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Experimental Corneal Vascularization and Its Management
E X P E R I M E N T A L CORNEAL VASCULARIZATION AND ITS MANAGEMENT O. P. A H U J A , M.S.,. LNDH. V. NEMA, M.S. Aligat \, India
Corneal vascularization presents a serious problem in clinical practice, particularly in keratoplasty, and various procedures have been advocated for the management of this condition. Rycroft and Romanes, 1 Cook and Langham2 and Ashton 3 observed that local corticosteroids were effective in producing rapid and complete regression of blood vessels from the cornea. Similar results were ob tained with beta radiation by Boles-Carenini and Cima,4 Michaelson, Gluecker and Stieglitz5 and others. In evaluating these modalities in experi mental animals, different methods of pro ducing corneal vascularization were em ployed. Flocks, Tsukahara and Miller6 used an encircling rubber tube around the eyeball to produce experimental glaucoma and, coincidentally, it was observed that the pro cedure resulted in corneal vascularization as well. These findings were confirmed by Levene, Shapiro and Baum.7 Langham 8 and Rock9 advocated intracam eral injection of 0.4 cc of 2 % alloxan ( p H 6.5) as useful in producing corneal vascu larization. Lavergne and Colmant10 achieved this objective by touching the cornea with a tampon soaked in 20% sodium hydroxide. The present study was designed to assess various methods of experimental production of corneal vascularization and to compare the effectiveness of thio-tepa* and Decadronf in the treatment of this condition. PRESENT STUDY
A. Vascularization of the cornea was proFrom the Institute of Ophthalmology, Aligarh Muslim University (Director of Research: Prof. B.R. Shukla). * N, N', N"—triethylenethiophosphoramide, cour tesy of Dr. J. F. Britto, medical director, Lederle Laboratory Division of Cyanamid (India) Ltd. t Dexamethasone, manufactured by Merck, Sharp & Dohme.
duced by encircling tube,6 caustic soda cauterization10 and intracameral alloxan injection.8'9 Ten rabbit eyes were employed for each of these procedures and the ap pearance and course of vessels were ob served. B. Langham's technique8 was employed to produce corneal vascularization in 80 rabbit eyes via intracameral injection of 0.4 cc of 2% alloxan solution (pH 6.5). The animals were then divided into eight groups of 10 eyes each as follows: Group 1. These eyes were treated by local instillation of sesame oil drops three times daily beginning on the day of alloxan in jection. Group 2. Sesame oil was started 10 days after alloxan injection. (Groups 1 and 2 served as controls.) Group 3. This group was treated by bi weekly subconjunctival injections (0.25 cc) and thrice-daily local instillations of Decadron (dexamethasone) solution. The treat ment began on the day of alloxan injection. Group 4. Decadron, in the same dosage as in Group 3, was started 10 days after al loxan injection. Group 5. The eyes were treated by local instillation of thio-tepa drops ( 1 % in se same oil) three times daily beginning on the day of alloxan injection. Group 6. Thio-tepa treatment was started 10 days after alloxan injection. Group 7. Biweekly subconjunctival in jections of Decadron (0.25 cc) were com bined with thrice-daily instillation of thiotepa drops ( 1 % oily suspension) beginning on the day of alloxan injection. Group 8. Combined treatment as in Group 7 was started 10 days after alloxan injection. The course and disappearance of corneal vessels in these groups were observed and compared.
708
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1966
RESULTS
DISCUSSION
The placement of an encircling tube around the globe was found to be inconsistent in producing corneal vascularization. Seven out of 10 eyes showed fine peripheral cor neal vascularization which was irregular and short lived. Chemical cautery of the cornea with 20% sodium hydroxide consistently produced in tense vascularization after about a week but this process was accompanied by destruction of corneal tissue and corneal ulceration. Descemetocele formation and perforations were encountered in a few eyes. Intracameral injection of alloxan pro duced a generalized corneal haze and edema and, after seven to nine days, a measurable degree of vascularization was seen in all eyes thus treated. The fate of new vessels after treatment was as follows: Group 1. The vessels first grew gradually in both size and intensity and then regressed. They finally disappeared in 28 to 38 days (34 days on the average) after their first ap pearance. Group 2. The vessels behaved essentially like those in Group 1, disappearing after 30 to 37 (average 32) days. Group 3. The vessels failed to grow in all but one eye, in which the corneal vasculariza tion cleared in 10 days. Group 4. A fair degree of vascularization had already appeared when treatment was started. After Decadron therapy, the vessels disappeared in 16 to 21 (average 19) days after their appearance. Group 5. Only four corneas of 10 eyes developed vascularization. This was of much less intensity than in the control eyes and disappeared after eight to 11 (average nine) days. Group 6. The vessels disappeared 12 to 18 (average 15) days after their appearance. Group 7. No vascularization appeared. Group 8. The vessels disappeared nine to 14 (average 12) days after their appearance.
The production of a standard corneal vas cularization is essential to the experimental study of the comparative effect of various physical and chemical agents oil vasculariza tion. With this end in view, the first part of our study compared various procedures rec ommended for the experimental production of corneal vascularization. The results indicate that the encircling tube technique6'7 is not an ideal procedure, inasmuch as the resulting vascularization was inconsistent and irregular and thera peutic evaluation of the effect of a drug on such eyes might give erroneous and mislead ing results. Caustic soda cauterization10 produced cor neal vascularization in all eyes but was fre quently accompanied by significant necrosis of corneal tissue. Under these circum stances, the growth of vessels was likely to be affected by secondary factors, such as the extent of corneal destruction and the pres ence and nature of secondary infection. Some of these eyes ended with perforation, thereby terminating the observation. In contrast, intracameral injection of 2 % alloxan produced a standard vascularization in all eyes. The procedure could be conduct ed under uniform conditions by injecting the same amount, concentration and prep aration of alloxan into all eyes. The reaction obtained was considered standard. The results of the present study confirm earlier reports that both thio-tepa and Deca dron suppress corneal vascularization. Langham 11 noticed inhibition of new vessel growth into the edematous cornea by thiotepa either given systemically or used topi cally, and suggested that this inhibition was due to suppression of capillary endothelial proliferation, which recommenced on with drawal of thio-tepa. Similar observations were made by Rock9 who reported that the effect seemed temporary, with active vascu larization occurring upon cessation of thera py-
VOL. 62, NO. 4
EXPERIMENTAL CORNEAL VASCULARIZATION
709
TABLE 1 RESULTS OF TREATMENT (vascularization in days)
No
i 2 3 4 5 6 7 8 9 10 AVERAGE
Groups I
II
III
IV
V
VI
VII
VIII
32 36 37 28 32 36 30 35 38 36
34 32 37 30 31 32 30 31 33 30
N.D.V.* N.D.V. N.D.V. N.D.V. 10 N.D.V. N.D.V. N.D.V. N.D.V. N.D.V.
18 20 19 21 18 20 18 19 16 21
N.D.V. 8 N.D.V. N.D.V. 9 N.D.V. N.D.V. N.D.V. 8 11
14 16 14 18 IS 12 13 17 15 16
N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V.
11 13 14 10 9 14 13 10 12 14
34
30
19
9
15
—
12
—
* N.D.V., vessels did not develop.
Recently Lavergne and Colmant,10 in a histopathologic study, demonstrated that thio-tepa inhibited the progression of corneal vascularization by acting directly on capillary endothelium. However, they have shown that Decadron did not check the growth of vessels into the cornea. (Our findings with Decadron agree with those of Ashton and Cook12 and Duke-Elder and Ashton 13 who reported regression of corneal vessels with the use of cortisone.) It is important, however, to note that the efficacy of thio-tepa and Decadron depended largely upon the age of the newly formed vessels. When a fair amount of vasculariza tion was present before the start of treat ment, these agents, used individually or in combination, had less effect than when used before the development of vascularization (table 1). In the latter group, when the drugs were given individually, only a few vessels appeared, lasting only a short time. When the drugs were used in combination, no vessels were seen. Lavergne and Colmant10 obtained similar results with thiotepa. We conclude that the use of corticosteroids and thio-tepa locally may be beneficial in the treatment of corneal vascularization, particularly when vascularization is antici pated or threatening. The use of corticoste-
roids in the early postoperative period, how ever, carries the danger of delayed healing. (The effect of thio-tepa on the healing pro cess was not considered in this study, but it is presumed that, because of its action as an antimitotic agent, thio-tepa also may retard the healing of surgical wounds. Poor wound healing attributed to fibroblastic inhibition was recorded by Rock9 in a small percentage of his treated eyes.) SUMMARY
Various techniques for experimental pro duction of corneal vascularization were evaluated in rabbit eyes. Intracameral injection of 0.4 cc of 2% alloxan (pH 6.5) was found most reliable and suitable for evaluation of inhibitory drugs, consistently producing uniform vascularization. The role of thio-tepa and Decadron in the management of corneal vascularization was studied in 80 rabbit eyes. It was observed that, although both these agents were useful, their effectiveness depended largely upon the age of the vessels under treatment. These agents were found to be capable of suppressing impending vascularization but their effect on established vessels was much less marked. Institute of Ophthalmology
710
AMERICAN JOURNAL OF OPHTHALMOLOGY REFERENCES
1. Rycroft, B. W., and Romanes, J.: Lamellar corneal grafts. Brit. J. Ophth. 36:337, 19S2. 2. Cook, C, and Langham, M. E.: Corneal thickness in interstitial keratitis. Brit. J. Ophth. 37 :301, 19S3. 3. Ashton, N.: In Duke-Elder, S., and Perkins, E. S. (ed.) : The transparency of cornea: A sym posium. Oxford, Blackwell Scientific Publica tions, 1962, p. 131. 4. Boles-Carenini, B., and Cima, V. The result of P-therapy in some diseases of lids, conjunctiva and cornea. Am. J. Ophth. 40:4SS, 19SS. 5. Michaelson, J. C, Gluecker, L., and Stieglitz, E.: Influence of low-voltage radiation on inhibition and prevention of new vessels in cor nea. Arch. Ophth. 52 :77, 1954. 6. Flocks, M., Tsukahara, J., and Miller, M.: Mechanically induced glaucoma in animals. Am. J. Ophth. 48:11, 1959. 7. Levene, R., Shapiro, A., and Baum, J.: Ex-
OCTOBER, 1966
perimental corneal vascularization. Arch. Ophth. 70:242, 1963. 8. Langham, M. E.: Observations on the growth of blood vessels in cornea: A new tech nique. Brit. J. Ophth. 37:210, 1953. 9. Rock, R. L.: Inhibition of corneal vasculari zation by triethylene-thiophosphoramide (thiotepa). Arch. Ophth. 69 :330, 1963. 10. Lavergne, E., and Colmant, J. A.: Compar ative study of the action of thio-tepa and triamcinolone on corneal vascularization in rabbit. Brit. J. Ophth. 48:416, 1964. 11. Langham, M. E.: The inhibition of corneal vascularization by triethylene-thiophosphoramide. Am. J. Ophth. 49:1111, 1960. 12. Ashton, N., and Cook, C.: Effect of corti sone on healing of corneal wounds. Brit. J. Ophth. 35 :708-717, 1951. 13. Duke-Elder, S., and Ashton, N.: Action of cortisone on tissue reactions of inflammation and repair with special reference to the eye. Brit. J. Ophth. 37:301-304, 1953.
OCULAR ABSORPTION O F THIABENDAZOLE-"C BY T H E RABBIT HARRY J. ROBINSON, M.D.,
OTTO E.
GRAESSLE, P H . D . ,
EDWARD G. L E H M A N , K A N E L. KELLEY, RAYMOND F. GEOFFROY, M.S., CHARLES ROSENBLUM,
B.S.,
AND
PH.D.
Rahway, New Jersey
The incidence of external ocular fungus rum audouini infections in humans.5 Asperdisease has risen sharply in the past decade. gillus fumigatus, an organism frequently Although some advances have been made in associated with human keratomycosis, is the prevention and therapy of these serious highly susceptible in vitro to thiabendazole. infections, prophylaxis and particularly As little as 2 jig to 4 |xg of the drug per ml treatment remain far from satisfactory. will inhibit the growth of most strains of Thiabendazole, a known orally effective an- this organism, and slightly higher concen thelmintic, has been shown recently to be trations are fungicidal. Studies reported highly effective in vitro against many elsewhere6 indicate that thiabendazole is strains of saphrophytic and pathogenic well tolerated when applied topically to the fungi.1"3 The in vitro activity of the drug is eye. not affected by organic matter. The present investigation was undertaken Topically applied thiabendazole has proved to determine if topically applied thiabenda to be efficacious against experimental zole would penetrate ocular tissues and Trichophyton mentagrophytes infections in reach sufficient concentrations to consider guinea pigs4 and against Trichophyton ru- the use of this agent for the treatment of brum, T. mentagrophytes, T. interdigitalis, keratomycosis. This point was investigated Epidermophyton floccosum and Microspo- initially with thiabendazole-14C applied for one hour to the eye of the rabbit in an From the Merck Institute for Therapeutic Re ophthalmic ointment base and as an ophthal search and the Merck Sharp & Dohme Research mic suspension, and microbiologically with Laboratories.
Corneal vascularization presents a serious problem in clinical practice, particularly in keratoplasty, and various procedures have been advocated for the management of this condition. Rycroft and Romanes, 1 Cook and Langham2 and Ashton 3 observed that local corticosteroids were effective in producing rapid and complete regression of blood vessels from the cornea. Similar results were ob tained with beta radiation by Boles-Carenini and Cima,4 Michaelson, Gluecker and Stieglitz5 and others. In evaluating these modalities in experi mental animals, different methods of pro ducing corneal vascularization were em ployed. Flocks, Tsukahara and Miller6 used an encircling rubber tube around the eyeball to produce experimental glaucoma and, coincidentally, it was observed that the pro cedure resulted in corneal vascularization as well. These findings were confirmed by Levene, Shapiro and Baum.7 Langham 8 and Rock9 advocated intracam eral injection of 0.4 cc of 2 % alloxan ( p H 6.5) as useful in producing corneal vascu larization. Lavergne and Colmant10 achieved this objective by touching the cornea with a tampon soaked in 20% sodium hydroxide. The present study was designed to assess various methods of experimental production of corneal vascularization and to compare the effectiveness of thio-tepa* and Decadronf in the treatment of this condition. PRESENT STUDY
A. Vascularization of the cornea was proFrom the Institute of Ophthalmology, Aligarh Muslim University (Director of Research: Prof. B.R. Shukla). * N, N', N"—triethylenethiophosphoramide, cour tesy of Dr. J. F. Britto, medical director, Lederle Laboratory Division of Cyanamid (India) Ltd. t Dexamethasone, manufactured by Merck, Sharp & Dohme.
duced by encircling tube,6 caustic soda cauterization10 and intracameral alloxan injection.8'9 Ten rabbit eyes were employed for each of these procedures and the ap pearance and course of vessels were ob served. B. Langham's technique8 was employed to produce corneal vascularization in 80 rabbit eyes via intracameral injection of 0.4 cc of 2% alloxan solution (pH 6.5). The animals were then divided into eight groups of 10 eyes each as follows: Group 1. These eyes were treated by local instillation of sesame oil drops three times daily beginning on the day of alloxan in jection. Group 2. Sesame oil was started 10 days after alloxan injection. (Groups 1 and 2 served as controls.) Group 3. This group was treated by bi weekly subconjunctival injections (0.25 cc) and thrice-daily local instillations of Decadron (dexamethasone) solution. The treat ment began on the day of alloxan injection. Group 4. Decadron, in the same dosage as in Group 3, was started 10 days after al loxan injection. Group 5. The eyes were treated by local instillation of thio-tepa drops ( 1 % in se same oil) three times daily beginning on the day of alloxan injection. Group 6. Thio-tepa treatment was started 10 days after alloxan injection. Group 7. Biweekly subconjunctival in jections of Decadron (0.25 cc) were com bined with thrice-daily instillation of thiotepa drops ( 1 % oily suspension) beginning on the day of alloxan injection. Group 8. Combined treatment as in Group 7 was started 10 days after alloxan injection. The course and disappearance of corneal vessels in these groups were observed and compared.
708
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1966
RESULTS
DISCUSSION
The placement of an encircling tube around the globe was found to be inconsistent in producing corneal vascularization. Seven out of 10 eyes showed fine peripheral cor neal vascularization which was irregular and short lived. Chemical cautery of the cornea with 20% sodium hydroxide consistently produced in tense vascularization after about a week but this process was accompanied by destruction of corneal tissue and corneal ulceration. Descemetocele formation and perforations were encountered in a few eyes. Intracameral injection of alloxan pro duced a generalized corneal haze and edema and, after seven to nine days, a measurable degree of vascularization was seen in all eyes thus treated. The fate of new vessels after treatment was as follows: Group 1. The vessels first grew gradually in both size and intensity and then regressed. They finally disappeared in 28 to 38 days (34 days on the average) after their first ap pearance. Group 2. The vessels behaved essentially like those in Group 1, disappearing after 30 to 37 (average 32) days. Group 3. The vessels failed to grow in all but one eye, in which the corneal vasculariza tion cleared in 10 days. Group 4. A fair degree of vascularization had already appeared when treatment was started. After Decadron therapy, the vessels disappeared in 16 to 21 (average 19) days after their appearance. Group 5. Only four corneas of 10 eyes developed vascularization. This was of much less intensity than in the control eyes and disappeared after eight to 11 (average nine) days. Group 6. The vessels disappeared 12 to 18 (average 15) days after their appearance. Group 7. No vascularization appeared. Group 8. The vessels disappeared nine to 14 (average 12) days after their appearance.
The production of a standard corneal vas cularization is essential to the experimental study of the comparative effect of various physical and chemical agents oil vasculariza tion. With this end in view, the first part of our study compared various procedures rec ommended for the experimental production of corneal vascularization. The results indicate that the encircling tube technique6'7 is not an ideal procedure, inasmuch as the resulting vascularization was inconsistent and irregular and thera peutic evaluation of the effect of a drug on such eyes might give erroneous and mislead ing results. Caustic soda cauterization10 produced cor neal vascularization in all eyes but was fre quently accompanied by significant necrosis of corneal tissue. Under these circum stances, the growth of vessels was likely to be affected by secondary factors, such as the extent of corneal destruction and the pres ence and nature of secondary infection. Some of these eyes ended with perforation, thereby terminating the observation. In contrast, intracameral injection of 2 % alloxan produced a standard vascularization in all eyes. The procedure could be conduct ed under uniform conditions by injecting the same amount, concentration and prep aration of alloxan into all eyes. The reaction obtained was considered standard. The results of the present study confirm earlier reports that both thio-tepa and Deca dron suppress corneal vascularization. Langham 11 noticed inhibition of new vessel growth into the edematous cornea by thiotepa either given systemically or used topi cally, and suggested that this inhibition was due to suppression of capillary endothelial proliferation, which recommenced on with drawal of thio-tepa. Similar observations were made by Rock9 who reported that the effect seemed temporary, with active vascu larization occurring upon cessation of thera py-
VOL. 62, NO. 4
EXPERIMENTAL CORNEAL VASCULARIZATION
709
TABLE 1 RESULTS OF TREATMENT (vascularization in days)
No
i 2 3 4 5 6 7 8 9 10 AVERAGE
Groups I
II
III
IV
V
VI
VII
VIII
32 36 37 28 32 36 30 35 38 36
34 32 37 30 31 32 30 31 33 30
N.D.V.* N.D.V. N.D.V. N.D.V. 10 N.D.V. N.D.V. N.D.V. N.D.V. N.D.V.
18 20 19 21 18 20 18 19 16 21
N.D.V. 8 N.D.V. N.D.V. 9 N.D.V. N.D.V. N.D.V. 8 11
14 16 14 18 IS 12 13 17 15 16
N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V. N.D.V.
11 13 14 10 9 14 13 10 12 14
34
30
19
9
15
—
12
—
* N.D.V., vessels did not develop.
Recently Lavergne and Colmant,10 in a histopathologic study, demonstrated that thio-tepa inhibited the progression of corneal vascularization by acting directly on capillary endothelium. However, they have shown that Decadron did not check the growth of vessels into the cornea. (Our findings with Decadron agree with those of Ashton and Cook12 and Duke-Elder and Ashton 13 who reported regression of corneal vessels with the use of cortisone.) It is important, however, to note that the efficacy of thio-tepa and Decadron depended largely upon the age of the newly formed vessels. When a fair amount of vasculariza tion was present before the start of treat ment, these agents, used individually or in combination, had less effect than when used before the development of vascularization (table 1). In the latter group, when the drugs were given individually, only a few vessels appeared, lasting only a short time. When the drugs were used in combination, no vessels were seen. Lavergne and Colmant10 obtained similar results with thiotepa. We conclude that the use of corticosteroids and thio-tepa locally may be beneficial in the treatment of corneal vascularization, particularly when vascularization is antici pated or threatening. The use of corticoste-
roids in the early postoperative period, how ever, carries the danger of delayed healing. (The effect of thio-tepa on the healing pro cess was not considered in this study, but it is presumed that, because of its action as an antimitotic agent, thio-tepa also may retard the healing of surgical wounds. Poor wound healing attributed to fibroblastic inhibition was recorded by Rock9 in a small percentage of his treated eyes.) SUMMARY
Various techniques for experimental pro duction of corneal vascularization were evaluated in rabbit eyes. Intracameral injection of 0.4 cc of 2% alloxan (pH 6.5) was found most reliable and suitable for evaluation of inhibitory drugs, consistently producing uniform vascularization. The role of thio-tepa and Decadron in the management of corneal vascularization was studied in 80 rabbit eyes. It was observed that, although both these agents were useful, their effectiveness depended largely upon the age of the vessels under treatment. These agents were found to be capable of suppressing impending vascularization but their effect on established vessels was much less marked. Institute of Ophthalmology
710
AMERICAN JOURNAL OF OPHTHALMOLOGY REFERENCES
1. Rycroft, B. W., and Romanes, J.: Lamellar corneal grafts. Brit. J. Ophth. 36:337, 19S2. 2. Cook, C, and Langham, M. E.: Corneal thickness in interstitial keratitis. Brit. J. Ophth. 37 :301, 19S3. 3. Ashton, N.: In Duke-Elder, S., and Perkins, E. S. (ed.) : The transparency of cornea: A sym posium. Oxford, Blackwell Scientific Publica tions, 1962, p. 131. 4. Boles-Carenini, B., and Cima, V. The result of P-therapy in some diseases of lids, conjunctiva and cornea. Am. J. Ophth. 40:4SS, 19SS. 5. Michaelson, J. C, Gluecker, L., and Stieglitz, E.: Influence of low-voltage radiation on inhibition and prevention of new vessels in cor nea. Arch. Ophth. 52 :77, 1954. 6. Flocks, M., Tsukahara, J., and Miller, M.: Mechanically induced glaucoma in animals. Am. J. Ophth. 48:11, 1959. 7. Levene, R., Shapiro, A., and Baum, J.: Ex-
OCTOBER, 1966
perimental corneal vascularization. Arch. Ophth. 70:242, 1963. 8. Langham, M. E.: Observations on the growth of blood vessels in cornea: A new tech nique. Brit. J. Ophth. 37:210, 1953. 9. Rock, R. L.: Inhibition of corneal vasculari zation by triethylene-thiophosphoramide (thiotepa). Arch. Ophth. 69 :330, 1963. 10. Lavergne, E., and Colmant, J. A.: Compar ative study of the action of thio-tepa and triamcinolone on corneal vascularization in rabbit. Brit. J. Ophth. 48:416, 1964. 11. Langham, M. E.: The inhibition of corneal vascularization by triethylene-thiophosphoramide. Am. J. Ophth. 49:1111, 1960. 12. Ashton, N., and Cook, C.: Effect of corti sone on healing of corneal wounds. Brit. J. Ophth. 35 :708-717, 1951. 13. Duke-Elder, S., and Ashton, N.: Action of cortisone on tissue reactions of inflammation and repair with special reference to the eye. Brit. J. Ophth. 37:301-304, 1953.
OCULAR ABSORPTION O F THIABENDAZOLE-"C BY T H E RABBIT HARRY J. ROBINSON, M.D.,
OTTO E.
GRAESSLE, P H . D . ,
EDWARD G. L E H M A N , K A N E L. KELLEY, RAYMOND F. GEOFFROY, M.S., CHARLES ROSENBLUM,
B.S.,
AND
PH.D.
Rahway, New Jersey
The incidence of external ocular fungus rum audouini infections in humans.5 Asperdisease has risen sharply in the past decade. gillus fumigatus, an organism frequently Although some advances have been made in associated with human keratomycosis, is the prevention and therapy of these serious highly susceptible in vitro to thiabendazole. infections, prophylaxis and particularly As little as 2 jig to 4 |xg of the drug per ml treatment remain far from satisfactory. will inhibit the growth of most strains of Thiabendazole, a known orally effective an- this organism, and slightly higher concen thelmintic, has been shown recently to be trations are fungicidal. Studies reported highly effective in vitro against many elsewhere6 indicate that thiabendazole is strains of saphrophytic and pathogenic well tolerated when applied topically to the fungi.1"3 The in vitro activity of the drug is eye. not affected by organic matter. The present investigation was undertaken Topically applied thiabendazole has proved to determine if topically applied thiabenda to be efficacious against experimental zole would penetrate ocular tissues and Trichophyton mentagrophytes infections in reach sufficient concentrations to consider guinea pigs4 and against Trichophyton ru- the use of this agent for the treatment of brum, T. mentagrophytes, T. interdigitalis, keratomycosis. This point was investigated Epidermophyton floccosum and Microspo- initially with thiabendazole-14C applied for one hour to the eye of the rabbit in an From the Merck Institute for Therapeutic Re ophthalmic ointment base and as an ophthal search and the Merck Sharp & Dohme Research mic suspension, and microbiologically with Laboratories.