- Email: [email protected]
Use of BC-48 (Demecarium Bromide) in Treatment of Glaucoma*
554
P H I L I P G. SPAETH AND PATRICIA M. O'NEILL
fusion in a large percentage of cases. T o overcome the problem takes a lot of effort, but the functional and, therefore, cosmetic results are good. I t is necessary to institute early treatment if the desired result of first-,
second-, or third-degree fusion is to be ob tained. T h e use of corrective contact lenses gives most satisfactory results. 1930 Chestnut
Street
(3).
REFERENCES
1. Goar, E. L.: The management of monocular cataracts. A.M.A. Arch. Ophth., 54:73 (July) 1955. 2. Little, M. F.: Treatment of unilateral cataract with contact glasses. Arch. Ophth., 11:446 (Apr.) 1934. 3. Town, A. E.: Contact glasses for correction of refractive errors in monocular aphakia: Production of single binocular vision. Arch. Ophth., 21:1021 (June) 1939. 4. Rockwell, P. A.: The correction of the refractive error in uniocular aphakia. Thesis-U. Pa. Grad. School Med., 1952. 5. Gettes, B. C, and Ravdin, E. M.: Monocular aphakia and exotropia corrected by contact lens. Am. J. Ophth., 38:850 (June) 1949. 6. Spaeth, E. B.: Treatment of monocular aphakia. Tr. Ophth. Soc. U. Kingdom, 77:517-532, 1957. 7. Goar, E. L.: Contact lens in monocular aphakia. A.M.A. Arch. Ophth., 57:417 (Sept.) 1957. 8. : Monocular cataracts: Management. Sect. Ophth. A.M.A., 1955. 9. Constantine, E. F., and McLean, J. M.: Contact lens in aphakia. A.M.A. Arch. Ophth., 51:212 (Feb.) 1954. 10. Scobee, R. G. : The Ocular Rotary Muscles. St. Louis, Mosby, 1952, ed. 2. 11. Cowan, A.: Refraction of the Eye. Lea, Philadelphia, 1948, ed. 3. 12. Gesell: Vision: Its Development in Infant and Child. New York, Hoeber, 1949. 13. Duke-Elder, W. S.: Text Book of Ophthalmology. St. Louis, Mosby, 1942, v. 2, p. 1375. 14. Bennett, A. G: Optics of Contact Lens. London, A. Dispensing Opticians, 1956, ed. 2. 15. Ames, A., et al.: Size and shape of ocular images. Arch. Ophth., 7:576 (June) 1932. 16. Lyle, K. : Personal communication.
USE OF BC-48 (DEMECARIUM BROMIDE) IN TREATMENT OF GLAUCOMA* NARENDRA KRISHNA,* M.B. New Delhi, India AND IRVING H .
LEOPOLD,
M.D.
Philadelphia, Pennsylvania INTRODUCTION
Anticholinesterase agents are of value in the treatment of glaucoma. Several cholinesterase inhibitors have been tried in its * From the Department of Ophthalmology, Grad uate School of Medicine of the University of Penn sylvania and the Research and Clinical Departments of the Wills Eye Hospital. Presented in part at the Eastern Section meeting of the Association for Research in Ophthalmology, New York UniversityBellevue Medical Center, New York, November 21, 1958. BC-48 used in this study was provided by Merck, Sharp & Dohme, Research Laboratories, Division of Merck & Co., Inc., West Point, Penn sylvania through the courtesy of Dr. Edmund W. J. DeMaar. Trade name: Humorsol. ♦ Fight for Sight research fellow of the National Council to Combat Blindness, Inc., New York.
management from time to time. A m o n g the short acting cholinesterase inactivators physostigmine (eserine, introduced by L a q u e u r ) and neostigmine (prostigmine, introduced by Rossi) are the drugs of choice. Of the long-acting cholinesterase inactivators D F P (Floropryl, introduced by Leopold and Comr o e ) , T E E P (tetraethylpyrophosphate, in troduced by G r a n t ) , Bayer E 6 0 0 (Mintacol, introduced by Thiel, and Glees and Wustenb u r g ) have so far been the most popular agents, and 217-MI (echothiophate, phospholine iodide, introduced by Leopold, Gold and Gold) promises to be a very use ful agent. BC-48 (demecarium bromide, in troduced by Gittler and Pillât) a new long-
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USE OF BC-48 acting cholinesterase inhibitor forms the sub ject of the present study. BC-48 (generic name: demecarium bro mide; chemical name: decamethylene bis [Nmethylcarbaminoyl - m - trimethylammoniumphenol bromide] ) is the most powerful of the synthetic cholinesterase inhibitors be longing to the group polymethylene-bis-(Nmethylcarbaminoyl - m - trimethylammoniumphenols, Kraupp, Stumpf, Herzfeld and Pillât; Kraupp, Schwarzacher and Stumpf). It combines with true or specific cholines terase mainly and readily (Herzfeld and Stumpf; Leopold, Krishna and Lehman). In addition it possesses certain inherent muscarinic properties by virtue of being a quaternary ammonium compound (Pillât, Stumpf, Gittler and Pommer). It is soluble in water and is stable for indefinite periods under ordinary conditions (Gittler and Pil lât). Gittler and Pillât, and Krishna and Leo pold have shown that in normal rabbits and human eyes BC-48 produces rapid, marked and prolonged miosis accompanied by con gestion of the eye, spasm of accommodation and ciliary pain. Miosis of BC-48 is easily abolished by atropine and homatropine. Mio sis is easily induced by BC-48 in atropinized and homatropinized eyes. BC-48 produces lowering of intraocular pressure and increase in the coefficient of aqueous outflow facility after one local application to normal eyes which last for several days (occasionally some eyes show a rise in intraocular pres sure). No permanent damage has been de tected in the eyes treated to date. BC-48 in duces some systemic muscarinic and nicotinic effects in some normal human subjects and rabbits, when instilled locally into the eyes. Physostigmine when given first does not block the action of BC-48 in normal rabbits. Gittler and Pillat's study on the use of BC-48. in the treatment of glaucoma was confined to its use for a period of less than two weeks in the majority of cases. In their study only one strength of BC-48,
that is, one-percent aqueous solution was em ployed. Miller, Divert and Crouzet utilized only 0.5-percent concentration of BC-48. Gougnard studied the tension-lowering effect of BC-48 after a 24-hour period in a very small series of glaucoma cases when em ployed in the strength of 0.1 to O.S-percent solution. Consequently the present investiga tion was undertaken to determine the efficacy of BC-48 when observed in a larger series, for a longer period of time and employing various concentrations. METHODS
Materials. A total of 106 glaucomatous eyes of 59 patients were tested with BC-48 during a period of six months. These cases were picked at random, regardless of the type of glaucoma, from the clinics of Wills Eye Hospital. Included in this series are also six eyes of three cases with angle-closure glaucoma (acute and subacute) from pri vate practice. All of them were treated with the usual antiglaucoma agents prior to the use of BC-48. Aqueous solution of the compound BC-48 was employed. The solution was kept at ordinary room temperature. The concentra tions employed were 0.1, 0.25, and 0.5 per cent and the frequency of instillation varied from twice a week to twice daily. An attempt was made to use the weakest concentration of BC-48 which when used alone as infre quently as possible would control the intra ocular pressure. In some eyes with chronic wide-angle glaucoma acetazolamide (Diamox) 125 mg. to 250 mg. two to four times a day orally was used in addition, if BC-48 alone failed to control intraocular pressure. The clinic visits varied from twice a week to every two weeks. A small percentage of cases were hospitalized and later on followed in the outpatient clinic. On each clinic visit ocular tensions were measured with Schi^tz tonometer and visual acuities recorded with Snellen's charts. Visual fields both periph eral and central were checked at regular in tervals with perimeter and one-meter tangent
NARENDRA KRISHNA AND IRVING H. LEOPOLD
SS6
screen respectively. Gonioscopic examina tions were done at periodic intervals using the Koeppe lens, Barkan hand illuminator and the Goldmann biomicroscopic head. Re peated tonographic tracings were obtained, using the Mueller electronic tonometer con nected to a Leeds and Northrup recorder. Ophthalmoscopic and biomicroscopic ex aminations were done at repeated intervals. Based on these examinations, a case was considered to be controlled, which for a mini mum period of four months showed: con sistently lower tensions which never exceded 25 mm. Hg (Schi^tz) ; no loss of vis ual acuities which could be explained on the basis of glaucoma; no further loss of visual fields; no new peripheral anterior synechias or goniosynechia formation ; increase in the coefficient of aqueous outflow facility above 0.16 cu. mm./min./mm. Hg or a definite increase as compared to the original value; no further increase in glaucomatous cup ping; no complications such as retinal de tachment, iris cysts, synechias, atrophy and corneal epithelial bullae or corneal edema. Cases which did not fulfill these criteria or in which therapy had to be discontinued be cause of local or systemic side-effects were classified as uncontrolled. Patients who re fused medication after one to three days merely because of the symptoms of ciliary spasm were not included.
TABLE 1 T Y P E S OF GLAUCOMA TREATED WITH BC-48 (DEMECAMUM BROMIDE)
Type of Glaucoma
Number of Eyes
1. Open-angle a. Noncongestive b. Congestive c. (Absolute)*
80
2. Angle-closure a. Acute b. Subacute c. (Absolute) f
20
75 5 (6) 6 14 (1)
3. Secondary a. Aphakia b. Uveitis
6
4 2
106
TOTAL
* Included in the noncongestive group of openangle type. t Included in the subacute group of angle-closure type. RESULTS
Table 1 summarizes the types of glaucoma treated with BC-48. Of the total of 106 eyes, 80 eyes had open-angle type, 20 angle-closure type, and six secondary type of glaucoma. Table 2 summarizes the results on these 106 eyes. Favorable results were obtained when BC-48 therapy was employed (87 con trolled and 19 uncontrolled) compared with previous therapy (49 controlled and 57 un controlled) in all types of glaucoma. Table 3 shows the duration in months for
TABLE 2 SUMMARY OF RESULTS ON 106 EYES
Type of Glaucoma
Controlled on Pre vious Therapy (No. of eyes)
Open-angle Noncongestive Congestive (Absolute)
41 1 (2)
Angle-closure Acute Subacute (Absolute)
0 4 (0)
Secondary Aphakia Uveitis
2 1
TOTAL
42
4
3
49
Uncontrolled on Previous Therapy (No. of eyes) 34 4 (4) 6 10 (1) 2 1
38
16
3
57
Controlled on BC48 Therapy (No. of eyes) 60 5 (4) 3 14 (1) 3 2
65
17
5
87
Uncontrolled on BC-48 Therapy (No. of eyes) 15 0 (2) 3 0 (0) 1 0
15
3
1
19
557
USE OF BC-48 TABLE 3 DURATION OF BC-48 (DEMECARIUM BROMIDE) THERAPY
Number of Months Number of Eyes Controlled 4 4-5 5-6 6-7 7-8
34 17 9 14 13
TOTAL
87
which 87 eyes were controlled successfully on BC-48 therapy. Table 4 compares the dosage of BC-48 therapy and previous therapy in the same controlled eyes which total 49. In all except two eyes the glaucoma was controlled on BC48 alone. These two eyes needed acetazolamide (Diamox) in addition to bring them under control. The use of BC-48 alone, its lower concentrations and the relative infrequency of instillation are in marked contrast to the combined use of various antiglaucoma agents, their greater concentrations and the more frequent instillations required to bring about the control of glaucoma in the same eyes. Table 5 records the effect of BC-48 ther apy on the facility of aqueous outflow of some of these glaucomatous eyes. In most of the eyes where intraocular pressure was brought under control there was an increase in the coefficient of aqueous outflow facility.
In some there was an actual embarrassment in the outflow facility within the first few hours. In two eyes which were controlled on previous therapy and not on BC-48 ther apy, there was an actual decrease in the coefficient of aqueous outflow with the coin cident increase in intraocular pressure. There were 19 eyes uncontrolled on BC48. These included two eyes in which there was an actual increase in intraocular pres sure with BC-48 which were otherwise con trolled on previous therapy. One eye of a patient with bilateral chronic narrow-angle glaucoma, developed corneal edema during the course of BC-48 therapy though the pressure had not risen ; the edema cleared on cessation of BC-48 therapy and after a basal iridectomy. The other eye of the same pa tient was well controlled on BC-48 therapy without any local side-effects. One glaucoma subject developed nausea, vomiting and diar rhea after one single instillation in each eye and the BC-48 therapy was discontinued; there were two eyes of another glaucoma pa tient in whom BC-48 had to be discontinued because of difficulty in breathing, feeling of constriction of chest and sinking sensation in the precordium after one single instilla tion. This patient gave a history of bronchial asthma. The majority of patients complained of browache, headache, pain localized in the globe and transient blurring of vision, which
TABLE 4 COMPARISON OF DOSAGE OF BC-48 (DEMECARIUM BROMIDE) THERAPY AND OTHER
GLAUCOMA THERAPY IN THE SAME CONTROLLED EYES
No. of Eyes 12 13 3 2 3 3 13
Previous Therapy
BC-48 Therapy
Pilocarpine 1% tid-qid Pilocarpine 2% tid-qid Carcholine 1.5% tid-qid DFP 0.05-0.1% od-bid 217-MI 0.1-0.25% od-bid (Pilocarpine 3 % tid-qid+ Physostigmine 0.5% tid-qid + Diamox 125 mg.-250 mg. bid-qid) (Pilocarpine 4% tid-qid+ Physostigmine 0.5% tid-qid+ Diamox 125 mg-250 mg. bid-qid)
0 . 1 % twice a week, once daily 0. l%-0.25% twice a week-bid 0 . 1 % twice a week, once daily 0 . 1 % twice a week, alternate days 0 . 1 % twice a week, alternate days 0.25%, once daily, bid 0.25-0.5%, once daily, bid*
49 (TOTAL)
* Diamox (125 mg.) bid in addition to 0.25% BC-48 bid in two eyes.
NARENDRA KRISHNA AND IRVING H. LEOPOLD
558
TABLE 5 EFFECT OF BC-48 (DEMECARIUM BROMIDE) THERAPY ON THE FACILITY OF AQUEOUS OUTFLOW OF GLAUCOMATOUS EYES
Patient
Coefficient of aqueous outflow facility in mm./min./mm.Hg
Time
1. M.C.
No medication for 60 hr. 2 hr. after continuation of BC-48 therapy
O.D. 0.13 0.17
O.S. 0.10 0.17
2. W.B.
No medication for 48 hr. 2 hr. after continuation of BC-48 therapy
0.13 0.15
0.14 0.15
3. J.M.
No medication for 6 hr. 6 hr. after continuation of BC-48 therapy
0.13 0.13
0.09 0.11
4. E.M.
No medication for 36 hr. 24 hr. after continuation of BC-48 therapy
0.07 0.10
0.09 0.17
5. A.C.
No medication for 24 hr. 23 hr. after continuation of BC-48 therapy
0.27 0.26
0.13 0.16
6. N.T.
No medication for 36 hr. 68 hr. after continuation of BC-48 therapy
0.05 0.04
0.07 0.14
7. A.F.
No medication for 48 hr. 68 hr. after continuation of BC-48 therapy
0.07 0.11
0.09 0.10
8. D.I.
No medication for 24 hr. 24 hr. after continuation of BC-48 therapy
0.10 0.19
0.08 0.19
9. D.N.
No medication for 8 hr. 24 hr. after continuation of BC-48 therapy
0.07 0.10
0.03 0.05
10. H.D.
No medication for 24 hr. 3 hr. after continuation of BC-48 therapy
0.05 0.07
0.08 0.08
11. L.T.
No medication for 48 hr. 2 hr. after continuation of BC-48 therapy
0.04 0.08
0.06 0.07
12. I.T.
No medication for 48 hr. 3 hr. after continuation of BC-48 therapy
0.13 0.06
0.09 0.09
lasted for two to three days after instituting BC-48 therapy. Conjunctival injection both superficial and deep persisted for a few days initially and then gradually subsided. The incidence of these symptoms was higher in patients who had formerly employed pilocarpine alone in contrast to those who had been using an anticholinesterase agent in addition. All these symptoms disappeared a few days after continued BC-48 adminis tration. There has been no incidence of iris cysts, retinal detachment, local sensitivity reaction, follicular conjunctivitis or iritis in the present series. CONCLUSIONS
The present study confirms the findings of Gittler and Pillât, Gougnard, and Miller,
Divert and Crouzet that BC-48 is an effec tive agent in the control of glaucoma. It ap pears to control intraocular pressure even in eyes uncontrolled on conventional glaucoma therapy. Regarding its evaluation as an ideal anti cholinesterase agent in ophthalmology accord ing to the criteria laid down by Krishna and Leopold in the evaluation of echothiophate (phospholine iodide) (217-MI) it possesses the following distinct advantages: 1. BC-48 is a potent, long-acting cholinesterase inhibitor with great intensity and duration of action. Concentrations of 0.1, 0.25 and 0.5 percent, used as little as twice weekly to twice a day, control intraoculat pressure in eyes with various stages and types of glaucoma. It offers the distinct advantage
USE OF BC-48 of infrequent instillations and reduction of the diurnal fluctuations. It eliminates the undesirable need of administration of ther apy during the sleeping hours. 2. BC-48 is readily soluble in aqueous solution. It is indefinitely stable under or dinary conditions and does not deteriorate at room temperature. Thus it offers the advan tage of easy storage and freedom from sen sitivity reaction due to the vehicle employed in dispensing some anticholinesterase inhibi tors. 3. BC-48 seems to be synergistic with other anticholinesterase agents and unlike D F P or 217-MI, its action is not blocked when eserine is given first. Thus it has the advantage that good results may be ex pected even when other anticholinesterase agents have been used previously in the same eye.* •BC-48 however possesses certain disad vantages. 1. Locally it produces undesirable symp toms of spasm of accommodation, ciliary pain and vasodilation in most instances, which gradually disappear. In some eyes it may cause paradoxical rise of tension. 2. Systemically it produces certain unde sirable muscarinic and nicotinic actions. Thus BC-48 is by no means an ideal anti cholinesterase agent. But by virtue of cer tain advantages that it offers, it appears to be a useful cholinesterase inhibitor in the control of glaucoma. Based on the present study the following conclusions may be made: 1. As low concentrations as will effectively control the intraocular pressure should be utilized. This should tend to reduce systemic toxicity. 2. Frequency of instillations should be de
559
termined according to the individual cases. In no case should it exceed more than twice a day. 3. It may be combined with other anti cholinesterase inhibitors where BC-48 alone or the other anticholinesterase agents fail to bring down the tension. 4. It should be used with caution in angleclosure glaucoma. 5. It should be used with caution where parasympathomimetic agents are contraindicated, namely marked vagotonia, vasomotor instability, bronchial asthma, spastic gastro intestinal disturbances, hypotension, myocardial infarction, epilepsy, Parkinsonism. SUMMARY
BC-48 (demecarium bromide) a very po tent long-acting anticholinesterase agent is described. Its use in the control of glaucoma using 0.1, 0.25 and 0.5-percent in aqueous solutions, twice weekly to twice a day in 106 glaucomatous eyes is discussed. Favor able results in 87 eyes with various types of glaucoma with BC-48 therapy are reported. The advantages and disadvantages of this new anticholinesterase inhibitor are dis cussed. 1601 Spring Garden Street (SO). ACKNOWLEDGMENT
We gratefully acknowledge the help of Miss Gretchen Egeressy in the tonographic studies and of Mrs. Gertrude Wood in the follow-up of the clinic patients. * This observation is based on our experimental data on rabbit eyes and has been confirmed in two cases of acute glaucoma where tension could be brought under control only after the addition of BC-48, a course of mecholyl and prostigmine fol lowed by pilocarpine and physostigmine along with Diamox having been tried before without any beneficial results. These observations are at variance with those of Gittler and Pillât and need further evaluation.
REFERENCES
1. Gittler, R., and Pillât, B.: Die Verwendung von Dekamethylen-bis-(N-methyl-Carbaminoyl-mTrimethylammoniumphenol) (BC-48) bei der thérapie des glaukoms. Arch. f. Ophth., 157:473, 1956. 2. Glees, M., and Wustenberg, W.: Ueber Erfahrungen mit Mintacol am normalen und glaukonkranhen aug. Klin. Monatsbl. f. Augenh., 114:455, 1959. 3. Gougnard, L. : Le traitaient de l'hypertension oculaire par le bromure de decamethylene-bis-N-methylCarbaminoyl-4-trimethylammonium phenol (BC-48). Bull. Soc. Belge ophtal., 1957, No. 116, p. 411.
560
NARENDRA KRISHNA AND IRVING H. LEOPOLD
4. Grant, W. M.: Miotic and antiglaucomatous activity of tetraethylpyrophosphate in human eyes. Arch. Ophth., 39:579,1948. 5. Herzfeld, E., and Stumpf, G: Untersuchungen über die cholinesterasehemmwirkung der Polymethylene-bis-(N-methyl-Carbaminoyl-m-Trimethylammoniumphenol). Arch, internat. Pharmacodyn., 107: 33, 1956. 6. Kraupp, O., Schwarzacher, H. G., and Stumpf, G: Ueber die pharmakologischen Eigenschaften einiger Polymethylene-bis-(Carbaminoyl-m-Trimethylammoniumphenole). Arch, exper. Path. U. Pharmakol., 225:117, 1955. 7. Kraupp, O., Stumpf, C, Herzfeld, E., and Pillât, B.: Pharmakologische Eigenschaften einiger langwirksamer cholinesterase-Hemmkorper aus der Reihe der Polymethylene-bis-(Carbaminoyl-mTrimethylammoniumphenole). Arch. Internat. Pharmacodyn., 102:281, 1955. 8. Krishna, N., and Leopold, I. H.: Phospholine iodide or echothiophate iodide (217-MI) in treatment of glaucoma: Further observations. Arch. Ophth., in press. 9. Krishna, N. and Leopold, I. H.: The effect of BC-48 (demecarium bromide) on normal rabbit and human eyes. Am. J. Ophth., in press. 10. Leopold, I. H., Krishna, N., and Lehman, R. A.: The effects of anticholinesterase agents on the blood cholinesterases levels of normal and glaucoma subjects. Tr. Am. Ophth. Soc, 57:1959. 11. Laqueur: Ueber eine neue therapeutische Verwendung des Physostigmins, Centralbl. f. d. med. Wissensch., 1876, No. 24, p. 421. 12. Leopold, I. H., and Comroe, J. H.: Use of Di-isopropyl fluorophosphate (DFP) in treatment of glaucoma. Arch. Ophth., 36:1, 1946. 13. Leopold, I. H., Gold, P., and Gold, D.: Use of the thiophosphinyl quaternary compound (217-MI) in treatment of glaucoma. Arch. Ophth., 58:363, 1957. 14. Miller, H. A., Divert, J., and Crouzet, j . : Le bromure de decamethylene bis neostigmine (BC-48) dans le traitement des hypertonies oculaires. Bull. Soc. franc, ophthal., 70:518, 1957. 15. Pillât, B., Stumpf, G, Gittler, R., and Pommer, H.: Permeabilitatsveranderungen durch Dekamethylylen-bis-(N-Methyl-Carbaminoyl-m-Trimethylammoniumphenol) (BC-48), Arch, internat. Pharmacodyn., 108:481, 1956. 16. Rossi, G.: Azione sull'occhio di un nuovo formace sintetico simile la prostigmina. Arch. Ottal., 42: 341 1935. 17. Thiel, H. L.: Klin. Monatsbl. f. Augenh., 114:454, 1949.
THE PATHOGENESIS AND PATHOLOGY OF OCULAR ONCHOCERCIASIS PART IV. F.
C.
THE
RODGER,
PATHOLOGY
M.D.,
M.CHIR.
Oxford, England T h e pathology of every ocular manifesta tion attributed to onchocerciasis is given here and this section contains microscopic proof of my claim that the posterior segmental lesions are of two types. T h e following are the conditions de scribed: 1. " B u n g " eye 2. Limbitis 3. Superficial punctate keratitis 4. Sclerosing keratitis 5. Anterior uveitis 6. Posterior uveitis 7. Chorioretinal degeneration (the poste
rior degenerative lesion of onchocercia sis) 8. Optic atrophy 1. " B U N G " EYE
This colorful descriptive term was coined by Owen and Henessey 1 2 to describe a (per manent) swelling of the upper lids com monly found in association with ocular on chocerciasis. T h e usual explanation of the phenomenon has been that edema is the cause. Macroscopically there is edema of the dermis in which many engorged vessels are present. T h e subcutaneous tissue, however,
P H I L I P G. SPAETH AND PATRICIA M. O'NEILL
fusion in a large percentage of cases. T o overcome the problem takes a lot of effort, but the functional and, therefore, cosmetic results are good. I t is necessary to institute early treatment if the desired result of first-,
second-, or third-degree fusion is to be ob tained. T h e use of corrective contact lenses gives most satisfactory results. 1930 Chestnut
Street
(3).
REFERENCES
1. Goar, E. L.: The management of monocular cataracts. A.M.A. Arch. Ophth., 54:73 (July) 1955. 2. Little, M. F.: Treatment of unilateral cataract with contact glasses. Arch. Ophth., 11:446 (Apr.) 1934. 3. Town, A. E.: Contact glasses for correction of refractive errors in monocular aphakia: Production of single binocular vision. Arch. Ophth., 21:1021 (June) 1939. 4. Rockwell, P. A.: The correction of the refractive error in uniocular aphakia. Thesis-U. Pa. Grad. School Med., 1952. 5. Gettes, B. C, and Ravdin, E. M.: Monocular aphakia and exotropia corrected by contact lens. Am. J. Ophth., 38:850 (June) 1949. 6. Spaeth, E. B.: Treatment of monocular aphakia. Tr. Ophth. Soc. U. Kingdom, 77:517-532, 1957. 7. Goar, E. L.: Contact lens in monocular aphakia. A.M.A. Arch. Ophth., 57:417 (Sept.) 1957. 8. : Monocular cataracts: Management. Sect. Ophth. A.M.A., 1955. 9. Constantine, E. F., and McLean, J. M.: Contact lens in aphakia. A.M.A. Arch. Ophth., 51:212 (Feb.) 1954. 10. Scobee, R. G. : The Ocular Rotary Muscles. St. Louis, Mosby, 1952, ed. 2. 11. Cowan, A.: Refraction of the Eye. Lea, Philadelphia, 1948, ed. 3. 12. Gesell: Vision: Its Development in Infant and Child. New York, Hoeber, 1949. 13. Duke-Elder, W. S.: Text Book of Ophthalmology. St. Louis, Mosby, 1942, v. 2, p. 1375. 14. Bennett, A. G: Optics of Contact Lens. London, A. Dispensing Opticians, 1956, ed. 2. 15. Ames, A., et al.: Size and shape of ocular images. Arch. Ophth., 7:576 (June) 1932. 16. Lyle, K. : Personal communication.
USE OF BC-48 (DEMECARIUM BROMIDE) IN TREATMENT OF GLAUCOMA* NARENDRA KRISHNA,* M.B. New Delhi, India AND IRVING H .
LEOPOLD,
M.D.
Philadelphia, Pennsylvania INTRODUCTION
Anticholinesterase agents are of value in the treatment of glaucoma. Several cholinesterase inhibitors have been tried in its * From the Department of Ophthalmology, Grad uate School of Medicine of the University of Penn sylvania and the Research and Clinical Departments of the Wills Eye Hospital. Presented in part at the Eastern Section meeting of the Association for Research in Ophthalmology, New York UniversityBellevue Medical Center, New York, November 21, 1958. BC-48 used in this study was provided by Merck, Sharp & Dohme, Research Laboratories, Division of Merck & Co., Inc., West Point, Penn sylvania through the courtesy of Dr. Edmund W. J. DeMaar. Trade name: Humorsol. ♦ Fight for Sight research fellow of the National Council to Combat Blindness, Inc., New York.
management from time to time. A m o n g the short acting cholinesterase inactivators physostigmine (eserine, introduced by L a q u e u r ) and neostigmine (prostigmine, introduced by Rossi) are the drugs of choice. Of the long-acting cholinesterase inactivators D F P (Floropryl, introduced by Leopold and Comr o e ) , T E E P (tetraethylpyrophosphate, in troduced by G r a n t ) , Bayer E 6 0 0 (Mintacol, introduced by Thiel, and Glees and Wustenb u r g ) have so far been the most popular agents, and 217-MI (echothiophate, phospholine iodide, introduced by Leopold, Gold and Gold) promises to be a very use ful agent. BC-48 (demecarium bromide, in troduced by Gittler and Pillât) a new long-
S5S
USE OF BC-48 acting cholinesterase inhibitor forms the sub ject of the present study. BC-48 (generic name: demecarium bro mide; chemical name: decamethylene bis [Nmethylcarbaminoyl - m - trimethylammoniumphenol bromide] ) is the most powerful of the synthetic cholinesterase inhibitors be longing to the group polymethylene-bis-(Nmethylcarbaminoyl - m - trimethylammoniumphenols, Kraupp, Stumpf, Herzfeld and Pillât; Kraupp, Schwarzacher and Stumpf). It combines with true or specific cholines terase mainly and readily (Herzfeld and Stumpf; Leopold, Krishna and Lehman). In addition it possesses certain inherent muscarinic properties by virtue of being a quaternary ammonium compound (Pillât, Stumpf, Gittler and Pommer). It is soluble in water and is stable for indefinite periods under ordinary conditions (Gittler and Pil lât). Gittler and Pillât, and Krishna and Leo pold have shown that in normal rabbits and human eyes BC-48 produces rapid, marked and prolonged miosis accompanied by con gestion of the eye, spasm of accommodation and ciliary pain. Miosis of BC-48 is easily abolished by atropine and homatropine. Mio sis is easily induced by BC-48 in atropinized and homatropinized eyes. BC-48 produces lowering of intraocular pressure and increase in the coefficient of aqueous outflow facility after one local application to normal eyes which last for several days (occasionally some eyes show a rise in intraocular pres sure). No permanent damage has been de tected in the eyes treated to date. BC-48 in duces some systemic muscarinic and nicotinic effects in some normal human subjects and rabbits, when instilled locally into the eyes. Physostigmine when given first does not block the action of BC-48 in normal rabbits. Gittler and Pillat's study on the use of BC-48. in the treatment of glaucoma was confined to its use for a period of less than two weeks in the majority of cases. In their study only one strength of BC-48,
that is, one-percent aqueous solution was em ployed. Miller, Divert and Crouzet utilized only 0.5-percent concentration of BC-48. Gougnard studied the tension-lowering effect of BC-48 after a 24-hour period in a very small series of glaucoma cases when em ployed in the strength of 0.1 to O.S-percent solution. Consequently the present investiga tion was undertaken to determine the efficacy of BC-48 when observed in a larger series, for a longer period of time and employing various concentrations. METHODS
Materials. A total of 106 glaucomatous eyes of 59 patients were tested with BC-48 during a period of six months. These cases were picked at random, regardless of the type of glaucoma, from the clinics of Wills Eye Hospital. Included in this series are also six eyes of three cases with angle-closure glaucoma (acute and subacute) from pri vate practice. All of them were treated with the usual antiglaucoma agents prior to the use of BC-48. Aqueous solution of the compound BC-48 was employed. The solution was kept at ordinary room temperature. The concentra tions employed were 0.1, 0.25, and 0.5 per cent and the frequency of instillation varied from twice a week to twice daily. An attempt was made to use the weakest concentration of BC-48 which when used alone as infre quently as possible would control the intra ocular pressure. In some eyes with chronic wide-angle glaucoma acetazolamide (Diamox) 125 mg. to 250 mg. two to four times a day orally was used in addition, if BC-48 alone failed to control intraocular pressure. The clinic visits varied from twice a week to every two weeks. A small percentage of cases were hospitalized and later on followed in the outpatient clinic. On each clinic visit ocular tensions were measured with Schi^tz tonometer and visual acuities recorded with Snellen's charts. Visual fields both periph eral and central were checked at regular in tervals with perimeter and one-meter tangent
NARENDRA KRISHNA AND IRVING H. LEOPOLD
SS6
screen respectively. Gonioscopic examina tions were done at periodic intervals using the Koeppe lens, Barkan hand illuminator and the Goldmann biomicroscopic head. Re peated tonographic tracings were obtained, using the Mueller electronic tonometer con nected to a Leeds and Northrup recorder. Ophthalmoscopic and biomicroscopic ex aminations were done at repeated intervals. Based on these examinations, a case was considered to be controlled, which for a mini mum period of four months showed: con sistently lower tensions which never exceded 25 mm. Hg (Schi^tz) ; no loss of vis ual acuities which could be explained on the basis of glaucoma; no further loss of visual fields; no new peripheral anterior synechias or goniosynechia formation ; increase in the coefficient of aqueous outflow facility above 0.16 cu. mm./min./mm. Hg or a definite increase as compared to the original value; no further increase in glaucomatous cup ping; no complications such as retinal de tachment, iris cysts, synechias, atrophy and corneal epithelial bullae or corneal edema. Cases which did not fulfill these criteria or in which therapy had to be discontinued be cause of local or systemic side-effects were classified as uncontrolled. Patients who re fused medication after one to three days merely because of the symptoms of ciliary spasm were not included.
TABLE 1 T Y P E S OF GLAUCOMA TREATED WITH BC-48 (DEMECAMUM BROMIDE)
Type of Glaucoma
Number of Eyes
1. Open-angle a. Noncongestive b. Congestive c. (Absolute)*
80
2. Angle-closure a. Acute b. Subacute c. (Absolute) f
20
75 5 (6) 6 14 (1)
3. Secondary a. Aphakia b. Uveitis
6
4 2
106
TOTAL
* Included in the noncongestive group of openangle type. t Included in the subacute group of angle-closure type. RESULTS
Table 1 summarizes the types of glaucoma treated with BC-48. Of the total of 106 eyes, 80 eyes had open-angle type, 20 angle-closure type, and six secondary type of glaucoma. Table 2 summarizes the results on these 106 eyes. Favorable results were obtained when BC-48 therapy was employed (87 con trolled and 19 uncontrolled) compared with previous therapy (49 controlled and 57 un controlled) in all types of glaucoma. Table 3 shows the duration in months for
TABLE 2 SUMMARY OF RESULTS ON 106 EYES
Type of Glaucoma
Controlled on Pre vious Therapy (No. of eyes)
Open-angle Noncongestive Congestive (Absolute)
41 1 (2)
Angle-closure Acute Subacute (Absolute)
0 4 (0)
Secondary Aphakia Uveitis
2 1
TOTAL
42
4
3
49
Uncontrolled on Previous Therapy (No. of eyes) 34 4 (4) 6 10 (1) 2 1
38
16
3
57
Controlled on BC48 Therapy (No. of eyes) 60 5 (4) 3 14 (1) 3 2
65
17
5
87
Uncontrolled on BC-48 Therapy (No. of eyes) 15 0 (2) 3 0 (0) 1 0
15
3
1
19
557
USE OF BC-48 TABLE 3 DURATION OF BC-48 (DEMECARIUM BROMIDE) THERAPY
Number of Months Number of Eyes Controlled 4 4-5 5-6 6-7 7-8
34 17 9 14 13
TOTAL
87
which 87 eyes were controlled successfully on BC-48 therapy. Table 4 compares the dosage of BC-48 therapy and previous therapy in the same controlled eyes which total 49. In all except two eyes the glaucoma was controlled on BC48 alone. These two eyes needed acetazolamide (Diamox) in addition to bring them under control. The use of BC-48 alone, its lower concentrations and the relative infrequency of instillation are in marked contrast to the combined use of various antiglaucoma agents, their greater concentrations and the more frequent instillations required to bring about the control of glaucoma in the same eyes. Table 5 records the effect of BC-48 ther apy on the facility of aqueous outflow of some of these glaucomatous eyes. In most of the eyes where intraocular pressure was brought under control there was an increase in the coefficient of aqueous outflow facility.
In some there was an actual embarrassment in the outflow facility within the first few hours. In two eyes which were controlled on previous therapy and not on BC-48 ther apy, there was an actual decrease in the coefficient of aqueous outflow with the coin cident increase in intraocular pressure. There were 19 eyes uncontrolled on BC48. These included two eyes in which there was an actual increase in intraocular pres sure with BC-48 which were otherwise con trolled on previous therapy. One eye of a patient with bilateral chronic narrow-angle glaucoma, developed corneal edema during the course of BC-48 therapy though the pressure had not risen ; the edema cleared on cessation of BC-48 therapy and after a basal iridectomy. The other eye of the same pa tient was well controlled on BC-48 therapy without any local side-effects. One glaucoma subject developed nausea, vomiting and diar rhea after one single instillation in each eye and the BC-48 therapy was discontinued; there were two eyes of another glaucoma pa tient in whom BC-48 had to be discontinued because of difficulty in breathing, feeling of constriction of chest and sinking sensation in the precordium after one single instilla tion. This patient gave a history of bronchial asthma. The majority of patients complained of browache, headache, pain localized in the globe and transient blurring of vision, which
TABLE 4 COMPARISON OF DOSAGE OF BC-48 (DEMECARIUM BROMIDE) THERAPY AND OTHER
GLAUCOMA THERAPY IN THE SAME CONTROLLED EYES
No. of Eyes 12 13 3 2 3 3 13
Previous Therapy
BC-48 Therapy
Pilocarpine 1% tid-qid Pilocarpine 2% tid-qid Carcholine 1.5% tid-qid DFP 0.05-0.1% od-bid 217-MI 0.1-0.25% od-bid (Pilocarpine 3 % tid-qid+ Physostigmine 0.5% tid-qid + Diamox 125 mg.-250 mg. bid-qid) (Pilocarpine 4% tid-qid+ Physostigmine 0.5% tid-qid+ Diamox 125 mg-250 mg. bid-qid)
0 . 1 % twice a week, once daily 0. l%-0.25% twice a week-bid 0 . 1 % twice a week, once daily 0 . 1 % twice a week, alternate days 0 . 1 % twice a week, alternate days 0.25%, once daily, bid 0.25-0.5%, once daily, bid*
49 (TOTAL)
* Diamox (125 mg.) bid in addition to 0.25% BC-48 bid in two eyes.
NARENDRA KRISHNA AND IRVING H. LEOPOLD
558
TABLE 5 EFFECT OF BC-48 (DEMECARIUM BROMIDE) THERAPY ON THE FACILITY OF AQUEOUS OUTFLOW OF GLAUCOMATOUS EYES
Patient
Coefficient of aqueous outflow facility in mm./min./mm.Hg
Time
1. M.C.
No medication for 60 hr. 2 hr. after continuation of BC-48 therapy
O.D. 0.13 0.17
O.S. 0.10 0.17
2. W.B.
No medication for 48 hr. 2 hr. after continuation of BC-48 therapy
0.13 0.15
0.14 0.15
3. J.M.
No medication for 6 hr. 6 hr. after continuation of BC-48 therapy
0.13 0.13
0.09 0.11
4. E.M.
No medication for 36 hr. 24 hr. after continuation of BC-48 therapy
0.07 0.10
0.09 0.17
5. A.C.
No medication for 24 hr. 23 hr. after continuation of BC-48 therapy
0.27 0.26
0.13 0.16
6. N.T.
No medication for 36 hr. 68 hr. after continuation of BC-48 therapy
0.05 0.04
0.07 0.14
7. A.F.
No medication for 48 hr. 68 hr. after continuation of BC-48 therapy
0.07 0.11
0.09 0.10
8. D.I.
No medication for 24 hr. 24 hr. after continuation of BC-48 therapy
0.10 0.19
0.08 0.19
9. D.N.
No medication for 8 hr. 24 hr. after continuation of BC-48 therapy
0.07 0.10
0.03 0.05
10. H.D.
No medication for 24 hr. 3 hr. after continuation of BC-48 therapy
0.05 0.07
0.08 0.08
11. L.T.
No medication for 48 hr. 2 hr. after continuation of BC-48 therapy
0.04 0.08
0.06 0.07
12. I.T.
No medication for 48 hr. 3 hr. after continuation of BC-48 therapy
0.13 0.06
0.09 0.09
lasted for two to three days after instituting BC-48 therapy. Conjunctival injection both superficial and deep persisted for a few days initially and then gradually subsided. The incidence of these symptoms was higher in patients who had formerly employed pilocarpine alone in contrast to those who had been using an anticholinesterase agent in addition. All these symptoms disappeared a few days after continued BC-48 adminis tration. There has been no incidence of iris cysts, retinal detachment, local sensitivity reaction, follicular conjunctivitis or iritis in the present series. CONCLUSIONS
The present study confirms the findings of Gittler and Pillât, Gougnard, and Miller,
Divert and Crouzet that BC-48 is an effec tive agent in the control of glaucoma. It ap pears to control intraocular pressure even in eyes uncontrolled on conventional glaucoma therapy. Regarding its evaluation as an ideal anti cholinesterase agent in ophthalmology accord ing to the criteria laid down by Krishna and Leopold in the evaluation of echothiophate (phospholine iodide) (217-MI) it possesses the following distinct advantages: 1. BC-48 is a potent, long-acting cholinesterase inhibitor with great intensity and duration of action. Concentrations of 0.1, 0.25 and 0.5 percent, used as little as twice weekly to twice a day, control intraoculat pressure in eyes with various stages and types of glaucoma. It offers the distinct advantage
USE OF BC-48 of infrequent instillations and reduction of the diurnal fluctuations. It eliminates the undesirable need of administration of ther apy during the sleeping hours. 2. BC-48 is readily soluble in aqueous solution. It is indefinitely stable under or dinary conditions and does not deteriorate at room temperature. Thus it offers the advan tage of easy storage and freedom from sen sitivity reaction due to the vehicle employed in dispensing some anticholinesterase inhibi tors. 3. BC-48 seems to be synergistic with other anticholinesterase agents and unlike D F P or 217-MI, its action is not blocked when eserine is given first. Thus it has the advantage that good results may be ex pected even when other anticholinesterase agents have been used previously in the same eye.* •BC-48 however possesses certain disad vantages. 1. Locally it produces undesirable symp toms of spasm of accommodation, ciliary pain and vasodilation in most instances, which gradually disappear. In some eyes it may cause paradoxical rise of tension. 2. Systemically it produces certain unde sirable muscarinic and nicotinic actions. Thus BC-48 is by no means an ideal anti cholinesterase agent. But by virtue of cer tain advantages that it offers, it appears to be a useful cholinesterase inhibitor in the control of glaucoma. Based on the present study the following conclusions may be made: 1. As low concentrations as will effectively control the intraocular pressure should be utilized. This should tend to reduce systemic toxicity. 2. Frequency of instillations should be de
559
termined according to the individual cases. In no case should it exceed more than twice a day. 3. It may be combined with other anti cholinesterase inhibitors where BC-48 alone or the other anticholinesterase agents fail to bring down the tension. 4. It should be used with caution in angleclosure glaucoma. 5. It should be used with caution where parasympathomimetic agents are contraindicated, namely marked vagotonia, vasomotor instability, bronchial asthma, spastic gastro intestinal disturbances, hypotension, myocardial infarction, epilepsy, Parkinsonism. SUMMARY
BC-48 (demecarium bromide) a very po tent long-acting anticholinesterase agent is described. Its use in the control of glaucoma using 0.1, 0.25 and 0.5-percent in aqueous solutions, twice weekly to twice a day in 106 glaucomatous eyes is discussed. Favor able results in 87 eyes with various types of glaucoma with BC-48 therapy are reported. The advantages and disadvantages of this new anticholinesterase inhibitor are dis cussed. 1601 Spring Garden Street (SO). ACKNOWLEDGMENT
We gratefully acknowledge the help of Miss Gretchen Egeressy in the tonographic studies and of Mrs. Gertrude Wood in the follow-up of the clinic patients. * This observation is based on our experimental data on rabbit eyes and has been confirmed in two cases of acute glaucoma where tension could be brought under control only after the addition of BC-48, a course of mecholyl and prostigmine fol lowed by pilocarpine and physostigmine along with Diamox having been tried before without any beneficial results. These observations are at variance with those of Gittler and Pillât and need further evaluation.
REFERENCES
1. Gittler, R., and Pillât, B.: Die Verwendung von Dekamethylen-bis-(N-methyl-Carbaminoyl-mTrimethylammoniumphenol) (BC-48) bei der thérapie des glaukoms. Arch. f. Ophth., 157:473, 1956. 2. Glees, M., and Wustenberg, W.: Ueber Erfahrungen mit Mintacol am normalen und glaukonkranhen aug. Klin. Monatsbl. f. Augenh., 114:455, 1959. 3. Gougnard, L. : Le traitaient de l'hypertension oculaire par le bromure de decamethylene-bis-N-methylCarbaminoyl-4-trimethylammonium phenol (BC-48). Bull. Soc. Belge ophtal., 1957, No. 116, p. 411.
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NARENDRA KRISHNA AND IRVING H. LEOPOLD
4. Grant, W. M.: Miotic and antiglaucomatous activity of tetraethylpyrophosphate in human eyes. Arch. Ophth., 39:579,1948. 5. Herzfeld, E., and Stumpf, G: Untersuchungen über die cholinesterasehemmwirkung der Polymethylene-bis-(N-methyl-Carbaminoyl-m-Trimethylammoniumphenol). Arch, internat. Pharmacodyn., 107: 33, 1956. 6. Kraupp, O., Schwarzacher, H. G., and Stumpf, G: Ueber die pharmakologischen Eigenschaften einiger Polymethylene-bis-(Carbaminoyl-m-Trimethylammoniumphenole). Arch, exper. Path. U. Pharmakol., 225:117, 1955. 7. Kraupp, O., Stumpf, C, Herzfeld, E., and Pillât, B.: Pharmakologische Eigenschaften einiger langwirksamer cholinesterase-Hemmkorper aus der Reihe der Polymethylene-bis-(Carbaminoyl-mTrimethylammoniumphenole). Arch. Internat. Pharmacodyn., 102:281, 1955. 8. Krishna, N., and Leopold, I. H.: Phospholine iodide or echothiophate iodide (217-MI) in treatment of glaucoma: Further observations. Arch. Ophth., in press. 9. Krishna, N. and Leopold, I. H.: The effect of BC-48 (demecarium bromide) on normal rabbit and human eyes. Am. J. Ophth., in press. 10. Leopold, I. H., Krishna, N., and Lehman, R. A.: The effects of anticholinesterase agents on the blood cholinesterases levels of normal and glaucoma subjects. Tr. Am. Ophth. Soc, 57:1959. 11. Laqueur: Ueber eine neue therapeutische Verwendung des Physostigmins, Centralbl. f. d. med. Wissensch., 1876, No. 24, p. 421. 12. Leopold, I. H., and Comroe, J. H.: Use of Di-isopropyl fluorophosphate (DFP) in treatment of glaucoma. Arch. Ophth., 36:1, 1946. 13. Leopold, I. H., Gold, P., and Gold, D.: Use of the thiophosphinyl quaternary compound (217-MI) in treatment of glaucoma. Arch. Ophth., 58:363, 1957. 14. Miller, H. A., Divert, J., and Crouzet, j . : Le bromure de decamethylene bis neostigmine (BC-48) dans le traitement des hypertonies oculaires. Bull. Soc. franc, ophthal., 70:518, 1957. 15. Pillât, B., Stumpf, G, Gittler, R., and Pommer, H.: Permeabilitatsveranderungen durch Dekamethylylen-bis-(N-Methyl-Carbaminoyl-m-Trimethylammoniumphenol) (BC-48), Arch, internat. Pharmacodyn., 108:481, 1956. 16. Rossi, G.: Azione sull'occhio di un nuovo formace sintetico simile la prostigmina. Arch. Ottal., 42: 341 1935. 17. Thiel, H. L.: Klin. Monatsbl. f. Augenh., 114:454, 1949.
THE PATHOGENESIS AND PATHOLOGY OF OCULAR ONCHOCERCIASIS PART IV. F.
C.
THE
RODGER,
PATHOLOGY
M.D.,
M.CHIR.
Oxford, England T h e pathology of every ocular manifesta tion attributed to onchocerciasis is given here and this section contains microscopic proof of my claim that the posterior segmental lesions are of two types. T h e following are the conditions de scribed: 1. " B u n g " eye 2. Limbitis 3. Superficial punctate keratitis 4. Sclerosing keratitis 5. Anterior uveitis 6. Posterior uveitis 7. Chorioretinal degeneration (the poste
rior degenerative lesion of onchocercia sis) 8. Optic atrophy 1. " B U N G " EYE
This colorful descriptive term was coined by Owen and Henessey 1 2 to describe a (per manent) swelling of the upper lids com monly found in association with ocular on chocerciasis. T h e usual explanation of the phenomenon has been that edema is the cause. Macroscopically there is edema of the dermis in which many engorged vessels are present. T h e subcutaneous tissue, however,