Bio-Ophthalmology

Old drug for new tricks: Nilvadipine shows promise in treating retinal degeneration

Nilvadipine, the calcium-channel-blocker drug currently indicated for treating systemic hypertension, may also be able to slow photoreceptor degeneration, according to Japanese and American researchers. 

In a new report, the researchers detailed how rats injected with nilvadipine exhibited significant protection from retinal degeneration. Because the drug has already been approved for use in humans for hypertension, clinical tests of the drugs for retinal degeneration may be shorter than normal because of the existing body of research on nilvadipine.

The research team, led by Dr Hitoshi Yamazaki in the Department of Ophthalmology at Hirosaki School of Medicine, published their findings in a recent edition of Investigative Ophthalmology & Visual Science IOVS (Vol. 43[4]:919-926). The research, similar to a wide range of ocular disease studies, was undertaken with the Royal College of Surgeons (RCS) rats.  These experimental animals are among the most widely used animal model for the study of retinal degeneration, having been identified in the 1970s by US researchers. The current study additionally involved collaborators from the University of Washington School of Medicine, Seattle, Washington. USA and the Yokohama School of Medicine in Japan.

Although the results of the studies do not provide a “cure” for retinal degeneration, they may provide a means to extend photoreceptor cell longevity. Other research findings have indicated that simply by extending photoreceptor cell life meaningful vision may also be extended which of course has significant implications for those facing the prospect of ever deteriorating sight.

Calcium antagonists, such as nilvadipine, induce relaxation of vascular smooth muscle cells and increase regional blood flow in several organs.  Studies aimed at examining drug behaviour within they body have found that nilvadipine is well distributed through out a range of tissues, including the brain, following a systemic injection beneath the peritoneum. This will be an important point if the research is to advance to human testing as the delivery of nilvadipine to the eye may not require the same degree of sophisticated drug delivery systems as other ocular therapies may demand. 
Furthermore, the current use of nilvadipine for the treatment of hypertension in humans may reduce the burden of toxicity studies required by the U.S. Food and Drug Administration. Again this may prove critical in terms of costs should pharmaceutical researchers wish to reproduce the Japanese findings and try to develop the groundwork for clinical trials of the drug.

The researchers based their experimental design on the concentration of nilvadipine already in clinical use. In their study, they used RCS rats that already harboured a retinal degenerative disorder. The animals were injected with either nilvadipine or an identical suspension without the drug.  The researchers administered the drug every morning over a period of two weeks. The retinas of the animals receiving nilvadipine demonstrated significantly healthier morphological structure and functioning when compared to control animals. 

Currently, the researchers are simply identifying and reporting their observations. So far, they have only tentative, possible explanations about why the drug has produced such a beneficial effect. The therapeutic advantages in the context of retinal degeneration may be mediated by making blood vessels in the retina dilate or through causing intracellular calcium levels to be lowered to levels found in normal retinas.

Researchers already know that calcium plays a key role in mediating the biochemical visual transduction cascade within retinal photoreceptors. Consequently, abnormal calcium ion movement may induce photoreceptor cell death. The RCS animal model used in the Japanese studies may have a pathology linked to abnormal calcium ion movement and so the connection with nilvadipine may lie somewhere along this biochemical pathway. If the drug is in some way capable of restoring calcium ion movement within a more tolerable range, then the researchers may indeed hold a valuable tool to extend photoreceptor cell longevity in the RCS model.

Additionally, “apoptosis,” the mechanism of photoreceptor cell death observed in virtually all cases of retinal degeneration, has been shown previously to involve calcium ions. This again provides another tantalising clue as to how nilvadipine may work.

What also strikes the researchers as an important discovery is that nilvadipine overcame the so-called “blood-brain barrier,” which has represented a significant obstacle in developing drugs to target the central nervous system, brain, and eyes.
As a result, the findings of the Japanese-led research with nilvadipine carry promising potential for delivering therapeutic molecules to relatively inaccessible organs.
The researchers will need to carry out further studies to determine the mechanics of nilvadipine in the retina.

This of course is not the first example of a drug developed to treat a particular disorder and subsequently found to have beneficial effects in unexpected quarters. For instance, Pfizer Pharmaceuticals had originally developed the drug sildenafil for the treatment of specific coronary conditions. However, in the course of clinical trials, the secondary effects of the drug proved extremely beneficial in unexpected ways. And now sildenafil is marketed under the trade name of Viagra — and become a multi-billion dollar success story for Pfizer.

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