Treatment and prevention of retinal edema with dopaminergic antagonists

Retinal edema, in particular cystoid macular edema, is prevented or treated by administering to the patient afflicted with retinal edema or in danger of experiencing retinal edema an amount of a dopaminergic antagonist effective to reduce the edema. A preferred dopaminergic antagonist is haloperidol. The activity of the dopaminergic antagonist may be potentiated by concurrent administration of ascorbic acid.

BACKGROUND OF THE INVENTION 
1. Field of the Invention: 
This invention relates to pharmacological treatment and prevention of 
retinal edema and more particularly to treatment and prevention of cystoid 
macular edema by administration of dopaminergic antagonists. 
2. Description of the Prior Art: 
Retinal edema is a physiological condition characterized by accumulation of 
excess fluid in the retina of the eye. A particularly troublesome type of 
retinal edema is cystoid macular edema (CME), a condition in which small 
cysts filled with a watery fluid form principally in the inner nuclear 
layer and outer plexiform layer of the retina, in and around the macula. 
Since the macular area of the retina is the location of the most acute 
vision, CME is particularly detrimental to vision. CME is associated with 
a number of diseases, e.g., hypertensive vascular diseases and diabetes. 
However, a particularly difficult form of the disease is CME which follows 
successful cataract extraction. In a relatively high percentage of cases, 
cystoid macular edema develops some weeks after surgery, resulting in a 
deterioration of the vision which had been restored by successful cataract 
extraction. In most patients the condition gradually clears spontaneously, 
but in some it persists and affects their vision more or less permanently. 
The cause of CME is unknown, and hitherto there has been no certainly 
effective treatment for the condition. 
A number of treatments have been proposed for alleviating CME after 
cataract surgery. Since it is believed that retinal trauma produced by 
tension on retinal attachments of the vitreous may be a cause of CME, 
cases of chronic CME have been treated with some success by surgical 
severing of vitreous strands attached to the surgical wound (Fung, W. E., 
Ophthalmology 89(8), 898-901 (1982)). 
Because of the association of CME with inflammatory conditions of the eye, 
topical and systemic anti-inflammatory drugs have been administered. 
Corticosteroids and non-steroid anti-inflammatories, e.g. ibuprofen, 
indomethacin, have been used, and have apparently been of some use in 
alleviating the condition (Jampol, L. M., Ophthalmology 89(8), 891-897 
(1982)). However, no completely reliable treatment for CME has been 
discovered hitherto. 
Therefore a need has continued to exist for a method of treating and 
preventing retinal edema and particularly cystoid macular edema, which is 
effective and reliable. 
SUMMARY OF THE INVENTION 
Accordingly it is an object of this invention to provide a method of 
treating and preventing retinal edema. 
A further object is to provide a method for treating and preventing cystoid 
macular edema. 
A further object is to provide a pharmacological method for treating and 
preventing cystoid macular edema. 
Other objects of the invention will become apparent from the description of 
the invention which follows. 
The objects of the invention are achieved by a method for treatment and/or 
prevention of retinal edema which comprises administering to a patient in 
danger of being afflicted with retinal edema an amount of a dopaminergic 
antagonist effective to prevent the edema or reduce it. Ascorbic acid may 
be administered concurrently to potentiate the action of the dopaminergic 
antagonist.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
Any dopaminergic antagonist is an effective drug for treating retinal 
edema, and particularly CME, by the process of this invention. Such drugs 
are well known to those skilled in the art and include reserpine and 
related rauwolfia alkaloids; phenothiazine derivatives frequently used as 
tranquilizers such as chlorpromazine, triflupromazine, mesoridazine, 
piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, 
trifluoperazine, and the like; thioxanthines, such as chlorprothixene, 
thiothixene, and the like; substituted butyrophenones such as haloperidol; 
dibenzoxazepines such as loxapine; and other dopaminergic antagonists, 
such as molindone, and the like. The compounds can be administered as the 
free compound or in the form of a pharmacologically acceptable salt. 
A preferred dopaminergic antagonist useful in the process of this invention 
is haloperidol. 
The dopaminergic antagonists used in the process of this invention may be 
administered orally, parenterally, such as by intravenous or periorbital 
injection, or topically by instillation into the eye. 
The method of administration of the dopaminergic antagonists is adapted to 
the condition of the patient. At the time of the surgical procedure for 
cataract extraction, the drugs may be administered parenterally, e.g. by 
intravenous or intramuscular injection, and preferably by periorbital 
injection for maximum efficacy. After the surgical procedure, the patient 
will normally have to continue to receive the medication for several 
months; accordingly topical or oral administration is preferred for this 
phase of the treatment. The dose used will vary with the effectiveness of 
the individual drug as a dopaminergic antagonist. Since these drugs have 
long been used for their psychopharmacological effect, which is known to 
be the result of their dopaminergic antagonism, effective amounts of each 
individual drug are well known. Long term therapy may be accomplished by 
administration of the drug orally, in the form of capsules, tablets, 
suspensions, and the like, or by topical administration to the eye in a 
suitable ophthalmologically acceptable vehicle. A suitable topical 
composition comprises an effective amount of the drug in a buffered 
isotonic saline aqueous solution, suitable for instillation. 
Alternatively, the drug may be formulated in an ophthalmologically 
acceptable ointment. Should the particular drug being used exhibit poor 
absorption when used topically in the eye, an absorption promoter such as 
dimethyl sulfoxide may be incorporated into the vehicle. The concentration 
of the drug in the ophthalmologic vehicle will vary with the potency of 
the compound, but will typically be between 0.1 and 100 mg/ml of vehicle. 
For the preferred drug, haloperidol, a preferred concentration range is 
from about 2 to about 40 mg/ml, and the most preferred concentration is 
about 2 mg/ml in a buffered aqueous solution. This solution may be used 
for injection or applied topically to the eye. A typical dosage regimen 
for long term therapy would be one drop of the topical preparation four 
times per day. Formulation of suitable dosage forms is entirely 
conventional and is well within the capability of the skilled practitioner 
referring to standard pharmacy references such as., e.g., Remington's 
Practice of Pharmacy, A. Osol, Ed., Mack Publishing Co., Easton, Pa. 
It is preferred that the dopaminergic antagonist be administered beginning 
immediately after a procedure for catarct extraction or even during the 
operation and that the administration be continued for a period of several 
months in order to prevent the onset of cystoid macular edema. However, it 
is also according to the invention to treat patients who have already 
developed CME in order to cure the disease. 
While the inventor does not wish to be bound by theoretical considerations, 
it is believed that the presence of dopamine in the retina, secreted as a 
consequence of stimulation of dopaminergic neurons by the surgical trauma, 
particularly by tension placed on the retina at its points of attachment 
to the vitreous, may be at least one contributing cause of the edema. It 
is known that dopamine can increase the permeability of capillary walls, 
an effect which may contribute to the leakage of fluid from the retinal 
capillaries to form the characteristic cysts of CME. 
Because dopaminergic antagonists have other effects, and particularly 
psychopharmaceutical affects, it is desirable to avoid these effects as 
far as possible by keeping the dose as low as possible. For example, 
haloperidol, a preferred dopaminergic antagonist of this invention, has 
strong tranquilizing effects and is also particularly prone to cause 
extrapyramidal discharges. 
It has now been found that the activity of haloperidol is potentiated by 
the presence of ascorbic acid, as discussed in G. V. Rebec et al., Science 
227, 438-440 (1985). Accordingly, in a preferred embodiment of the 
invention, in order to keep the systemic effects of the antidopaminergic 
drug as small as possible while retaining maximum efficacy in the eye, 
both a dopaminergic antagonist and ascorbic acid are administered to the 
eye for prevention and/or treatment of retinal edema, particularly of 
cystoid macular edema. If both drugs are administered topically to the 
eye, the amount of dopaminergic antagonist can be reduced, so that smaller 
amounts of the psychopharmaceutical compound are transferred to the 
general circulation. In another embodiment, one of the drugs may be given 
systemically, while the other is administered topically to to eye. In, 
this way it is possible, for example, to administer the dopaminergic 
antagonist systemically, e.g., by oral administration, in amounts too 
small to cause psychological effects, while at the same time administering 
ascorbic acid to the eye to potentiate the activity of the dopaminergic 
antagonist at that site to perform the desired anti-edema function. 
Alternatively, the dopaminergic antagonist can be administered topically 
to the eye, e.g., by instillation or injection, and the ascorbic acid can 
be administered systemically. In this embodiment, the dose of dopaminergic 
antagonist to the eye can be reduced, so that side effects caused by the 
drug entering the general circulation are proportionally reduced. 
The invention having now been fully described, it will be apparent to one 
skilled in the art that many variations and modifications may be made 
therein without departing from the spirit or scope of the invention.