PRIMARY ANGLE-CLOSURE GLAUCOMA 419

peripheral or other iridectomy 10% phenyl-ephrine drops are favored for producing pupil dilatation and preventing posterior synechiae. In 60 such eyes no angle closure occurred but one unfavorable outcome re-sulted from a coincidence of pupil dilatation with other factors.

For eyes with shallow anterior chambers and intact irises, there is a danger in dilat-ing pupils for examinations toward the end of consulting times because the wait for subsequent miosis tends to be too short and

acute angle-closure glaucoma is likely to de-velop.

82 Collins Street (C.l).

A c KNOWLEDGMENTS

These investigations formed part of Research Project No. 14 of The Ophthalmic Research Insti-tute of Australia and Project No. 13 of the Royal Victorian Eye and Ear Hospital. They were con-ducted in the Glaucoma Unit of the Hospital where the tonographies were performed by Dr. Magda Horvat. I wish to thank my colleagues for their co-operation in permitting examination of their pa-tients and access to their records.

REFERENCES

1. Lowe, R. F. : Primary angle-closure glaucoma : Investigations after surgery for pupil block. Am. J. Ophth, 57 :931, 1964.

2. : Primary angle-closure glaucoma: Postoperative tests with 1-epinephrine base. Am. J. Ophth., 58 :S81, 1964.

3. Becker, B., Gage, T., Kolker, A. E., and Gay, A. J.: The effect of phenylephrine hydrochloride on the miotic treated eye. Am. J. Ophth.. 48 :313, 1959.

E C H O T H I O P H A T E I O D I D E *

T H E E F F E C T O F 0 . 0 6 2 5 % S O L U T I O N O N BLOOD C H O L I N E S T E R A S E

J O S E P H W . W A H L , M . D . , A N D G E O R G E S. T Y N E R , M . D .

Denver, Colorado

This study was undertaken to learn the effect of topically applied 0.0625% echothio-phate iodide (Phospholine Iodide) upon red blood cell and plasma cholinesterase. In an earlier report from this institution Hum-phreys and Holmes1 demonstrated that the topical use of 0.25% echothiophate iodide produced a significant depression of red blood cell and plasma cholinesterase levels. At the present time the 0.0625% strength of echothiophate iodide is being used clinically in the treatment of glaucoma and accommo-dative esotropia. Therefore, it seemed im-portant to determine the degree of cholines-terase depression produced by this medica-tion.

* From the Division of Ophthalmology, Depart-ment of Surgery, University of Colorado School of Medicine. The echothiophate iodide used in this study was provided through the courtesy of Camp-bell Pharmaceutical Company, New York.

In 1957 echothiophate iodide (Phospho-line Iodide) was introduced as a topical agent for the treatment of glaucoma. Later it was used for the treatment of accommo-dative esotropia. This drug belongs to the family of long-acting organic phosphorus anticholinesterase agents which include di-isopropyl-flurophosphate (Floropryl) and demecarium bromide (Humorsol).2 Echo-thiophate iodide is related to chemical com-pounds which were developed as war gases and insecticides. It is water soluble and highly stable, especially if refrigerated. It is an irreversible inhibitor of the enzyme cho-linesterase.

The normal function of cholinesterase in the body is the hydrolysis of acetylcholine which is found at all peripheral autonomie ganglia, all skeletal muscle myoneural junc-tions, all peripheral effector organs in the parasympathetic nervous system, and at the

420 J O S E P H W. W A H L A N D GEORGE S. T Y N E R

anatomic endings of sympathetic fibers in the sweat glands and certain blood vessels.3

When cholinesterase activity is inhibited, acetylcholine accumulates in body tissues and fluids ; prolonged and intense parasympathe-tic activity results.

The ocular effects of locally instilled anti-cholinesterase agents, as cited by Leopold,2

are dilatation and increased permeability of blood vessels, miosis, edema of the iris and ciliary body, intensified accommodation, fa-cilitation of the outflow mechanism, and early increase and late decrease of the intra-ocular pressure.

As with any potent drug, certain undesi-rable local as well as systemic side-effects may occur (table 1). Previous studies indi-cate that systemic toxicity occurs as a result of depression of the body cholinesterase ac-tivity secondary to absorption of anticholin-esterases through either the conjunctival or nasopharyngeal mucosa.4'15'16

There is good clinical evidence that echo-thiophate iodide is effective in the treatment of open-angle and aphakic glaucoma and ac-commodative esotropia.5·13 The drug has been used in concentrations ranging from 0.0625% to 0.25%. Local side-effects are fre-quent but rarely severe enough to interfere with therapy. An occasional patient has de-

veloped severe systemic toxicity.10 Hum-phreys and Holmes1 reported that systemic toxicity may result from topical instillation of echothiophate iodide in 0.25% concentra-tion; these authors emphasized the value of monitoring the blood cholinesterase activity as a useful guide in therapy. Klendshou and Olmstead14 recently reported several cases in which the erythrocyte cholinesterase lev-els were reduced by topical instillation of echothiophate iodide. They mentioned two patients who developed symptoms suggest-ing central nervous system toxicity as the result of cholinesterase depression. It has been the general impression that echothio-phate iodide is unable to penetrate the blood brain barrier and therefore unable to pro-duce central nervous system side-effects." Certainly, the majority of reported systemic side-effects have not been the result of cen-tral nervous system toxicity.

MATERIALS AND METHODS

Two groups of patients were observed in this clinical study. The control group con-sisted of 14 males between the ages of 35 and 76 years. Each of these patients was under treatment for tuberculosis at the Vet-erans Administration Hospital, Denver, Colorado. All but one were being treated

TABLE 1

POSSIBLE SIDE-EFFECTS FOLLOWING SYSTEMIC ABSORPTION OF ANTICHOLINESTERASE AGENTS

(Modified from Leopold2)

"Tightness in chest," wheezing, dyspnea, chest pain, cough, prolonged wheezing expiration, increased bronchial secretion, rhinorrhea

Respiratory

Gastrointestinal

Cardiovascular

Sweat, salivary & lacri-

mal glands

Genitourinary

Muscular

Central nervous system

Anorexia, nausea, vomiting, diarrhea, tenesmus, involuntary defecation, abdomi-nal cramps, epigastric and substernal discomfort, "heartburn," eructation

Bradycardia, elevated blood pressure, lowered blood pressure Increased sweating, salivation and lacrimation

Frequency, involuntary micturation

Weakness, twitching, fasciculations, cramps, easy fatiguability

Giddiness, jitteriness, restlessness, insomnia, nightmares. Emotional lability, ten-sion, anxiety, tremor, headache, apathy, depression withdrawal, drowsiness, con-fusion, difficulty concentrating, slowness of recall, E E G abnormalities; slurred speech, ataxia, weakness, convuslions, coma, areflexia, Cheyne-Stokes respiration, dyspnea, cyanosis, hypotension

ECHOTHIOPHATE IODIDE 421

with a combination of para-aminosalicylic acid, isoniazid and streptomycin. The other patient was receiving a new antituberculosis drug, 4-4'-diisoamyloxythiocarbanilide (Is-oxyl). None of the patients had any significant eye disease. Each patient was carefully interviewed regarding existing ocular and systemic symptoms. Blood sam-ples were obtained for a baseline blood cho-linesterase determination. One drop of an 0.0625% solution of echothiophate iodide was administered to each eye daily. This was continued for eight weeks in 12 patients and for six weeks in another two patients. For the first month of the study, blood cho-linesterase levels were obtained at weekly intervals. The patients were questioned about the development of any new ocular or systemic symptoms. During the second month of the study, blood cholinesterase lev-els were obtained at biweekly intervals.

The clinic group consisted of 13 patients ranging in age from 11 to 87 years. There were eight females and five males. Eleven were patients in the Eye Clinic of Colorado General Hospital and two were private pa-tients. Each of these patients had a significant eye disorder. Eleven had open-angle glaucoma. One patient had aphakic glaucoma due to peripheral anterior syne-chiae, and one patient, the only child in the study, had accommodative esotropia. As in the control group, a baseline evaluation, in-cluding blood cholinesterase determinations, was made on each patient. All previous eye medications were discontinued and each pa-tient was started on one drop of 0.0625% echothiophate iodide in each eye at bedtime. As the study progressed the frequency of instillation was increased to twice a day in those patients whose ocular tensions were uncontrolled by the bedtime dosage alone. No patient received drops more than twice daily. Each patient had a periodic evaluation including blood cholinesterase determina-tions and careful questioning concerning symptoms of toxicity. Five of the 13 pa-tients were observed for a period of less

TABLE 2

LOCAL SIDE-EFFECTS

Con- ny ■ t 1 Llmic

Group G ™ U P

(14 t u v pa-

tients) t i e n t s )

1.

2. 3. 4. 5. 6. 7. 8. 9.

10. 11.

Transient eye discomfort (burning, stinging, pain) Transient browache Transient blurring Myopic effect Severe headache, blurring Floaters, photopsia Eyelid twitch, transient No symptoms Miosis (1-2 mm) Conjunctival injection Iris cyst (no visual impairment)

ö 3 2 1 0 1 0 5

14 0 0

2 4 4 3 1 0 2 7

13 0 1

than three months. One patient was ob-served for four months, one for seven months, and six patients for a period rang-ing from 9-14 months.

All blood cholinesterase determinations were performed in the research laboratory of Dr. Joseph H. Holmes, professor of medicine at the University of Colorado School of Medicine. The method used was that of Michelle as described in a previous publication.1 Both plasma and red blood cell cholinesterase levels were determined. Ear-lier studies by Holmes have established that red blood cell cholinesterase levels are a more valid index of systemic absorption of echothiophate iodide than are plasma cholin-esterase levels. Therefore, only the RBC cholinesterase values were utilized for anal-ysis in this study. In this laboratory the normal red blood cell cholinesterase levels vary from 0.60 to 1.2 delta pH units per hour.

RESULTS

The local side-effects encountered in each group are listed in Table 2. Only one pa-tient out of both groups experienced local symptoms severe enough to warrant stop-ping the drops. This patient developed se-vere ocular pain after initial instillation of the medication ; he had never used glaucoma medication before.

422 J O S E P H W. W A H L AND GEORGE S. T Y N E R

TABLE 3

SYSTEMIC SIDE-EFFECTS

1.

2. 3. 4. 5. 6. 7. 8.

Abdominal pain with without nausea and vomi Diarrhea, weight loss Rhinorrhea Sweating Salivation None Muscle cramps (??) Central nervous system symptoms (??)

or itine

Control Group

(14 patients)

2 0 0 0 0

11 0

1

Clinic Group

(13 patients)

4 1 1 2 2 6 1

0

The systemic side-effects encountered in each group are listed in Table 3. In the con-trol group two patients developed symptoms which were interpreted as systemic toxicity ; one of these patients also developed central nervous system symptoms. It was impossi-ble to determine whether the neurologic symptoms were associated with echothio-phate iodide therapy; a neurologic evalua-tion indicated a possible ischémie episode of the sensory cortex.

The RBC cholinesterase values are corre-lated with the presence or absence of system-ic side-effects in Table 4. In the control group, 10 of the 14 patients developed an av-erage RBC cholinesterase value between 0.40 and 0.60 delta pH units. Of these 10 patients only two became symptomatic. The remaining four patients had normal cholin-esterase values ; they were asymptomatic. In the clinic group there were 10 patients whose average RBC cholinesterase value was below normal ; six of these became symptomatic. Of these six patients, two had RBC cholinesterase values between 0.40 and 0.60 delta pH units, and four had values less than 0.40 delta pH units. Three patients in the clinic group had normal cholines-terase values. One of these patients de-veloped questionable symptoms which con-sisted of transient muscular cramps in the lower extremities. The average RBC cholin-esterase value in the patients who were symptomatic was 0.49 delta pH units in the

control group and 0.39 delta pH units in the clinic group.

The relationship between duration and frequency of treatment to red blood cell cholinesterase may be summarized as fol-lows : In the control group the average RBC cholinesterase after six to eight weeks of treatment was 0.50 delta pH units in 10 pa-tients and 0.62 delta pH units in four pa-tients. In the clinic group the average RBC cholinesterase value for those patients who received the drops once daily was 0.52 delta pH units ; in those patients who received the drops twice daily the average RBC cholines-terase was 0.38 delta pH units. Seven of the 13 patients in the clinic group showed a RBC cholinesterase value below normal within one month of treatment with echo-thiophate iodide. Two other patients de-veloped low cholinesterase values within three months of therapy. Thus in nine of the 13 patients in the clinic group the cho-linesterase value became lower than normal within three months after the medication was started.

Comparative erythrocyte and plasma cho-linesterase levels before and after treat-ment with 0.0625% echothiophate iodide in the clinic group are given in Table 5. All RBC cholinesterase values are below normal in those patients who received drops for longer than two and one-half months. How-

TABLE 4

RELATIONSHIP BETWEEN RBC CHOLINESTERASE

LEVELS AND THE DEVELOPMENT OF SYSTEMIC SYMPTOMS

RBC Cholinesterase

(average values)

Control Group (14 patients)

Clinic Group (13 patients)

No. Pa-

No. Symp-

No. Pa-

No. Symp-

tients tomatic tients tomatic

1. Normal values (0.60 to 1.2 ΔρΗ units) 4

2. Decreased values a) 0 .4to0.6ApH

units 10 b) <0.4ΔρΗ

u nits 0

6 2

4 4

ECHOTHIOPHATE IODIDE 423

TABLE 5 SUMMARY OF CLINIC GROUP

Age

1. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13.

11, 70, 76, 67, 71, 83, 66, 69, 87, 72, 68, 68, 69,

(yr) Sex, Race & Diagnosis

W F accom. esotropia WF, aphakic glaucoma WF, open-angle glaucoma NF, open-angle glaucoma WF, open-angle glaucoma NF, open-angle glaucoma WM, open-angle glaucoma

NF, open-angle glaucoma WM, open-angle glaucoma WM, open-angle glaucoma WM, open-angle glaucoma

WF, open-angle glaucoma WM, open-angle glaucoma

Pre treatment Cholinesterase

Levels*

RBC

0.67 0.79 0.75 0.67 0.78 0.72 0.88 0.68 0.77 0.80 —

0.80 0.86

Plasma

1.02 0.77 0.86 0.99 0.80 0.62 1.44 0.95 0.88 — —

0.89 1.31

Cholinesterase Levels After Treatment*

(average

RBC

0.38 0.70 0.33 0.47 0.44 0.36 0.46 0.57 0.48 0.56 0.52 0.69 —

values)

Plasma

0.53 0.80 0.44 0.74 0.56 0.40 0.84 0.88 0.37 0.62 0.92 0.90 —

Dosage & Duration of Treatment

1 drop O.U. daily for 3 mo 1 drop O.U. daily for 1 mo 1 drop O.U. b.i.d. for 14 mo 1 dropO. U. daily for 1 3 | mo 1 drop O.U. b.i.d. for 13 mo 1 drop O.U. b.i.d. for 6 mo 1 drop O.U. daily for 9J mo 1 drop O.U. daily for 9§ mo 1 drop O.U. daily for 3J mo 1 drop O.U. daily for 1 | mo 1 drop O.U. daily for 13 mo 1 drop O.U. b.i.d. for 2\ mo 1 drop O.U. daily for 1 wk

* Delta pH units per hour

ever, some of the plasma cholinesterase val-ues are within the normal range even though the patients had several months of treatment.

COMMENTS

In this study, local side-effects to topical echothiophate iodide therapy were common. They occurred in nine of the 14 control pa-tients and in six of the 13 clinic patients. The increased incidence of side-effects in the control group could be partially attrib-uted to two factors. As volunteers, these pa-tients were aware of possible side-reactions and were naturally quite anxious. Secondly, these patients had not received earlier miotic therapy as had the clinic group. The intensi-ty of the local side-reactions varied a great deal ; in only one clinic patient were the symptoms severe enough to warrant discon-tinuing the treatment.

The incidence of systemic side-effects in our cases was higher than other investiga-tors have reported. This part of the study may be somewhat biased and not altogether accurate. We were looking carefully for sys-temic side-reactions and may have been guilty of creating symptoms by suggestion. However, as will be pointed out later, the occurrence of systemic reactions was related

to lowered RBC cholinesterase values, and we were unaware of these values when pa-tient interviews were conducted. It should also be mentioned that evaluation of system-ic side-effects was particularly difficult in the control group. These patients were re-ceiving antituberculosis medications, and the side-reactions to these drugs conceivably could resemble side-reactions to echothio-phate iodide. This was kept in mind when patients were interviewed, and only those symptoms which appeared to be directly as-sociated with the administration of echothio-phate iodide drops were acceptable as toxic symptoms. The lower incidence of systemic side-reactions in the control group supports the accuracy of the interviews.

Systemic side-effects occurred in three of the 14 control patients and in seven of the 13 clinic patients. Gastrointestinal symptoms were the most common disorders ; they oc-curred in two of the control patients and in four of the clinic group. Although some pa-tients developed increased sweating, saliva-tion and rhinorrhea, they did not sponta-neously complain about these symptoms but gave a history of them only when specifically questioned.

The development of systemic side-effects was associated with lowered RBC cholines-

424 JOSEPH W. WAHL AND GEORGE S. TYNER

terase levels. The depression of chohnes-terase was related to the frequency and du-ration of treatment with echothiophate io-dide. In most patients symptoms occurred when the blood chohnesterase level was below 0.4 delta pH units (table 4) . How-ever, not all of the patients with lowered RBC chohnesterase levels developed system-ic side-effects. With one possible exception none of the patients with normal chohnes-terase levels developed systemic side-effects.

The rapid systemic absorption of echo-thiophate iodide is verified by the number of patients in both groups whose chohnesterase activity was depressed to levels below nor-mal within one to three months after initia-tion of therapy (table 5). Initially both the RBC and plasma chohnesterase levels were depressed. Over a period of time the plasma chohnesterase levels returned to normal val-ues (0.6 to 1.0 delta pH units) in several patients. This interesting finding can possi-bly be explained by the fact that echothio-phate iodide primarily inhibits the true specific chohnesterase, which in blood is in the red cells. Nonspecific pseudocholines-terase is in the plasma. It is only partially inhibited by echothiophate iodide, and it is replenished by continuous formation in the liver.4·9·15

CONCLUSIONS

Despite the relatively small number of pa-tients in this study we feel that several con-clusions can be drawn :

1. Echothiophate iodide in a 0.0625% con-

centration is a potent inhibitor of the en-zyme chohnesterase both locally in the eye and systemically in the blood. This appears to be true both in patients with and without eye disease.

2. When used topically even for a rela-tively short period of time, enough systemic absorption of echothiophate iodide may occur to lower significantly blood chohnes-terase activity.

3. The decrease of RBC chohnesterase is usually proportional to the frequency of ap-plication and to the duration of treatment.

4. Systemic toxicity is not common even though RBC chohnesterase is reduced. However, when side-effects do occur the chohnesterase level is decreased significantly.

5. The reduction of RBC chohnesterase may be as great with the 0.0625% solution of echothiophate iodide as with the 0.25% solu-tion. Therefore, the same precautions apply to patients receiving the weaker strength as to patients treated with stronger concentra-tions.

Determinations of red blood cell chohnes-terase levels before and during treatment provide a method of evaluating a potential hazard to the patient with the use of echo-thiophate iodide. Patients receiving this drug should be questioned carefully at each visit to determine the presence of side-effects.

4200 East Ninth Avenue (80220).

ACKNOWLEDGMENT

We wish to thank Dr. Joseph Holmes for his valu-able assistance in this study.

REFERENCES

1. Humphreys, J. A., and Holmes, J. H. : Systemic effects produced by echothiophate iodide in treat-ment of galucoma. Am. J. Ophth., 69:737, 1963.

2. Leopold, I. H. : Ocular chohnesterase and chohnesterase inhibitors : The Friedenwald Memorial Lecture. Am. J. Ophth., 5 1 : 885/13, 1961.

3. Goodman, L. S., and Gilman, A. : The Pharmacological Basis of Therapeutics. New York, Mac-Millan, 1955, ed. 2.

4. Holmes, J. : Personal communication. 5. Schlossman, A. : Trends in ophthalmology. Newer miotics in the treatment of strabismus. E E N T

Monthly, 40 :554, 1961. 6. Leopold, I. H., Gold, P., and Gold, D.:!Use of a Thiophosphinyl quarternary compound (217-MI) in

treatment of glaucoma. Arch. Ophth., 58:363, 1957. 7. Hill, K., and Stromberg, A. E. : Echothiophate iodide in the management of esotropia. Am. J. Ophth.,

53 :488, 1962.

ECHOTHIOPHATE IODIDË 425

8. Miller, J. E. : A comparison of miotics in accomodative esotropia. Am. J. Ophth., 49:1350, 1960. 9. Krishna, N., and Leopold, I. H.: Echothiophate (Phospholine) iodide (217-MI) in treatment of

glaucoma : Further observations. Arch. Ophth., 62:300, 1959. 10. Drance, S. M., and Carr, F.: Effects of Phospholine Iodide (217-MI) on intraocular pressure in

man. Am. J. Ophth., 49 :470, 1960. 11. Lawlor, R. C, and Lee, P. F.: Use of echothiophate (Phospholine Iodide) in the treatment of

glaucoma. Am. J. Ophth., 49:808, 1960. 12. Coyle, J. T., Weiner, A., Frank, P., and Leonard, A. : The management of glaucoma in the in-

digent clinic patient with echothiophate iodide. Am. J. Ophth., 52:867-871 (Dec), 1961. Drance, S. M. : The use of the long-acting cholinesterase inhibitor Phospholine Iodide (217-MI) in the

management of chronic simple glaucoma. Tr. Ophth. Soc. U. Kingdom, 80 :387, 1960. 14. Glendshoj, N. C, and Olmsted, E. P. : Observation of dangerous side effect of Phospholine Iodide

in glaucoma therapy. Am. J. Ophth., 56:247, 1963. 15. Holmes, J. H. : Medical comments on the use of insecticides. Unpublished. 16. Kadin, M. : Systemic effects of Co-Rol and Caralox on ocular instillation in the rabbit, dog, and

human. Am. J. Ophth., 50:622, 1960.

C A R D I A C A R R E S T O C C U R R I N G I N A P A T I E N T O N E C H O T H I O P H A T E I O D I D E T H E R A P Y *

P. E. A. Hiscox , M.D., AND C L E M E N T M C C U L L O C H , M.D.

Toronto, Canada

Anticholinesterase compounds are widely used in the treatment of open-angle glauco-ma, aphakic glaucoma, and accommodative esotropia. According to their duration of action, these drugs can be classified into : (a) short acting and reversible, for exam-ple, physostigmine (eserine) and neostig-mine (prostigmine) ; (b) long-acting and irreversible, for example, di-isopro-pylfktorphosphate ( D F P ) , echothiophate iodide (Phospholine Iodide) and demecari-um bromide (Humorso l ) .

Those agents in the second group have the advantage that they do not require fre-quent instillations to maintain their desired action. They exert their effect through the inhibition of the enzyme cholinesterase, thereby preventing rapid inactivation of ace-tylcholine. This occurs at the neuromuscular junctions and synapses throughout the cen-tral and peripheral nervous systems. Acetyl-choline accumulates, then exerts its muscar-inic action on the heart, smooth muscle and secretory glands, and its nicotinic action on skeletal muscle and autonomie ganglia.

* From the Department of Ophthalmology, Fac-ulty of Medicine, University of Toronto.

There are two types of human cholines-terases : (a) true, or acetylcholinesterase, which is present in the red blood cells, cen-tral nervous system, muscle and motor end-plate, and (b) pseudocholinesterase, found in the plasma and various tissues.

Anticholinesterase drugs may react with both types of enzymes but it is the inhibi-tion of acetylcholinesterase that may result in toxic symptoms and signs. Repeated small exposures to anticholinesterase sub-stances may depress the acetylcholinesterase level considerably without producing clinical evidence of toxicity. However, symptoms may occur following single large doses with-out significant enzyme inhibition.

I t has been shown that there exists no significant difference in the mean values of red blood cell cholinesterase levels of normal and glaucomatous individuals. Certain anti-cholinesterases instilled in the eye may be sufficiently absorbed so as to affect the blood cholinesterase levels. Leopold et al3 found red blood cell and plasma cholinesterase de-pression in glaucomatous patients on Phos-pholine Iodide and on Humorsol therapy for over two months.

In a study of 24 patients with glaucoma