Patients with mild heart failure stand to benefit from a new drug that can halt the progression of their disease and reduce their risk of cardiovascular-related death. But the drug—a tablet that combines the agents valsartan and sacubitril, sold under the trade name Entresto by drugmaker Novartis—may be too good to be true, according to Arthur M. Feldman, MD, PhD, executive dean of the Lewis Katz School of Medicine at Temple University.
In an article published online December 7th in the Journal of the American Medical Association, Dr. Feldman and colleagues at Thomas Jefferson University and the University of Florida warn that valsartan/sacubitril could theoretically increase patients’ risk of Alzheimer’s disease and macular degeneration. The article raises these concerns about the drug, which was approved by the Food and Drug Administration in July 2015.
“Basic science data has caused us to speculate that off-target effects of valsartan/sacubitril may cause an exacerbation of Alzheimer’s disease and could also exacerbate the course of macular degeneration,” Dr. Feldman said. He went on to note that “doctors are prescribing these drugs without knowledge of these theoretical risks.”
Valsartan/sacubitril works by inhibiting an enzyme known as neprilysin, which normally plays a critical role in breaking down a wide array of peptides in cells. Among those substances are the so-called natriuretic peptides, which function in regulating scarring and cell growth in the heart when neprilysin is blocked. Because of those activities, valsartan/sacubitril can delay the progression of heart failure in some patients.
Neprilysin, however, also normally degrades amyloid beta, a peptide that can accumulate in the brain, where it contributes to Alzheimer’s disease, and in the eye, where it is implicated in macular degeneration. The balance between the production and clearance of amyloid beta is crucial to the pathogenesis of Alzheimer’s disease and is suspected to influence the development of macular degeneration. In animal models, blocking neprilysin disturbs that balance and exacerbates development of Alzheimer’s pathology.
Valsartan/sacubitril was approved for heart failure via the FDA’s fast-track program, in which drugs that promise to fulfill unmet medical needs undergo an accelerated review process. In the studies that led to the drug’s approval, no adverse events related to dementia were reported. However, according to Dr. Feldman and his colleagues, patients were followed for too short a period of time to confidently rule out potential adverse effects on cognitive function or vision, and specific tests were not performed to assess whether early changes in either Alzheimer-specific cognitive function or macular degeneration had occurred.
Moreover, preclinical studies and trials of the drug involved young monkeys and normal human volunteers. In both groups, the blood-brain barrier functions as it should. In heart failure patients, however, the blood-brain barrier frequently is compromised by hypertension and other vascular conditions, allowing drugs to enter the central nervous system.
The FDA has required Novartis to conduct a thorough assessment of the cognitive risks associated with valsartan/sacubitril in a clinical trial in patients with heart failure and preserved ejection fraction. The data from that study will not be available until 2022.
“My hope is that physicians will be prudent with the use of this new drug,” Dr. Feldman said. “The risks are theoretical, but every precaution should be taken to avoid them. The outcomes could be devastating for patients.”
Keeping Hungry Lens Cells in Check
Researchers from Florida Atlantic University have discovered that epithelial cells in close proximity to each other can sense when a cell is dying due to environmental stressors like UV light, smoke and other pollutants, and eat the cell before it becomes toxic.
In a study published in the Journal of Biochemistry and Molecular Biology, the researchers not only demonstrate that this happens with lens cells, but they uncover the molecules that are required to do it. They also reveal that the molecules needed for the cells to eat each other are degraded by UV light. When that happens, the cells lose the ability to eat each other. Since these systems are not confined to the lens and diseases of the eye such as cataracts, uncovering the mechanisms and functions will provide important information in more complex tissues and disease states.
It has long been known that environmental damage is associated with cell death and that it kills tissue because it is toxic. Yet, the lens, which does not have a blood supply, gets hit by UV light and other stressors that continuously kill cells. Consistently, the lens has evolved multiple protective and repair systems to preserve its transparent function in the face of environmental insults. That’s what the researchers sought to understand in this novel study.
They were able to establish that the intact lens is indeed capable of removing apoptopic lens cell debris and worked to identify a molecular mechanism for this process by lens cells. By using the lens as a model, they searched to understand how other cells and tissues might operate in a different way than by using blood cells.
“Accumulation of apoptopic material is toxic to epithelial cell populations, which include the cornea, skin, lungs and other tissue, and is associated with the development of multiple autoimmune, inflammatory, aging and degenerative diseases,” said Marc Kantorow, PhD, author of the paper and a professor and director of graduate studies in FAU’s College of Medicine. “Identifying the cell systems that protect against the effects of apoptosis-inducing insults is an important step toward understanding and developing therapies to treat these diseases.”
Using embryonic chicken lenses, Dr. Kantorow and his collaborators engineered the lens cells to be either fluorescent red or fluorescent green—instead of what would normally be a clear lens cell. They created artificial dead green cells and fed them to the red cells. When the red cells ate the green cells, they turned yellow. They observed this mechanism in real-time using microscopy to track the digesting cells and utilized antibodies to specific molecules to determine which molecules were needed for the cells to eat each other.
“It is widely known that cells have very specific functions and that environmental damage is associated with cell death,” said Lisa Brennan, PhD, associate research professor and a collaborator on the study. “Before this study, the common knowledge was that what removed these dead cells were specialized immune cells that literally go into the tissue and eat these dead cells and that’s how your body got rid of them. We looked at the eye lens as a model to try to search for alternate ways to get rid of these dead cells to keep a tissue alive.”
“Twenty percent of all cataracts are associated with UV light exposure and at some point in their lifetime, most people will get cataracts,” said Dr. Kantorow. “Our work has the potential to lead to the development of treatments and therapies that would eliminate the need for surgery, which is the only way to treat cataracts today.”
Dry Eye Tied to Chronic Pain
Researchers with Bascom Palmer Eye Institute have found a link between dry eye and chronic pain syndromes—a finding that suggests that a new paradigm is needed for diagnosis and treatment to improve patient outcomes.
“Our study indicates that some patients with dry eye have corneal somatosensory pathway dysfunction and would be better described as having neuropathic ocular pain,” said Anat Galor, MD, MSPH, a cornea and uveitis specialist and associate professor of clinical ophthalmology at BPEI at the University of Miami Miller School of Medicine, and lead author of the study, “Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes,” published recently in the American Pain Society’s Journal of Pain.
Roy C. Levitt, MD, a neuroanesthesiologist, pain specialist and geneticist also at the Miller School, and corresponding author, noted, “A multidisciplinary approach used for chronic pain treatment may also benefit these dry-eye patients.”
Their team evaluated 154 dry-eye patients from the Miami VA Hospital. “Dry-eye patients in our study reported higher levels of ocular and non-ocular pain associated with multiple chronic pain syndromes, and had lower scores on depression and quality-of-life indices consistent with a central sensitivity disorder,” said Dr. Levitt, a professor and vice chair of translational research and academic affairs. “We also suspect that neuropathic ocular pain may share causal genetic factors with other overlapping chronic pain conditions.
“Patients’ eyes may become hyper-sensitive to stimuli, such as wind or light, or have spontaneous pain such as a feeling of burning, which is typically associated with nerve injury,” said Dr. Levitt.
“Traditionally, eye specialists have treated dry eye with artificial tears or topical medications for the surface of the cornea,” said Dr. Galor. “However, even if these treatments improve some dry-eye symptoms, many patients continue to report underlying ocular and non-ocular pain.”
Of the implications of the study, Dr. Galor said, “Our highest priority is educating physicians that dry eye represents an overlapping chronic pain condition. Consequently, a multidisciplinary approach should be considered in the diagnosis and pain management of dry-eye patients.”
For further discussion of dry-eye-related pain, see Therapeutic Topics, p. 52. REVIEW