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Furmethide Iodide in the Production of Dacryostenosis*
F U R M E T H I D E IODIDE IN T H E PRODUCTION O F DACRYOSTENOSIS* ROBERT N.
SHAFFER, M.D.,
A: ) W I L L I A M L. R I D G W A Y ,
M.D.
San Francii >, California
It is the object of this paper to warn oph thalmologists against the prolonged use of furmethide in the treatment of glaucoma. Permanent obstruction of the tear passages has been observed in a large percentage of cases in which the drug was used for more than three months. Furmethide (Furtrethonium iodide, Smith, Kline and French) is a recent addition to drugs for treating glaucoma. In 1940, the animal pharmacology was developed by Fel lows and Livingston.1 Myerson and Thau 2 studied its ocular effects and thought it safe and worthy of a trial as a miotic. In 1943, the use of furmethide in comparison with other miotics for the treatment of glaucoma was described by Uhler. 3 Further studies were contributed by Ella Uhler Owens and A. C. Woods in 1946.4 In none of these papers was any evidence noted of local sensitivity or irritation to the drug. The only untoward reaction in over 100 cases was one patient who developed severe perspiration, salivation, and lacrimation.3 In 1949, Scheie stated that allergy to furmethide could occur and that tearing was a more prominent symptom than itching.5 For five years we have been using 10-per cent furmethide sporadically in the treatment of glaucoma. The drug was used only in those cases which were not well controlled by the more common miotics. Its ability to control tension seemed somewhat better than two-percent pilocarpine solution; conse quently it has been used increasingly over the past two years. During that time there has been a corre sponding increase in the number of patients asking for relief from their tears. A thor ough investigation of patients, from our pri vate practices and from the Glaucoma Clinic * From the Division of Ophthalmology, Univer sity of California Medical School.
of the University of California, confirmed our opinion that any furmethide user is in grave danger of developing dacryostenosis. Lacrimation is the first symptom of early toxicity, and it usually starts in from three to six months after the beginning of treat ment. At this stage the tear ducts can be irrigated successfully. If furmethide is not discontinued, actual mechanical block will occur within another three to six months. The obstruction can occur anywhere in the tear passages and is usually multiple. The commonest and most annoying stoppage is at the common punctum. In passing a No. 2 Bowman's probe along the canaliculi, definite adhesions are encountered which can be broken in the early stages. In two cases a membrane could be seen sealing the opening of the punctum. When this was broken with a punctum dilator, bleeding occurred. Two patients had occlu sions midway in the tear sac, and one of these suffered a dacryocystitis following probing. The major pathologic change, how ever, seems to be in the canaliculi. Conjunctival scrapings were made from several typical cases and stained with Giemsa stain. These showed consistent findings of nonspecific chronic inflammation. There were no eosinophils, no keratinization, and no bac teria. There were occasional polymorphonuclear leukocytes, monocytes, and lympho cytes. Biopsies were also taken in several cases. The conjunctivas showed nonspecific acute and chronic inflammation. There was mod erate desquamation with edema of the epi thelium and with scattered mononuclear cells in the edema spaces. The substantia propria showed diffuse chronic inflammation with mononuclear and polymorphonuclear cells in the area immediately adjacent to the basal cell layer of the epithelium. No eosinophils were seen. The deeper conjunctival layers
FURMETHIDE IODIDE AND DACRYOSTENOSIS
showed no alteration from normal. It was felt that there was no hyperkeratosis or al teration of the growth pattern of the conjunctival epithelium. The photomicrographs (figs. 1, 2, and 3) are of sections through the palpebral con junctiva and the punctum. The lumen of the punctum shows the typical fibrous occlusion with no marked changes in the epithelium. Some of the sections showed keratinization of the superficial layers of the epithelium with evidence of hyperplasia and folding. There was also some downgrowth of the
Fig. 1 (Shaffer and Ridgway). Biopsy of in ferior palpebral conjunctiva, showing nonspecific inflammation with epithelial edema.
interpapillary pegs, but no actual malignant transformation. The number of patients available for this study has been relatively few. In most cases, furmethide was used for only a few days if the elevated tension was not promptly brought under control. Many patients were on furmethide for one to eight weeks, but no epiphora appeared in anyone who used it for less than three months. Only two pa tients had tearing in three months' time, but one of these had already developed a small adhesion in the middle of the lower canalicu-
719
Fig. 2 (Shaffer and Ridgway). A section of the punctum near the surface, showing partial occlusion of the lumen by granulation tissue.
lus of one eye. The other eye was watery, but the tear passages were patent. In only 21 patients was furmethide used for more than three months. However, as can be seen by referring to the statistical summary, 71 percent of these patients de veloped tearing. Most of die actual obstruc tions seemed to appear between six and 12 months after furmethide was started. All patients with tearing, but with patent ducts, later developed dacryostenosis if furmethide therapy was continued. Of the entire group, only one patient was on furmethide more than 12 months without developing tearing. One-hundred-seventy glaucoma patients were selected at random as a control group. These patients had been treated over a num ber of years with pilocarpine, eserine, pro-
Fig. 3 (Shaffer and Ridgway). A deeper section of the punctum, showing almost complete fibrous occlusion of the lumen.
720
ROBERT N. SHAFFER AND WILLIAM L. RIDGWAY
stigmin, floropryl, or carcholin. F o u r pa tients, or only 2.5 percent of this group, complained of tearing. All of these had been on pilocarpine. T w o of them had actual ob struction of the ducts. W e are convinced that this significant statistical difference is entirely due to furmethide.
fered with sodium phosphate which is com monly used in eye solutions. T h e preserva tive is sodium ethyl mercuri thiosalicylate, 1:100,000. T h i s preservative is also used in several other Smith, Kline, and French spe cialties and apparently no deleterious effects have ever been noted.
T h e only other possible reason for these TABLE 1 STATISTICAL SUMMARY
A 21 patients using furmethide for three months or longer: IS had tearing within 3 to 12 months 71% B 15 patients with tearing: 12 had demonstrable occlusion of tear passages ! 80%
c
Control Group 170 glaucoma patients using other miotics: 4 had tearing
2.5%
results is that either the buffer or the pre servative is at fault. T h e p H of furmethide is adjusted to approximately 7.4 and it is buf
S U M M A R Y AND C O N C L U S I O N S
Seventy-one percent of glaucoma patients treated by furmethide for more than three months developed permanent occlusions of the canaliculi and tear ducts. In a large con trol series, only 2.5 percent of the patients treated by standard miotics developed tear ing. It is suggested that the use of furmethide be restricted to short-term therapy, such as in the presurgical reduction of tension, or as a rest period from other miotics. If it seems advisable to continue furmethide for more than two months, the patient should be warned to report to the physician at once should tearing develop. 490 Post Street
(2).
REFERENCES
1. Fellows, E. J., and Livingston, A. E.: The pharmacology of certain furfuryl and tetrahydrofurfuryl ammonium iodides. J. Pharmacol. & Exper. Therap., 68:231 (Feb.) 1940. 2. Myerson, A., and Thau, W.: Ocular pharmacology of furfuryl trimethyl ammonium iodide. Arch. Ophth., 24:758 (Oct.) 1940. 3. Uhler, E. M.: The use of furmethide in comparison with other miotics for the treatment of glau coma. Am. J. Ophth., 26:710 (July) 1943. 4. Owens, E. U., and Woods, A. C.: Furmethide: Further studies on use of furmethide in treatment of glaucoma. Am. J. Ophth., 29 :447-50 (April) 1946. 5. Scheie, H. G.: Symposium: Primary glaucoma: III. The treatment of primary glaucoma by medical means. Tr. Am. Acad. Ophth., Jan.-Feb., 1949, p. 186.
SHAFFER, M.D.,
A: ) W I L L I A M L. R I D G W A Y ,
M.D.
San Francii >, California
It is the object of this paper to warn oph thalmologists against the prolonged use of furmethide in the treatment of glaucoma. Permanent obstruction of the tear passages has been observed in a large percentage of cases in which the drug was used for more than three months. Furmethide (Furtrethonium iodide, Smith, Kline and French) is a recent addition to drugs for treating glaucoma. In 1940, the animal pharmacology was developed by Fel lows and Livingston.1 Myerson and Thau 2 studied its ocular effects and thought it safe and worthy of a trial as a miotic. In 1943, the use of furmethide in comparison with other miotics for the treatment of glaucoma was described by Uhler. 3 Further studies were contributed by Ella Uhler Owens and A. C. Woods in 1946.4 In none of these papers was any evidence noted of local sensitivity or irritation to the drug. The only untoward reaction in over 100 cases was one patient who developed severe perspiration, salivation, and lacrimation.3 In 1949, Scheie stated that allergy to furmethide could occur and that tearing was a more prominent symptom than itching.5 For five years we have been using 10-per cent furmethide sporadically in the treatment of glaucoma. The drug was used only in those cases which were not well controlled by the more common miotics. Its ability to control tension seemed somewhat better than two-percent pilocarpine solution; conse quently it has been used increasingly over the past two years. During that time there has been a corre sponding increase in the number of patients asking for relief from their tears. A thor ough investigation of patients, from our pri vate practices and from the Glaucoma Clinic * From the Division of Ophthalmology, Univer sity of California Medical School.
of the University of California, confirmed our opinion that any furmethide user is in grave danger of developing dacryostenosis. Lacrimation is the first symptom of early toxicity, and it usually starts in from three to six months after the beginning of treat ment. At this stage the tear ducts can be irrigated successfully. If furmethide is not discontinued, actual mechanical block will occur within another three to six months. The obstruction can occur anywhere in the tear passages and is usually multiple. The commonest and most annoying stoppage is at the common punctum. In passing a No. 2 Bowman's probe along the canaliculi, definite adhesions are encountered which can be broken in the early stages. In two cases a membrane could be seen sealing the opening of the punctum. When this was broken with a punctum dilator, bleeding occurred. Two patients had occlu sions midway in the tear sac, and one of these suffered a dacryocystitis following probing. The major pathologic change, how ever, seems to be in the canaliculi. Conjunctival scrapings were made from several typical cases and stained with Giemsa stain. These showed consistent findings of nonspecific chronic inflammation. There were no eosinophils, no keratinization, and no bac teria. There were occasional polymorphonuclear leukocytes, monocytes, and lympho cytes. Biopsies were also taken in several cases. The conjunctivas showed nonspecific acute and chronic inflammation. There was mod erate desquamation with edema of the epi thelium and with scattered mononuclear cells in the edema spaces. The substantia propria showed diffuse chronic inflammation with mononuclear and polymorphonuclear cells in the area immediately adjacent to the basal cell layer of the epithelium. No eosinophils were seen. The deeper conjunctival layers
FURMETHIDE IODIDE AND DACRYOSTENOSIS
showed no alteration from normal. It was felt that there was no hyperkeratosis or al teration of the growth pattern of the conjunctival epithelium. The photomicrographs (figs. 1, 2, and 3) are of sections through the palpebral con junctiva and the punctum. The lumen of the punctum shows the typical fibrous occlusion with no marked changes in the epithelium. Some of the sections showed keratinization of the superficial layers of the epithelium with evidence of hyperplasia and folding. There was also some downgrowth of the
Fig. 1 (Shaffer and Ridgway). Biopsy of in ferior palpebral conjunctiva, showing nonspecific inflammation with epithelial edema.
interpapillary pegs, but no actual malignant transformation. The number of patients available for this study has been relatively few. In most cases, furmethide was used for only a few days if the elevated tension was not promptly brought under control. Many patients were on furmethide for one to eight weeks, but no epiphora appeared in anyone who used it for less than three months. Only two pa tients had tearing in three months' time, but one of these had already developed a small adhesion in the middle of the lower canalicu-
719
Fig. 2 (Shaffer and Ridgway). A section of the punctum near the surface, showing partial occlusion of the lumen by granulation tissue.
lus of one eye. The other eye was watery, but the tear passages were patent. In only 21 patients was furmethide used for more than three months. However, as can be seen by referring to the statistical summary, 71 percent of these patients de veloped tearing. Most of die actual obstruc tions seemed to appear between six and 12 months after furmethide was started. All patients with tearing, but with patent ducts, later developed dacryostenosis if furmethide therapy was continued. Of the entire group, only one patient was on furmethide more than 12 months without developing tearing. One-hundred-seventy glaucoma patients were selected at random as a control group. These patients had been treated over a num ber of years with pilocarpine, eserine, pro-
Fig. 3 (Shaffer and Ridgway). A deeper section of the punctum, showing almost complete fibrous occlusion of the lumen.
720
ROBERT N. SHAFFER AND WILLIAM L. RIDGWAY
stigmin, floropryl, or carcholin. F o u r pa tients, or only 2.5 percent of this group, complained of tearing. All of these had been on pilocarpine. T w o of them had actual ob struction of the ducts. W e are convinced that this significant statistical difference is entirely due to furmethide.
fered with sodium phosphate which is com monly used in eye solutions. T h e preserva tive is sodium ethyl mercuri thiosalicylate, 1:100,000. T h i s preservative is also used in several other Smith, Kline, and French spe cialties and apparently no deleterious effects have ever been noted.
T h e only other possible reason for these TABLE 1 STATISTICAL SUMMARY
A 21 patients using furmethide for three months or longer: IS had tearing within 3 to 12 months 71% B 15 patients with tearing: 12 had demonstrable occlusion of tear passages ! 80%
c
Control Group 170 glaucoma patients using other miotics: 4 had tearing
2.5%
results is that either the buffer or the pre servative is at fault. T h e p H of furmethide is adjusted to approximately 7.4 and it is buf
S U M M A R Y AND C O N C L U S I O N S
Seventy-one percent of glaucoma patients treated by furmethide for more than three months developed permanent occlusions of the canaliculi and tear ducts. In a large con trol series, only 2.5 percent of the patients treated by standard miotics developed tear ing. It is suggested that the use of furmethide be restricted to short-term therapy, such as in the presurgical reduction of tension, or as a rest period from other miotics. If it seems advisable to continue furmethide for more than two months, the patient should be warned to report to the physician at once should tearing develop. 490 Post Street
(2).
REFERENCES
1. Fellows, E. J., and Livingston, A. E.: The pharmacology of certain furfuryl and tetrahydrofurfuryl ammonium iodides. J. Pharmacol. & Exper. Therap., 68:231 (Feb.) 1940. 2. Myerson, A., and Thau, W.: Ocular pharmacology of furfuryl trimethyl ammonium iodide. Arch. Ophth., 24:758 (Oct.) 1940. 3. Uhler, E. M.: The use of furmethide in comparison with other miotics for the treatment of glau coma. Am. J. Ophth., 26:710 (July) 1943. 4. Owens, E. U., and Woods, A. C.: Furmethide: Further studies on use of furmethide in treatment of glaucoma. Am. J. Ophth., 29 :447-50 (April) 1946. 5. Scheie, H. G.: Symposium: Primary glaucoma: III. The treatment of primary glaucoma by medical means. Tr. Am. Acad. Ophth., Jan.-Feb., 1949, p. 186.