CLINICAL NEWS
Fenofibrate Decreases the Need for Laser in Diabetic Retinopathy Patients
Type 2 diabetes patients taking fenofibrate had a reduced need for laser treatment for diabetic retinopathy (DR) when compared with patients receiving placebo, according to research published in the Lancet.
Prof. Tony Keech, MD, from the NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia, and colleagues from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study looked at 9,795 patients aged 50 to 75 years with type 2 diabetes randomized to fenofibrate 200 mg/day or placebo. In a substudy of 1,012 patients, fundus photos were graded by ETDRS (Early Treatment of Diabetic Retinopathy Study) criteria to determine the cumulative incidence of DR and its component lesions.
With an average follow-up of 5 years, fenofibrate reduced the frequency of first laser treatment for macular edema by 31% and proliferative DR by 30% compared with placebo. In the substudy, investigators found that fenofibrate reduced the risk of first laser treatment by >70% (the actual number of events was small, however, 23 in the placebo group vs five in the treatment group).
Transporters May Help Delay Diabetes-Related Retinal Damage
Two transporters that deliver alternative energy sources to the eye may help delay retinal damage that can occur in diabetes, according to researchers from the Medical College of Georgia, in Augusta.
The transporters, SMCT1 and SMCT2, can circumvent the eye's protective blood-retinal barrier, delivering the energy sources lactate and ketone bodies to a healthy eye, said Pamela Martin, PhD, a biochemist at the medical college.
The two transporters most likely work harder in diabetes to increase levels of lactate and ketone bodies, which may help explain why diabetes' impact on the eye may go undiagnosed for years, said Dr. Martin. Understanding how these transporters work normally and in diabetes may enable early diagnosis of DR and natural delivery mechanisms for drugs to stop it.
Previously there was no evidence that transporters which typically haul lactate and ketone bodies around, are elevated in diabetes. Recently discovered sodium-coupled transporters SMCT1 and SMCT2 are able to go against the concentration gradient and change substrates, such as lactate, from low to high concentrations inside the cells. The researchers have shown that SMCT1 is expressed in retinal neurons and in the retinal pigment epithelium, and SMCT2 is primarily expressed in supportive retinal MŸller cells.
"If you have these transporters, they can transport these substrates into your retina and hopefully prevent some of the neuronal cell damage that occurs," said Dr. Martin.
Carbohydrate Intake May Be Associated With AMD
A prospective evaluation of the effects of baseline dietary glycemic index found that higher carbohydrate intake is associated with a higher risk of age-related macular degeneration (AMD). The study, published in the American Journal of Clinical Nutrition, evaluated baseline dietary glycemic index and its effect on the progression of AMD in 3,977 patients, aged 55 to 80 years from AREDS (Age-Related Eye Disease Study).
Researchers found that the risk of progression over 8 years was significantly higher for patients with a higher dietary glycemic index than those with a low dietary glycemic intake. Patients with the highest glycemic index had a 17% greater chance for disease progression, compared to 8% and 5%, for the medium- and low-glycemic–index groups, respectively.
"[Individuals] at risk of AMD progression, especially those at high risk of advanced AMD, may benefit from consuming a small amount of refined carbohydrates," the authors concluded.
Protein Controls Blood Vessel Formation
A protein called CIB1, identified by researchers at the University of North Carolina at Chapel Hill School of Medicine appears to play a major role in controlling new blood vessel growth. The protein may offer a target for drug treatments to help the body repair itself after injury and control unwanted blood vessel growth.
"In the future, this knowledge may help our ability to control blood vessel growth in disease situations such as wound healing, retinal diseases, and diabetes," said Leslie Parise, PhD, senior study author.
The study, funded by the US National Institutes of Health, appeared in the journal Circulation Research.
Dr. Parise's lab first identified the CIB1 protein in 1997 in blood platelets. CIB1 keeps blood platelets from sticking together, acting as a natural anticoagulant to prevent clots that might lead to myocardial infarction or stroke. Further research, however, has shown that CIB1 appears in almost every cell type in the body, Dr. Parise said.
In the current study, Dr. Parise and colleagues found CIB1 in the endothelial cells that line all blood vessels. During angiogenesis, biological signals prompt endothelial cells to release enzymes and other chemicals that allow them to move away from existing blood vessels and form new ones.
"CIB1 appears to be an attractive drug target to control blood vessel growth, since it does not play an essential role during fetal development, but instead plays a role in the pathological forms of blood vessel growth," said Mohamed Zayed, PhD, coauthor of the study.
In experiments in mice missing CIB1 genes, the researchers found that CIB1 is critical for angiogenesis in the retina. In those mouse studies, the new blood vessel growth was prompted by ischemia.
Researchers believe that CIB1 could be a target for both pro- and antiangiogenic drug therapies.
Biennial Eye Exam Enough for Diabetic Patients
Eye screening every other year in patients with diabetes and no signs of retinal disease are as effective as annual exams and do not lead to any undue treatment delay, according to a report in the British Journal of Ophthalmology.
Einar Stefansson, MD, from the University of Iceland, Reykjavik, told Reuters Health that diabetic eye disease is one of the most common causes of blindness in the world. "The prevalence of diabetic blindness has been and can be decreased by 50% to 80% with the public health approach," he said. "Thousands of people around the world are blind because of inadequate public health organization in eye care."
Researchers sought to determine if exams every other year would suffice for diabetic patients, studying 296 patients with diabetes and no retinopathy during 1994 and 1995.
They were screened biennially and followed for 10 years. They concluded that based on their results, biennial screening exam suffices in both type 1 and type 2 diabetes patients.
Glaucoma-Like Optic Discs Detected in Teleretinal Program
Glaucoma has been linked to diabetes in several studies. Investigators reporting in the Journal of the American Optometric Association assessed the sensitivity and specificity of a diabetes teleretinal program to identify glaucoma-suspicious optic discs. A total of 1,644 outpatients with diabetes presenting to Veterans Affairs ambulatory clinics participated in a nonmydriatic digital retinal imaging (NMDRI) program. Technicians transmitted digital retinal images electronically to readers for grading and eye care recommendations, according to the report.
Patients were referred for ophthalmic care based on the level of DR and other ocular findings, including optic nerve changes suspicious for glaucoma.
Assessment of clinical data obtained after NMDRI found that 103 of 175 (59%) glaucoma suspects were identified as having glaucoma-suspicious optic discs. In the comparison group, only seven of 175 (4%) had glaucoma-suspicious optic discs. Although specificity was high (96%), modifications in diabetes teleretinal imaging programs are needed to improve the sensitivity of detecting optic discs suspicious for glaucoma.
Lutein, Zeaxanthin Intake Associated With Decreased Cataract Risk
Women who have higher dietary intake of lutein and zeaxanthin—compounds found in yellow or dark, leafy vegetables—as well as vitamin E, appear to have a lower risk for developing cataracts, according to a report in the Archives of Ophthalmology.
"The oxidative hypothesis of cataract formation posits that reactive oxygen species can damage lens proteins and fiber cell membrane, and that nutrients with antioxidant capabilities can protect against these changes," the authors wrote. Vitamins A and C, lutein and zeaxanthin are believed to have antioxidant properties. Lutein and zeaxanthin are the only carotenoids present in the lens of the human eye and may also protect against cataracts by filtering blue light.
William Christen, ScD, and colleagues at Harvard Medical School, Boston, analyzed dietary information from 35,551 female health professionals enrolled in the Women's Health Study in 1993. The women were then followed for an average of 10 years, and the diets of those who developed cataracts were compared with the diets of those who did not.
A total of 2,031 women developed cataracts during the study. When the participants were split into five groups based on the amount of lutein and zeaxanthin they consumed, those in the group who consumed the most (6,716 mg per day) had an 18% lower chance of developing cataracts than those who consumed the least (1,177 mg per day). Women who consumed the most vitamin E from food and supplements (approximately 262 mg per day) were 14% less likely to develop cataracts than those who had the least amount of vitamin E in their diet.
Smoking Related to Risk, Progression of Eye Disease
Smokers appear to have increased long-term risks of incidence and progression of AMD. According to a study in the Archives of Ophthalmology, smoking had already been identified as one of the few modifiable risk factors for AMD and may contribute to the disease through several pathways, including reducing antioxidant levels, decreasing blood flow around the eye, and affecting pigments in the retina.
Examining 4,926 participants in the Beaver Dam eye study, Ronald Klein, MD, MPH, and colleagues in Madison, Wisconsin, found that 21% of men and 18% of women smoked initially. Smokers had a 47% increase in their odds of developing early AMD. People who smoked also developed AMD at a younger age (69.2 years) than former smokers (72.3 years) and those who had never smoked (74.4 years). Smoking at the beginning of the study was also associated with the cumulative progression of AMD over the 15 years of the study.
INDUSTRY AND BUSINESS NEWS
Positive Preclinical Ocular Penetration Data With Topical Formulations of Retina Drug
Oxigene, Inc. (Waltham, Massachusetts), reported positive results from preclinical studies with topical formulations of combretastatin A4 phosphate (Zybrestat) for ophthalmologic indications. Studies performed in rabbit models showed that when applied topically, two formulations of combretastatin A4 phosphate were absorbed and resulted in concentrations of drug in target tissues in the back of the eye (ie, retina, choroid).
The company believes the levels of drug achieved will be sufficient for therapeutic activity in AMD and potentially other eye diseases in which abnormal neovascularization plays a role. These results confirm preliminary results seen in earlier preclinical studies.
"Achieving therapeutic concentrations of [combretastatin A4 phosphate] with topical delivery in relevant ocular tissues, such as the retina, in preclinical models represents a key milestone in Oxigene's ophthalmology program," said Oxigene's president and chief executive officer, Richard Chin, MD. "Having previously observed in clinical trials that intravenously [IV]-administered [combretastatin A4 phosphate] has clinical activity in patients suffering from a form of macular degeneration, we believe a topical formulation of [combretastatin A4 phosphate] that delivers sufficient quantities of drug to target tissues in the eye has a high likelihood of demonstrating activity in the clinic. We now have results from multiple preclinical studies suggesting that the development of such a formulation is feasible, and we believe that a topical formulation of [combretastatin A4 phosphate] could potentially be a major advance for patients with a variety of ophthalmic diseases and conditions."
Tolerability of the formulations was favorable in the rabbit studies, confirming data from earlier rodent studies. Based on these results, Oxigene is proceeding with further preclinical studies in nonrodent models, which, if consistent with results from rabbit and rodent studies, are expected to provide support for an investigational new drug submission, currently planned for the first half of 2008.
Companies Enter Into Licensing Agreement for AMD Treatment
Ophthotech Corp. (Princeton, New Jersey), along with Biogen Idec, Inc.(Cambridge, Massachusetts), and PDL BioPharma, Inc. (Redwood City, California), have entered into an exclusive worldwide licensing agreement for an antiangiogenesis antibody to treat AMD.
Under the terms of the agreement, Biogen Idec and PDL have granted Ophthotech worldwide development and commercial rights to all ophthalmic uses of volociximab (M200). Volociximab is an investigational monoclonal antibody targeting alpha-5 beta-1 integrin, a key protein involved in angiogenesis.
Other terms, including financial terms, related to the agreement have not been disclosed.
IN MEMORIAM
Remembering Judah Folkman
Harvard physician-scientist Judah Folkman, MD (1933-2008), died unexpectedly at the age of 74, according to news reports. Dr. Folkman was a founder and pioneer in cancer and angiogenesis research. His work revolutionized the modern understanding of cancer and paved the way for the development of a number of life-prolonging cancer therapies used today.
According to the Angiogenesis Foundation, Dr. Folkman was one of the greatest scientific minds of our time. "His vision inspired the creation of the Angiogenesis Foundation 14 years ago as a nonprofit organization dedicated to advancing the new field of angiogenesis treatments for more than 70 diseases."
Dr. Folkman was born in Cleveland in 1933, the son of a rabbi, and was raised in various places throughout the Midwest. He attended Ohio State University and Harvard Medical School. Dr. Folkman began experimenting with tumors while working for the US Navy. He hypothesized that tumor growth could be restricted by the blood supply it recieved. He also published work on the mechanism in tumors that induces the formation of new blood vessels.
"Dr. Folkman had the good fortune to witness the field he pioneered evolve, on a global scale, into a modern force in modern science and medicine," said Angiogenesis Foundation President, William W. Li.
An appreciation of the impact of Dr. Folkman's work on ophthalmology will appear in an upcoming issue of Retina Today.
Remembering Dr. Robert Hollenhorst
Mayo Clinic physician and neuroscience pioneer Robert W. Hollenhorst, MD, died at the age of 94. Dr. Hollenhorst was born in 1913, in St. Cloud, Minnesota, and attended the St. Cloud State Teachers College, St. John's University, and the University of Minnesota Medical School.
Dr. Hollenhorst was awarded a Bronze Star while serving in the Army Medical Corps. He was a member of many medical boards and associations including serving as president of the American Ophthalmology Society and vice chairman of the American Board of Ophthalmology. He was awarded the Howe Medal in 1986 and was the founder of the Minnesota Preschool Survey of Vision and Hearing. Dr. Hollenhorst described a phenomenon now known as Hollenhorst plaques—cholesterol bodies, sometimes found in the blood vessels of the retina, which are useful in diagnosing the risk of stroke and other circulatory problems.
Correction:
Above is the correct photo of the Opko Spectral OCT/SLO (Ophthalmic Technologies, Inc., Toronto). The product was featured in the Innovations section of Retina Today's November/December 2007 issue with a photo of the previous-generation of the device. The editors apologize for any confusion this may have caused.
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