDR) was defined as EB05[2.
Overall, 18/380 Preferred Terms and 1/83 Standardized
Medical Queries had SDRs. Most were small (EB05 = 2–4). Back pain and flank pain were the largest SDRs followed by events compatible with signs/symptoms of hypersensitivity. The general pattern of SDRs in the subset analysis was consistent with the overall analysis. Almost all events with SDRs were literally or conceptually labeled. Except for chest pain (higher in the age\65 years subgroup) and back pain (higher in the age C65 years subgroup), there were no statistically significant differences between age subsets. Except for the Preferred Terms Pruritus and Urticaria and the narrow Standardized Medical Queries Ventricular tachyarrhythmia, Angioedema, Oropharyngeal allergic conditions, and Hypersensitivity (higher in the stress test subgroup), there were no statistically significant reporting differences between indication subsets. There were no SDRs associated with the major cardiovascular events of death, myocardial infarction/ischemia, angina, arrhythmias, or convulsions in any analysis.
Our combined signal detection/evaluation analysis did not identify SDRs of novel adverse events ormajor cardiovascular events associated with perflutren ultrasound contrast agents. The negative results for major cardiovascular events extend previous signal evaluation exercises supporting the relative cardiovascular safety of these agents.
Key Points
Events with signals of disproportionate reporting identified through a disproportionality analysis of spontaneous reports with perflutren for echocardiography were either literally or conceptually labeled, i.e., there were no statistical signals of novel adverse events. A disproportionality analysis applied to spontaneous reports of perflutren used for echocardiography extends previous signal evaluation exercises that substantially weakened the initial signal of certain major cardiovascular and convulsion events generated by individual spontaneous case reports. A disproportionality analysis of spontaneous reports can support both signal detection and signal evaluation exercises.

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