Glaucoma Research

The studies on the living animal allow the determination of not only intraocular pressure effects but also the effect on other parameters, such as outflow facility and pseudofacility. Pseudofacility provides a measure not only of the ciliary epithelial permeability but also of the blood pressure changes in ciliary body caused by a redirection of blood flow to other parts of the eye, or a general change in blood flow through the whole eye. This may be correlated with the results on the isolated tissue to give an estimate of blood flow changes. Furthermore, if drugs are interpreted to alter blood flow through eye to any degree this will be confirmed by determinations of blood flow using a new microsphere entrapment technique. Using this system it is possible to introduce small radioactive uniform diameter spheres into the arterial blood system and after one circulation the spheres are entrapped in capillaries. Upon analysis of the tissue under study and comparison with arterial blood flow over a fixed time, it is possible by direct comparison to calculate the blood flow in the tissues of the eye. From a comparison of drug effect on all the parameters, as outlined above, together with a consideration of the experiments on isolated ciliary body it will be possible to completely describe drug effects on the eye as they relate to the regulation of intraocular pressure. In this way it is hoped that a more logical choice of drugs may be made for the treatment of glaucoma among currently used drugs and also among other agents not presently being used for the treatment of glaucoma. In the living rhesus monkey eye we will be able to establish a well-known baseline for all the measurable parameters in the living eye in the absence of drugs by repeated weekly measurements. We will then be able to study the effects of drugs on these same stable and well identified eyes. Each characteristic will be identified and drug-induced variations will be readily identifiable. These studies in the monkey eye will only be made in conscious animals using techniques normally applied in clinical ophthalmology. Some preliminary data in man has indicated that our concept of 75% of aqueous humor production is an ultrafiltration process also applies to man but there were drawbacks in the procedures. The primary problem was volunteer return, some were seen 42 times and some were seen only twice, thus, despite a 5 or 6 year time period in which measurements were made. This does not represent a wide database. In terms of a study of drug effects, the numbers of patients are much lower with 4 or 5 per drug being a high number and with few (three at most) return visits. With a stable monkey population (with an eye like that of man) we will be able in a relatively short-time to have many detailed and repeated observations in the absence of drugs; with 6 animals it will be possible to measure them every 2 days (Monday, Wednesday and Friday) to obtain the normal patterns for each subject. We will, therefore, quickly establish the normal database from which to begin drug studies. These will also progress fairly rapidly and in addition be in the same eye, so that each eye will act as its own control. We will be able to perform a control series of 2 weeks (6 sets of observations) followed by drug treatment on the next 2 occasions (Monday and Thursday) with a control week following, then another drug etc. The change in schedule is to allow time for all the drug to be lost from the body between tests. In this way we should be able to obtain data relatively rapidly on the acute effect of various drugs. This phase will be followed by a period when drugs are given for a one or two week period so that the sub-chronic effects can be examined on all the parameters. These studies on monkey eyes will provide initial studies on the aging response of the eye. It is proposed to begin with the studies outlined here and repeatedly, at approximately 3 or 6 month periods, to examine the normal ocular parameters and determine drug effects. We will, therefore, begin to accumulate data on the eyes as the monkey ages. This will provide an important database not only on aging but also the effect of aging on drug responses. The combination of isolated tissue and living eye experiments will allow a more precise definition of the effects of drugs. The drug studies will primarily be commonly used ophthalmic medications used in clinical practice but will also be extended to study other drugs which may be found to reduce intraocular pressure. Many such drugs in the latter group currently exist, yet have not been studied in detail to allow a definition of the ocular response to their use. Some of these drugs may prove clinically useful in reducing intraocular pressure. Only by an approach such as the above will it be possible to define how and which drugs act to influence intraocular pressure. Such knowledge will further our understanding of drug effects on the eye and may aid in the treatment of glaucoma.