Manley West, 0.M., Ph.D., is a professor of pharmacology at the University of the West Indies in Kingston, Jamaica.

 

Introduction

 

Glaucoma may be defined as a group of ocular conditions characterized by raised intraocular pressure. Approximately 300 persons per 100,000 suffer from glaucoma. The prevalence increases with age and involves about 1 percent of the population over 40. Almost 80,000 Americans are blind from glaucoma, which makes the disease the leading cause of preventable blindness in the United States. More than 2 million Americans have glaucoma of one form or another. Primary open angle glaucoma is the most common form; it causes insidious, asymptomatic, bilateral visual loss. About 15 percent of Caucasians with glaucoma have closed angle glaucoma, and this percentage may even be higher in Asians. Glaucoma is more prevalent, begins earlier in life, and progresses faster among blacks than among other races. Jamaica, in particular, with a population of about 3 million has about 3 percent of this number suffering from glaucoma.

 

Normal intraocular pressure is from 10 to 20 mm Hg. Elevated intraocular pressure is usually associated with damage to the optic disk and visual field loss. In spite of a fundamental interest and research in this area, the precise mechanism by which ocular hypertension damages the optic disk is not clearly understood.

 

Aqueous humor is the fluid that circulates within the eyes to provide nourishment to the tissues. It is produced by the ciliary processes in the posterior chamber of the eyes and passes from the posterior chamber through the pupil to the anterior chamber of the eyes and exits through the outflow system at the peripheral angle of the anterior chamber. Two factors are really important in the dynamics of aqueous humor: (1) irregularities in the inflow mechanism or aqueous humor production, and (2) abnormalities in drainage or outflow of the aqueous humor. The inflow should balance outflow to maintain a steady state of intraocular pressure. Reducing aqueous production and hence inflow should be an accepted method of reducing intraocular pressure in all forms of glaucoma. The treatment involves a medical or surgical approach. The surgical approach should be used only after all medical attempts have failed.

 

At present we do not know how either endogenous or exogenous stimulators or inhibitors may alter aqueous humor formation and intraocular pressure. However, the adenylate cyclase complex in the ciliary process acts to reduce flow in a manner that is not known. It is known that the cholera toxin induces a watery diarrhea by stimulating an intestinal epithelia adenylate cyclase with the result of sodium and water being drawn into the lumen of the intestines (Gregory et al. 1981). This same toxin increases endolymph production in the inner ear. Stimulation of adenylate cyclase activity will accelerate production of cyclic AMP in epithelial cells and cause movement of fluid from the basal to the apical portion of the cells and hence into the lumen. It is known that cyclic AMP will increase the permeability of luminal membranes. It is also known that adrenaline enhances the intraocular accumulation of cyclic AMP by activating adenylate cyclase. The same line of reasoning holds for the ciliary epithelium, but the movement of fluid is reversed due to the invagination of the optical vesicles during the development of the eye. Therefore, it should not be difficult to accept that the receptor complex in the secretory tissues of eye, the ciliary processes, may be the area where research should be directed to find an acceptable medication for glaucoma.

 

Treatment

 

The management of glaucoma is best left to the ophthalmologist, but the size and importance of the problem calls for the cooperation of other health professionals. The medical treatment is divided into two major areas: (1) reduction of aqueous humor production and (2) facilitation of aqueous humor outflow. Canasol is a fairly new drug that reduces inflow and has significant advantages when compared to the synthetic drugs.

 

Current antiglaucoma medications are not always effective and have significant side effects. Pilocarpine and other miotic drugs (which constrict the pupil, thereby increasing the fluid outflow) may cause blurred vision during the day due to ciliary body spasm and impaired vision at night caused by miosis. Furthermore, the miotics may contribute to the development of cataracts and may predispose the patient to uveitis and retinal detachment. The carbonic anhydrase inhibitors, such as Diamox, can produce electrolyte imbalance, fatigue, decreased appetite and weight loss, and kidney stones. Epinephrine eyedrops may cause eye pain or headache because they dilate the pupils (to inhibit the inflow of fluid). Because they can be absorbed into the circulation, they may also cause heart palpitations and nervousness. The most popular glaucoma medication is Timoptic (generic name, timolol maleate), a beta-blocker, which is believed to decrease eye fluid production. Initial adverse reactions noted were mild ocular irritation and a slight reduction in the resting heart rate. Later reports identified problems associated with nerves, digestion, vision, skin, and respiration (Miller 1980; the Harvard Medical School Health Letter 1979).

 

Canasol

 

For many years it was observed in Israel and the United States that the Cannabis plant has ocular hypotensive effects, and vast sums of money were invested in these countries in research to develop therapeutically useful compounds. These ocular hypotensive compounds represent a new class of chemicals that are more potent in reducing intraocular pressure than most of the other accepted drugs used clinically and with none of their side effects.

 

Canasol is a sterile ophthalmic preparation developed from Cannabis sativa specifically for the management of glaucoma. It is the result of ten years of basic scientific and clinical research done at the University of the West Indies in the pharmacology and ophthalmology departments and in private ophthalmic clinics (West and Lockhart 1978,1980). (See Table 1 and Figure 1.)

 

Whereas international researchers concentrated their efforts on some cannabinoids that are psychoactive, at the University of the West Indies our research efforts were directed at other compounds of this plant since we were looking at long-term therapy. Now that the effectiveness of Canasol in glaucoma has been established in the Caribbean region and, according to private communication, in Australia, New Zealand, Colombia, and England, research is being directed at its mode and mechanism of action (Gutierrez and Gutierrez 1995). There is evidence that we may be looking at adrenergic receptor control of aqueous humor dynamics. Here Canasol could make a significant contribution to ophthalmology.

Effect of,canasol ophthalmic solution 0.1 percent w/v applied topically to the human eye with glaucoma.

(Standard errors of mean are omitted on this and the following three figures.)

 

For Jamaica the introduction of this drug is timely considering the proportion of the population with glaucoma and the severe foreign exchange problems that now exist. For this reason the treatment of Jamaicans facilitates research in this area.

Pharmacology

 

Canasol is unique in that when applied to one eye it does not cross over to the contralateral eye. There is now evidence that no appreciable amount passes into the systemic circulation and thus it has a predominantly local effect. This action of Canasol may be a function of its chemical nature. As demonstrated in animals and humans, the onset of action is very rapid and can be detected within minutes after a single topical application into the eye. At 15 minutes there is a decrease of approximately 50 percent in the original intraocular pressure, and this reaches a maximum at 90 minutes after application (see Figure 2).

 

Canasol has no effect on pupil size. Laboratory and clinical studies have shown that Canasol is more effective on a weight basis in lowering intraocular pressure when Canasol is combined with pilocarpine or timolol maleate (see figures 3 and 4). Though there has been no scientific evaluation to verify this claim, recent reports by ophthalmologists in Jamaica indicate that patients on Canasol may have improved vision at night. Canasol lowers the pressure in both the normal eye and the eye with glaucoma; however, the ocular hypotensive effect is most pronounced in the eye with glaucoma. The mode and mechanism of the action of Canasol is not clear at this time, but this is not unique to Canasol; there are many drugs whose mechanisms of action were not worked out until after they had been in clinical use, for example, digitalis.

Percentage change in ocular hypotension by Canasol 0.1 percent and Timolol 0.5 percent (in dogs).

 

However, the significant fall in intraocular pressure in animals is counteracted by several adrenolytic agents, whether they are applied topically to the eye or injected intravenously. Examples of these agents are tolazoline, azapetine, and phenoxybenzamine. Clinical experience has shown that when patients are already on antihypertensive medication, particularly alpha adrenergic blocking drugs, the frequency of dosing should be increased to produce the desired effect. The depletion of catecholamine stores in animals significantly reduces the effectiveness of Canasol. Extensive animal studies show that Canasol has no effect on the outflow mechanism. In animals, if the cervical (sympathetic) nerve is severed, the intraocular pressure is increased and Canasol may not reduce it. Present knowledge indicates that Canasol lowers intraocular pressure by adrenergic stimulations, and the site may be in the ciliary apparatus.

Summation or potentiation of Timolol in the presence of Canasol. The potentiation is the same irrespective of which drug is instilled first (in dogs).

 

Canasol eyedrops may be used for (1) open or closed angle glaucoma or (2) raised intraocular pressure in patients who are at sufficient risk to require the lowering of their intraocular pressure. To date no adverse effects have been reported following the use of over 90,000 phials (vials or small bottles) of sterile Canasol eyedrops.

 

Canasol is supplied in boxes of 25 phials. The solution is sterile and is contained in standard plastic eyedrop bottles (5 ml). Concentration is 0.1 percent weight/volume. It should be stored in a cool dark place. In Jamaica it is manufactured by Ampec Chemicals Limited and marketed by Medigrace Limited in Kingston.

 

References

 

Colasanti, B. 1986. Review of Ocular hypotensive effect of marihuana cannabioids: Correlate of

central action or separate phenomenon? Journal of Ocular Pharmacology 2 (3): 295-304.

Crawford, W.J. and J.C. Merritt. 1979. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. International Journal of Clinical Pharmacology and Biopharmacology 17: 191-196.

Green, K. 1979. The ocular effects of cannabinoids. In Current Topics in Eye Research, ed. J.A. Zadunaisky, 175-215. New York: Academic Press.

Gregory, D., M. Sears, L. Bausher, H. Mishima, and A. Mead. 1981. Intraocular pressure and aqueous flow are decreased by cholera toxin. Investigative Ophthalmology and Visual Science 20 (3): 371-381.

Gutierrez, A.M. and D.L. Gutierrez. 1995. Ocular hypertension treatment with Cannabis sativa. 1990 (Paper presented at the Annual Congress of Ophthamology, Cali, Columbia, August 1995).

The Harvard Medical School Health Letter Understanding glaucoma: preventing silent blindness. April 1979.4 (6): 1-2.

Hepler, R.S. and I.M. Frank. 1971. Marihuana smoking and intraocular pressure. Journal of the American Medical Association 217 (10): 1392.

Merritt, J.C., W.J. Crawford, P.C. Alexander, A.L. Anduze, and S.S. Gelbart. 1980. Effect of

marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87 (3): 222-228. Merritt, J.C., J.L. Olsen, J.R. Armstrong, and S.M. McKinnon. 1980. Topical delta-9-tetrahy-

drocannabinol in hypertensive glaucomas. Journal of Pharmacy and Pharmacology 33: 40-41. Miller, R.W. 1980. Keeping an eye on glaucoma. FDA Consumer. Rockville, MD: U.S. Depart-

ment of Health and Human Services, HHS Publication No. (FDA) 80-3105.

West, M.E. and A.B. Lockhart. 1978. The treatment of glaucoma using a non-psychoactive preparation of Cannabis sativa. West Indian Medical Journal 27 (1): 16-25.

West, M.E. and A.B. Lockhart. 1980. The synergistic effect of Canasol and timolol maleate eye drops in glaucoma patients. World Conference on Clinical Pharmacology and Therapeutics (Paper No 0100). London.