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Results from two concurrent, prospective, double-blind, multi-center clinical trials show that pegaptanib (Macugen), an
anti-vascular endothelial growth factor therapy, is an effective treatment for neovascular age-related macular degeneration
(AMD), according to a recent paper in the New England Journal of Medicine. Macugen was approved by the Food and Drug
Administration on Dec. 17, 2004.
AMD is the leading cause of irreversible, severe loss of vision in people 50 years and older in the developed world and remains an area of unmet medical need. The neovascular or wet form of the disease represents about 10 percent of the overall disease prevalence, but is responsible for 90 percent of the severe vision loss. In wet AMD, abnormal blood vessels grow under the central retina and cause a progressive loss of central vision, interfering with driving, reading and other everyday tasks. As the population ages, almost 1 million people over the age of 55 years in the United States are expected to develop AMD in the next five years, making it a major public health issue in an increasing population of older persons.
The paper in the New England Journal of Medicine details two clinical trials that were held at 117 sites in the Unites States, Canada, Europe, Israel, Australia and South America. Patients were eligible for inclusion if they were 50 years of age or older and had subfoveal choroidal neovascularization caused by AMD and a range of best corrected visual acuity of 20/40 to 20/320 in the study eye and of 20/8000 or better in the other eye. Of the 1,208 patients randomly assigned to treatment in the two studies, (297 patients were assigned to receive 0.3 mg of pegaptanib; 305 patients, 1.0 mg of pegaptanib; 302 patients, 3.0 mg of pegaptanib; and 304 patients, sham injections), 1,190 received at least one study treatment. Treatments were given by injection into the eye.
According to lead author, Evangelos Gragoudas, M.D., Director of Retina Services at the Massachusetts Eye and Infirmary and Professor of Ophthalmology at Harvard Medical School, pegaptanib produced a statistically significant and clinically meaningful benefit in the treatment of wet AMD.
“Overall, a reduced risk of visual-acuity loss was observed with all doses as early as six weeks after treatment was begun, with evidence of an increasing benefit over time up to week 54,” the authors write. “Pegaptanib reduced the chance of not only the loss of 15 letters or more of visual acuity (considered a moderate loss) but also a loss of 30 letters or more (six lines on the eye chart, which is considered a severe loss). In addition, treatment with pegaptanib reduced the risk of progression to legal blindness in the study eye, promoted stability of vision, and in a small percentage of patients, resulted in more visual improvement at week 54 than among those receiving sham injections.”
The authors conclude that treatment with pegaptanib provide a statistically significant and clinically meaningful benefit in a broad spectrum of patients with neovascular AMD, regardless of the size or angiographic subtype of the lesion or the baseline visual acuity. The rate of injection-related adverse events represents a potentially modifiable risk but necessitates vigilance, the authors caution.
The Massachusetts Eye and Ear Infirmary (MEEI) in Boston participated in these clinical trials. In addition, researchers and physicians at MEEI -- Drs. Anthony P. Adamis (formerly of MEEI), Evangelos Gragoudas (MEEI) and Joan W.Miller (MEEI) -- were among the first to study the role of vascular endothelial growth factor (VEGF), which causes abnormal blood vessel growth in eye disease. Their experimental studies showed that levels of VEGF protein were increased in eyes that developed abnormal new blood vessels, and that VEGF-blocking drugs were able to prevent the growth of these abnormal blood vessels. Others, including Harvard's Dr. Lloyd Paul Aiello of the Joslin Diabetes Center, Dr. Pat D’Amore of the Schepens Eye Research Institute and Dr. Lois Smith of Children's Hospital, corroborated the importance of VEGF in neovascular eye disease. These studies formed the basis for the drug development and clinical trials of anti-VEGF therapies, including pegaptanib, and demonstrate the importance of translational research, in order to transform scientific discoveries into new therapies for patients.
Pegaptanib differs from current treatments, which are directed at the results of the disease. Current treatments, which employ a drug and laser, are able to slow vision loss, but have not been widely applicable to all patients. Pegaptanib is the first treatment designed to target the source of the disease and blocks the pathological form of a chemical called VEGF, which is produced in the eye of patients with wet AMD.
The results of the two studies provide validation of the aptamer-based therapy in the treatment of human disease and support ongoing investigations into the use of VEGF antagonists in patients with diabetic retinopathy and retinal-vein occlusion, which are other disorders associated with elevated levels of intraocular VEGF.
Founded in 1824, the Massachusetts Eye and Ear Infirmary is an international center for treatment and research and a teaching hospital of Harvard Medical School. For more information, call (617) 523-7900 or TDD (617) 523-5498 or visit www.meei.harvard.edu.
A miserable headache, a stuffy nose and that “run down”
feeling – everyone knows what it’s like to have a severe cold.
For millions of Americans, these symptoms are regular occurrences, lasting for weeks and months – even years. These are the sufferers of chronic sinusitis, infection or inflammation of the sinuses, hollow areas in the skull surrounding the nose.
Enduring countless infections and lingering symptoms for extended periods is not uncommon for chronic sufferers, says Gregory Randolph, M.D., Massachusetts Eye and Ear Infirmary’s Director of General Otolaryngology. Patients take over-the-counter medications to treat symptoms and antibiotics to combat infections, but another bout is usually right around the corner.
“It is remarkable what some of our patients go through before they come to us,” says Dr. Randolph. Dr. Randolph and other members of the otolaryngology staff at MEEI are finding better ways to diagnose and treat chronic sinusitis, and conducting research to understand its causes and effects.
When functioning normally, the four sets of sinuses around the eyes and nose humidify and warm air before it enters the lungs. They also aid the sense of smell and the sound of your voice, and help clean and moisturize the nasal passages.
Infections such as colds can inflame and thicken sinus membranes, hindering or blocking sinus drainage. This blocked air and moisture creates ideal conditions for a bacterial infection. Sinuses also become inflamed because of seasonal allergies, asthma and even fungus. Any, or a combination of, these conditions can permanently block sinuses and their drainage openings, causing a build-up that does not resolve.
Immune deficiencies or conditions such as cystic fibrosis cause sinusitis. Some patients may also develop small, fleshy outgrowths of nasal membranes called polyps that block sinus drainage. Structural problems with bones and connective tissue in the sinuses and nasal cavity make up the balance of underlying problems.
With a complex assortment of causes, finding the exact source of sinusitis is key for chronic sufferers, says Dr. Randolph. In some cases, a patient may undergo allergy testing to identify whether allergies are the cause. For most patients, a detailed history of symptoms is combined with computerized tomography (CT) imaging and an examination of the some of the sinuses through a thin telescope called an endoscope that is inserted into the nasal passages.
According to Dr. Randolph, most patients respond to careful medical management of sinusitis. For others, particularly those with polyps and structural abnormalities, surgery may be the best choice.
For many patients, MEEI otolaryngologists are using an advanced surgical technique that combines CT and endoscopy. Using CT imaging during the endoscopic procedures gives surgeons real-time images of blockages, polyps, scar tissues from trauma or past procedures, and structural problems. This combination of technologies allows physicians to more accurately navigate diseased passages and more precisely complete tissue removal and repair. The accuracy of this surgical procedure, often called “stealth,” makes it much safer for patients. Repair may include enlarging sinus drainage passages.
After a short recovery period, says Dr. Randolph, patients report dramatic relief in the short-term, and greatly reduced infections in the long-term. The effectiveness of sinus surgery and its impact on patients’ quality of life are the research interests of MEEI otolaryngologist and facial plastics expert Richard Gliklich, M.D.
In addition to those mentioned above, other important members of the Infirmary’s sinus team include Salah Salman, M.D., Jean Bruch, M.D., and Eric Holbrook, M.D. Dr. Salman has recently published two comprehensive endoscopic atlases, which will provide surgeons with extensive information to help treat their patients. Dr. Bruch is, in addition to being an otolaryngologist, a board certified oral surgeon who adds a vital dimension to the spectrum of surgical services available to patients.
The recent addition of Dr. Holbrook, an expert on smell and taste, has also enriched the department’s research program. Loss of smell is a symptom of a wide range of conditions, from sinusitis to aging. The sense of smell is unique among the senses, says Dr. Holbrook, because nerve tissue involved in the sensory process seems to have regenerative abilities. By studying these nerve cells in the laboratory, Dr. Holbrook is seeking to understand what causes the loss of this ability, with an eye to being able to repopulate these smell cells.
In his clinical practice, Dr. Holbrook has also been seeing patients whose livelihoods depend on their ability to smell and taste, including chefs and a wine taster. Smell and taste are closely related, says Dr. Holbrook, and patients who often report a lack of flavor in food are actually experiencing a problem with smell. When problems with smell are resolved, the flavor usually comes back.
Beyond the professionals, all people depend on the sense of smell, says Dr. Holbrook. The ability to smell smoke, gas, the appropriate amount of deodorant, spoiled food, or a diaper that needs to be changed is important for safety and day-to-day living.
“We understand that the inability to smell can also be considered a psychological loss,” says Dr. Holbrook. “There can be depression associated with the loss of smell. Patients tell us they miss their sense of smell or the ‘flavor’ of their lives. They want it back.”
“First and foremost, my main responsibility is
always patient care,” says George Papaliodis, M.D., as he discusses his
responsibilities as the newly appointed Acting Director of the Massachusetts Eye and Ear Infirmary’s Ocular Immunology
and Uveitis Service. The service provides a multidisciplinary approach to the treatment of uveitis, which is the third
leading cause of blindness in the United States, and other immunological disorders of the eye. As Acting Director,
Dr. Papaliodis will also serve as a consultant to referring physicians in the community who serve patients with uveitis
or inflammatory eye diseases.
Dr. Papaliodis, who is Board Certified in ophthalmology and internal medicine, notes that practicing ophthalmology was a good compromise between two realms that he enjoys — internal medicine and surgery. However, his interest in ophthalmology extends beyond a mere professional interest. “My grandmother lost vision to glaucoma and, as such, I could see the impact the ophthalmology care she received had upon her,” he says.
Dr. Papaliodis’ research interests in ocular immunology and ocular inflammatory disorders reiterate his enthusiasm for both domains. “The treatment of these conditions overlaps between internal medicine and ophthalmology. Each has some systemic basis for the ophthalmologic manifestations we observe. It is to the patient’s benefit and to the benefit of the field to have multiple specialists involved in their care,” he adds.
Related to this, Dr. Papaliodis, who has a dual faculty appointment at the Infirmary and MGH, seeks to utilize this position to encourage collaboration between the Infirmary’s Ocular Immunology and Uveitis Service and other departments in both clinical services and research.
Dr. Papaliodis expresses a continuing interest in research into new immunological agents for the treatment of inflammatory eye diseases. “Uveitis is often undertreated or treated in traditional manners despite newer, novel approaches to these diseases,” he says. As a Clinical Instructor of Ophthalmology at the Infirmary and at the Harvard Medical School, Dr. Papaliodis enjoys teaching because it provides a unique opportunity to train future physicians in the knowledge and approaches that are available to treat ocular inflammatory diseases.
The Friends of the Massachusetts Eye and Ear Infirmary are hosting their annual Black and White Ball on Sat.,
April 30, 6:30 p.m., at the Harvard Club, 274 Commonwealth Avenue, Boston. Tickets are $150 per
person. Join the Friends for dinner, music, dancing and a silent auction. This year's event will raise funds for
both ophthalmology and ENT research. Specifically, this is for research to understand the damage to the optic nerve
created by glaucoma, in addition to supporting ENT research into chemoprevention of squamous cell carcinomas.
For information, contact Ruth Doyle at 617-573-3164
The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) will visit the Infirmary from April 25 - 28. A nonprofit organization whose mission is to continuously improve the quality of care delivered by health care organizations, JCAHO provides accreditation to more than 15,000 health care organizations in the United States. Currently, the Infirmary is accredited by JCAHO. By remaining accredited, the Infirmary makes a commitment to abide by JCAHO standards, which provide guidelines for safe patient care. Remaining JCAHO accredited is consistent with the Infirmary's mission to provide the highest quality, patient-centered care.
The effort and dedication of physicians, nurses, researchers, staff members, friends and affiliates allows the Infirmary to accomplish this mission every day.
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