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Repository Drugs in the Treatment of Trachoma*
220
J. BOECK AND H. HUECKEL
3. Becker, B.: The effects of the carbonic anhydrase inhibitor, acetazolamide, on the composition of the aqueous humor. Am. J. Ophth., 40:129-136 (Feb. Pt. II) 1955. 4. Becker, B., and Constant, M. A.: The alterations in aqueous-humor lactate concentration following systemic carbonic anhydrase inhibition. Am. J. Ophth., 42:406-408, 1956. 5. Becker, B.: The bicarbonate concentration of guinea pig aqueous humor: Effect of scurvy and acetazolamide. Am. J. Ophth., 44:402-408 (Nov. Pt. II) 1957. 6. Boeck, J., Hiickel, H., and Karwounidis, C.: Ueber den Einfluss von Acetazolamid (Diamox) auf den Eiweissgehalt des Kammerwassers. Wien. Klin. Wchnschr., 1958, pp. 907-909. 7. Franceschetti, A., Marty, F., Dubler, H., Falbriard, A., and Sanz, M. C.: Ueber den Einfluss von Acetazolamid (Diamox) auf die Chemie des Kammerwassers. Docum. Ophth., 11:196-216, 1957. 8. Green, H., and Leopold, I. H.: Effects of locally administered Diamox. Am. T. Ophth., 40:137-139 (Feb. Pt. II) 1955. 9. Green, H., Mann, M. J., and Kroman, H. S.: Elaboration of bicarbonate ion in intraocular fluids: IV. Dynamic effects of acetazolamide (Diamox). Am. J. Ophth., 44:388-402 (Nov. Pt. II) 1957. 10. Harris, J. E., Carlson, A. E., Gruber, L., and Hoskinson, G.: The aqueous: serum sodium and potassium steady-state ratios in the rabbit. Am. J. Ophth., 44:409-419 (Nov. Pt. II) 1957. 11. Harris, J. E., Beaudreau, O., and Hoskinson, G.: Clinical and laboratory experiences with the carbonic anhydrase inhibitor, dichlorphenamide. Am. J. Ophth., 45:120, (July Pt. II) 1958. 12. Hoffmann-Ostenhof, O.: Enzymologie. Wien, Springer-Verlag, 1954. 13. Hiickel, H.: Der Eiweissgehalt im Kammerwasser des einen Auges nach Entnahme von Kammerwasser aus dem anderen Auge. Arch. f. Ophth., 160:293-300,1958. 14. Kinsey, V. E., Camacho, E., Cavanaugh, G. A., and Constant, M.: Diamox and intraocular fluid dynamics. Am. J. Ophth., 40:147-148 (Feb. Pt. II) 1955. 15. Langham, M. E., and Lee, P. M.: Action of Diamox and ammonium chloride on formation of aqueous humor. Brit. J. Ophth., 41:65-92, 1957. 16. Langham, M. E.: Specificity and comparative activity of the carbonic anhydrase inhibitors Neptazane and Diamox on animal and human eyes. Brit. J. Ophth., 42:577-588, 1958. 17. Levene, R. Z.: (a) Osmolarity in the normal state and following acetazolamide. Arch. Ophth., 59: 597-602, 1958; (b) Sodium and potassium concentrations following acetazolamide. Arch. Ophth., 59:868872, 1958. 18. Takaoka, S.: Change in the intraocular pressure and K-ion concentration in aqueous and serum by Diamox in primary glaucoma. Acta soc. ophth. Japan, 60:281-284, 1956. (Cited Zentralbl. f. Ophth., 69: 224, 1957. 19. Urrets-Zavalia, A. Jr., and Remedi, G.: Ionometry of the aqueous humor: Report on the mode of action of acetazolamide. Am. J. Ophth., 41:197-203, 1956. 20. Wistrand, P. T.: Carbonic anhydrase in the anterior uvea of the rabbit. Acta physiol. scand., 24: 144-148, 1951.
REPOSITORY DRUGS IN THE TREATMENT OF TRACHOMA* G.
B.
BIETTI,
M.D.
Rome, Italy Although sulfonamides and antibiotics have undoubtedly given excellent results in the treatment of trachoma, the manner of their administration and the duration of the treatment make them less suitable for use outside schools and certain communities. This applies both to areas in which the schools are not attended by all the children of school age, and to "contacts" of patients undergoing regular treatment (for example, children of preschool and postschool age * From the Ophthalmic Clinic, University of Rome.
and adults in the families of children under treatment at school). Mass treatment, more over, requires that the whole population should be treated alike, partly because of the risk of reinfection among children who have been cured by antibiotic or sulfonamide treatment and have left school. This risk, due to the weakness of the immunity con ferred by cured trachoma, has been con firmed by Bietti and Ferraris De Gespare 1 in cured patients living in a superendemic environment. It occurred to us to use "repository" (slowly-absorbed or slowly-eliminated) sub-
REPOSITORY DRUGS TN TRACHOMA
221
studies, and the research of T'ang 4 and his co-workers and of Collier5 on culture of the trachoma virus, which failed when the sam ple was treated with penicillin but not with streptomycin. All this work proves beyond doubt that penicillin acts on the trachoma virus. My first experiments were performed BENZATHINE PENICILLIN with my co-worker Pannarale 6 on 35 pa The first substance we used was a peni tients, mostly school children, who all had cillin with a prolonged action, N,N dibenzyl- well-established trachoma. ethylenediamine dipenicillin G (benzathine Eighteen of these patients received an penicillin), which has an exceptionally long- intramuscular injection of DBEP every 14 continued action and is absorbed gradually. days, 10 every 20 days, and seven every 30 The blood levels are at first low, but ther- days. In the first group only eight, in the apeutically active concentrations of peni second only six, and in the third only four cillin are maintained in the serum and tis injections were given. The treatment there sues for a very long time (fig. 1). This fore took about three months, and the use of penicillin is based on Bietti's2 ob dosage was calculated to give about 2,000 to servations since 1944 on its effects on the 2,500 units per kg. of body weight intra trachoma virus (degeneration and disap muscularly per day. For instance, a child pearance of inclusions, clinical cure of tra weighing 20 kg. received 900,000 units every choma). These observations have unfortu two weeks or 1,200,000 every 20 days. nately remained unnoticed for a long time. The results obtained four months after I should like, however, to mention Poleff's3 the start of treatment were: and Gilkes' and co-workers3b inclusions a. Of the 18 patients treated every 14 days, 12 were completely cured and two almost completely cured. oo/cc b. Of the 10 patients treated every three 2weeks, seven were completely and two nearly cured. c. Of the seven patients treated every 0.5 30 days, three were completely and two 0.25nearly cured. Two years after the start of treatment the 0.12results were even better. Not only had all 00.6' the patients considered cured four months 003 after the start of treatment remained so, but others had been completely cured. Thus 0Q1conjunctival hypertrophy had completely dis appeared in 16 of the first group of 18 DAYS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 patients (one case was not cured but im THE CORRESPONDING DOSAGE FOR TREATMENT GIVEN EVERY-14 DAYS proved, and another could not be found) ; nine patients out of the second group of 10 IDEM EVERY-20 DAYS (one case was treated elsewhere by other fDEM EVERY-30 DAYS means), and out of the third group of Fig. 1 (Bietti). Concentration of penicillin in seven those five patients who could be seen blood after injection of 2,500 units/kg. in subjects again, were completely cured. of 25 to 35 kg. body weight.
stances in an attempt to solve the problem of giving as full a treatment as possible to communities whose members will not collab orate well and cannot be altogether trusted to treat themselves. They can do so very easily, however, by using antibiotic eyedrops or ointment over a long enough period.
222
G. B. B I E T T I
% OF CURES 9080-
//
70 60
*'
,•
SO
7/
/
40-
fa /
y%3
/
°71
Ay
30-
y 20 B ft1
0
3
lla
MONTHS MONTHS TIME ELAPSED FROM END OF TREATMENT
-•
u
\\
n
20 w
Fig. 2 (Bietti). Percentage of patients cured with benzathine penicillin according to the schedule of ad ministration and the time elapsed from end of treat ment.
Inclusion bodies had already disappeared after the first shot of benzathine penicillin. Benzathine penicillin was used again by my co-worker Pannarale on four groups comprising 198 patients, showing an ac tive trachoma generally of average sever ity who received the same doses as in the first experiment every seven, 14, 20, and 30 days. After three months' treatment there was complete cure in 53 percent of the cases treated every seven days, in 41 percent of the cases treated every 14 days, in 24 per cent of those treated every 20 days, and in 21 percent of those treated every 30 days. Between one and two months after the end of the treatment the residual hyper trophy had resolved and complete cure could be observed in 82 percent of the cases treated every seven days, in 80 percent of the cases treated every 14 days, in 64 per cent of those treated every 20 days, and in 43 percent of those treated every 30 days. Between three and five months after the end of treatment there was complete cure in 89 percent of the cases treated every seven days, in 81 percent of those treated every 14 days, in 83 percent of those treated
every 20 days, and in 71 percent of the cases treated every 30 days. The most active treatment thus proved to be that given at intervals of seven to 20 days (fig. 2 ) . We are also exploring the possibility of treatment by spaced doses of benzathine penicillin per os. Milano7 and Brignola8 and Rende8b have also obtained satisfactory results with ben zathine penicillin. Yap 9 approves of its use but has not formed a precise opinion con cerning its action on the virus, considering its antibacterial action more important. In spite of these good results, however, benzathine penicillin treatment has the un deniable disadvantages of being costly and of requiring the injection of large doses of suspended antibiotic (especially when the patient has a high body weight). It also causes a certain amount of local discomfort at the site of injection, and sometimes a fever reaction after heavy doses (for ex ample, those given at 30-day intervals). There is also the theoretic possibility of al lergy and penicillin anaphylactic shock, though we have never seen them in patients treated with benzathine penicillin. Moreover, if kept in a hot climate, the present prepara tions of benzathine penicillin G are not absolutely certain to be stable. SULFONAMIDES
These considerations induced us to under take further research, especially since peni cillin treatment is certainly useless for the seasonal conjunctivitis of Koch-Weeks as sociated with trachoma in certain countries. We therefore used a sulfonamide of slow elimination, sulfamethoxypyridazine (Kynex, Cl 13.494, or Lederkyn, fig. 3), kindly put at our disposal by Lederle Laboratories.
H -S02N
( 3 SUIPHANILAMIOO - 6 -
ME T H O X V P Y R I O A Z I N E )
Fig. 3 (Bietti). Sulfamethoxypyridazine (Kyne orx Cl 13.494 or Lederkyn).
R E P O S I T O R Y DRUGS IN TRACHOMA
Our first experiments were carried out on 57' patients, mostly children of school age, suffering from trachoma II of average severity.10 They showed that sulfamethoxypyridazine given in doses of about 8.0 to 12 eg. per kg. of body weight every seven or 10 (sometimes 15) days for three months led to complete cure in 45 cases and to con siderable improvement, almost to cure, in the others. These results were noted three months after the end of the treatment; that is to say, spontaneous improvement of in completely cured cases was still possible. Actually 15 to 18 months after the end of treatment 50 cases were cured and the other seven were improved (table 1). Inclu sions usually cannot be found after the sec ond shot of the drug. I desire to point out that the dosage we used cannot be regarded as final. Good re sults would quite probably be obtained with still smaller doses.* We believe that for the * Further research still in progress conducted by my co-workers B. Latte and M. Lanzieri on 180 trachomatous individuals (mostly stage I I ) from Sardinia has actually shown that: 1. The administration of 8.0 eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be ex pected to become cured during the next months) in 48 out of 60 patients; 2. The administration of S.O eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be ex pected to become cured during the next months) in 42 out of 60 patients; 3. The administration of 3.0 eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be expected to become cure during the next months) in 18 out of 60 patients. These provisional results await further con firmation at another examination to be done after six months. The results obtained by another group of my coworkers ( P . F. Ferraris De Gaspare and M. Montaldi) among 750 individuals (plus 90 untreated controls) from Tripoli (Libia) affected by tra choma II or I I I lead to similar conclusions. Their work (still in progress and awaiting further check-ups) on groups of 30 patients each, has shown so far that:
223
time being 8.0 to 10 eg. per kg. of body weight every seven to 10 days for three months might be considered an active and practically nontoxic dose. We desire to em phasize that no incident worth noting has resulted from the administration of sulfamethoxypyridazine. Blood counts have shown excellent tolerance, since the only change observed was a certain decrease, be tween 36.4 and 10 percent, in the number of white cells. This leukopenia is most marked after the two first administrations; it then levels out at an average of 10 to 12 percent. The white cell count returns to normal a few weeks after the end of the 1. The administration of sulfamethoxypyridazine every seven days for three months was followed, three months after the end of treatment, by ( a ) 66 percent of cures, when 8.0 eg. per kg. body weight were given; (b) 60 percent of cures, when 5.0 eg. per kg. body weight were given; (c) 30 per cent of cures, when 3.0 eg. per kg. body weight were given. 2. The administration of sulfamethoxypiridazine every 10 days for three months was followed, three months after the end of treatment, by ( a ) 67 per cent of cures, when 8.0 eg. per kg. body weight were given; (b) 50 percent of cures, when 5.0 eg. per kg. body weight were given; ( c ) 24 percent of cures, when 3.0 eg. per kg. body weight were given. 3. The administration of sulfamethoxypyridazine every 12 days for three months was followed, three months after the end of treatment, by (a) 50 per cent of cures, when 8.0 eg. per kg. body weight were given; (b) 40 percent of cures, when 5.0 eg. per kg. body weight were given; ( C ) 2 0 percent of cures, when 3.0 eg. per kg. body weight were given. By adding aureomycin ointment (one percent, four times a day), the percentage of cures jumped to roughly 70 percent among the patients receiving the lowest dosage of sulfamethoxypyridazine (3.0 eg. every seven to 12 days) and almost to 90 per cent among those receiving 8.0 eg. Aureomycin ointment (one percent) if given alone for three months four times a day, was fol lowed by 60 percent of cures; if given for only four days a month during six months was followed by 30 percent of cures. The results obtained with sulfamethoxypyridazine correspond very closely to those observed after daily administration of 5.0 eg. per kg. body weight of Gantrisin. When the administration of Gantrisin took place only every seven days, the percentage of cures dropped to 23 percent. Among the 90 untreated patients only 10 percent improved consistently during the period of observa tion of six months.
224
G. B. B I E T T I TABLE 1 THERAPY WITH K Y N E X FOR THREE MONTHS
(Results obtained IS to 18 months after the end of the treatment) Number of Patients
Recovered
Almost Recovered
Much Improved
Slightly Improved
Unchanged
7
7
—
—
—
—
Group I I : Sect. A—2 gr. every 7 da., 10-11 eg. per kg. body weight
6
6
—
—
—
Group I I : Sect. B—3 gr. every 7 da.; 8.1-13 eg. per kg. body weight
10
9
1
—
—
Group I I : Sect. C—4 gr. every 7 da., 6.4-10.2 eg. per kg. body weight
8
6
2
—
—
—
Group I I I : Sect. A—2 gr. every 10 da., 9-11.8 eg. per kg. body weight
7
6
1
—
—
—
Group I I I : Sect. B—2.5 gr. every 10 da., 8.8-11 eg. per kg. body weight
5
4
1
—
—
—
Group I I I : Sect. C—3 gr. every 10 da., 9-11 eg. per kg. body weight
8
7
1
—
—
—
Group IV: 3 gr. every 15 da., 9-15 eg. per kg. body weight
6
5
1
—
—
—
57
50
7
—
—
—
Group I: 2 gr. every 5 da., 8-9 eg. per kg. body weight
TOTAL
treatment. Because of this finding we did not feel that we should continue the treat ment beyond three months in the more re sistant cases, though another course of treat ment might perhaps be considered after a two-month rest period. We also examined our patients' blood sulfonamide level, and noted that a dose of 8.0 to 10 eg. per kg. of body weight of sulfamethoxypyridazine per os gives a maxi mum concentration of about 17 mg, percent cc. at the 20th hour, and that the figure drops thereafter until on the fifth day it is very low (1.0 to 2.0 mg. percent), which may suggest that the effect on trachoma virus is then very weak (figs. 4 and 5). A more constant level of the sulfonamides in the blood can, of course, be obtained by giving every day, or every second or third
day respectively 0.5, 1.0 and 1.5 gr. of sulfamethoxypyridazine. But these dosages, which have proved in our hands fully effec tive in trachoma, can only have the aim to reduce the amount of sulfas to be given, while the purpose of using a sulfonamide of slow elimination (given periodically at regu lar intervals) is to reduce as much as pos sible the attendance of the patient to the dis pensary. In connection with the inconstant level of sulfas obtained with an intermittent ad ministration of Kynex, we wondered whether the good clinical effects which we have observed could not have been obtained by simply giving ordinary sulfonamide at periodic intervals, and whether it was nec essary to maintain any particular concen tration in the blood during the succeeding
225
R E P O S I T O R Y DRUGS IN TRACHOMA
days. Indeed, during the joint Unicef-WHO campaigns in Morocco and Egypt, Maxwell Lyons11 and Reinhards 12 noted a beneficial effect on the trachoma when spaced doses of antibiotics (for example, aureomycin oint ment twice a day on three or four consecu tive days monthly for six or seven months) were applied to the conjunctiva. To verify this finding we gave two or three gm. (according to weight) of sulfathyazol every seven days for three months to a group of eight children of body weight be tween 21 and 31.6 kg. Ten days after the end of the course no change was observed in four, little change in two others, but in the remaining two a well-marked improvement. The reduction of the hypertrophy was not comparable to that obtained in the patients treated with Kynex, but three months after the end of the treat ment we noted a later improvement which in two cases proceeded to cure. Thus, although the administration at periodic intervals of ordinary sulfonamides has a certain effect on the clinical picture of trachoma, this is less marked than the
IBS.
t
17 IS
is-l 1* 13 12 II10 9'
a ?■
6 54'
3
'
2 1HO URS
Fig. 4 (Bietti). Concentration of sulfonamide in blood after administration of 8.0 eg. of sulfamethoxypyridazine/kg. body weight. Solid line: free sulfonamide. Broken line: total.
mg. A
HOURS
20
44
68
92
116
140
i&4
tEe
ili
236~
Fig. 5 (Bietti). Concentration of sulfonamide in blood after administration of 10 eg. of sulfamethoxypyridazineAg- body weight. Solid line: free sulfonamide. Broken line: total.
effect of the same dose of a slowly-elimi nated sulfonamide which maintains after five to seven days' administration a bacteriostatic concentration in the blood and tis sues which, even though minimal, persists much longer than that produced by ordinary sulfonamides If it could be confirmed that the local intermittent antibiotic treatment (Maxwell Lyons-Reinhards) is equally effective in trachoma without bacterial contamination, the conclusion could be drawn that, since the same results cannot be obtained with spaced doses of ordinary sulfonamides, therefore antibiotics and Kynex act on the trachoma in a slightly different way: the antibiotics are active even if the action is limited to three days a month, but the sul fonamides must be present in the blood for longer in order to be fully active. We may have to do more research in order to arrive at a dosage which will be more suitable, economical, practical, effec tive, and of minimal toxicity, and in order to study the influence of sulfonamide ther apy with Kynex on the pathogenic bacterial flora associated with the trachoma (chiefly the Koch-Weeks bacillus). Nevertheless, it seems possible to state at present that slowly eliminated sulfonamides promise to be very
G. B. B I E T T I
226
useful in the mass treatment of trachoma especially in antibiotic-resistant cases (10 to 30 percent according to Reinhards). This has been recently confirmed by Rochat.13 They may sometimes be combined with local intermittent antibiotic treatment, es pecially in regions where associated bacterial conjunctivitis is a major problem. Other slowly eliminated sulfonamides (mainly sulfaphenazol) are now being tested. It may be that they will be as effective as sulfamethoxypyridazine has been shown to be. SUMMARY
The results of the clinical use in tra choma of "repository drugs" (slowly ab sorbed or eliminated substances: benzathine penicillin and sulfamethoxypyridazine) are reported. The administration of benzathine penicil lin as intramuscular injections for three months every seven to 14 to 20 days (2,500 to 2,000 units per kg. body weight per day) resulted in clinical cure of over 80 percent
of patients (89 percent every seven days). Also the administration of sulfamethoxy pyridazine at the dosage of 8.0 to 10 cg./kg. body weight every seven to 10 days for three months proved equally effective. The results have to be checked at about six months after the end of treatment, since a spontaneous improvement takes place after cessation of therapy. This intermittent schedule of treatment, especially with sulfamethoxypyridazine, which, from the practical point of view, has several advantages over penicillin, is par ticularly to be recommended for mass treat ment to communities whose members will not or cannot collaborate with the ordinary way of treatment with antibiotics. Sulfamethoxy pyridazine, moreover, offers the advantage of reducing the dosage in the ordinary therapy schedule of trachoma, as well as of other ophthalmic infectious diseases. It may also be used with benzathine penicillin and local anti biotics in special cases. University of Rome.
REFERENCES 1. Bietti, G. B., and Ferraris De Gaspare, P. F.: Rev. int. Trach., 31:47, 1954. 2. Bietti, G. B.: Policlinico Sez. Pratica, 52:36, 1945. 3. Poieff, L.: Rev. int. Trach., 31:434, 1954; Maroc Med., No. 243, 1953. 3b. Gilkes, M. J., Smith, C. H., and Sowa, J.: Brit. J. Ophth., 42:478, 1958., 4. T'ang, F. F., et al.: Scientia Sinica, Nos. 4, 5, 1956. 5. Collier, I. H.: Brit. M. J. in press; personal communication, X V I I I Cone, ophthalmologicum, 1958, Brussels. 6. Bietti, G. B , and Pannarale, M. R.: Rev. int. Trach., 32:354, 1955. 7. Milano: Rev. int. Trach., 33:515, 1956. 8. Brignola: Personal communication. 8b. Rende, S.: Rev. Ital. Tracoma, 8:134, 1956. 9. Yap: Communication to W H O . 10. Bietti, G. B., and Lanzieri, M.: Rev. int. Trach., 34:270, 1957. 11. Maxwell-Lyons, F . : W H O , Euro-158, 1/8, 1958. 12. Reinhards, J.: W H O , Euro-158, 1/11, 1958. 13. Rochat, G. F . : Excerpta Med., X V I I I Cone, ophthalmologicum, Brussels, 1958.
J. BOECK AND H. HUECKEL
3. Becker, B.: The effects of the carbonic anhydrase inhibitor, acetazolamide, on the composition of the aqueous humor. Am. J. Ophth., 40:129-136 (Feb. Pt. II) 1955. 4. Becker, B., and Constant, M. A.: The alterations in aqueous-humor lactate concentration following systemic carbonic anhydrase inhibition. Am. J. Ophth., 42:406-408, 1956. 5. Becker, B.: The bicarbonate concentration of guinea pig aqueous humor: Effect of scurvy and acetazolamide. Am. J. Ophth., 44:402-408 (Nov. Pt. II) 1957. 6. Boeck, J., Hiickel, H., and Karwounidis, C.: Ueber den Einfluss von Acetazolamid (Diamox) auf den Eiweissgehalt des Kammerwassers. Wien. Klin. Wchnschr., 1958, pp. 907-909. 7. Franceschetti, A., Marty, F., Dubler, H., Falbriard, A., and Sanz, M. C.: Ueber den Einfluss von Acetazolamid (Diamox) auf die Chemie des Kammerwassers. Docum. Ophth., 11:196-216, 1957. 8. Green, H., and Leopold, I. H.: Effects of locally administered Diamox. Am. T. Ophth., 40:137-139 (Feb. Pt. II) 1955. 9. Green, H., Mann, M. J., and Kroman, H. S.: Elaboration of bicarbonate ion in intraocular fluids: IV. Dynamic effects of acetazolamide (Diamox). Am. J. Ophth., 44:388-402 (Nov. Pt. II) 1957. 10. Harris, J. E., Carlson, A. E., Gruber, L., and Hoskinson, G.: The aqueous: serum sodium and potassium steady-state ratios in the rabbit. Am. J. Ophth., 44:409-419 (Nov. Pt. II) 1957. 11. Harris, J. E., Beaudreau, O., and Hoskinson, G.: Clinical and laboratory experiences with the carbonic anhydrase inhibitor, dichlorphenamide. Am. J. Ophth., 45:120, (July Pt. II) 1958. 12. Hoffmann-Ostenhof, O.: Enzymologie. Wien, Springer-Verlag, 1954. 13. Hiickel, H.: Der Eiweissgehalt im Kammerwasser des einen Auges nach Entnahme von Kammerwasser aus dem anderen Auge. Arch. f. Ophth., 160:293-300,1958. 14. Kinsey, V. E., Camacho, E., Cavanaugh, G. A., and Constant, M.: Diamox and intraocular fluid dynamics. Am. J. Ophth., 40:147-148 (Feb. Pt. II) 1955. 15. Langham, M. E., and Lee, P. M.: Action of Diamox and ammonium chloride on formation of aqueous humor. Brit. J. Ophth., 41:65-92, 1957. 16. Langham, M. E.: Specificity and comparative activity of the carbonic anhydrase inhibitors Neptazane and Diamox on animal and human eyes. Brit. J. Ophth., 42:577-588, 1958. 17. Levene, R. Z.: (a) Osmolarity in the normal state and following acetazolamide. Arch. Ophth., 59: 597-602, 1958; (b) Sodium and potassium concentrations following acetazolamide. Arch. Ophth., 59:868872, 1958. 18. Takaoka, S.: Change in the intraocular pressure and K-ion concentration in aqueous and serum by Diamox in primary glaucoma. Acta soc. ophth. Japan, 60:281-284, 1956. (Cited Zentralbl. f. Ophth., 69: 224, 1957. 19. Urrets-Zavalia, A. Jr., and Remedi, G.: Ionometry of the aqueous humor: Report on the mode of action of acetazolamide. Am. J. Ophth., 41:197-203, 1956. 20. Wistrand, P. T.: Carbonic anhydrase in the anterior uvea of the rabbit. Acta physiol. scand., 24: 144-148, 1951.
REPOSITORY DRUGS IN THE TREATMENT OF TRACHOMA* G.
B.
BIETTI,
M.D.
Rome, Italy Although sulfonamides and antibiotics have undoubtedly given excellent results in the treatment of trachoma, the manner of their administration and the duration of the treatment make them less suitable for use outside schools and certain communities. This applies both to areas in which the schools are not attended by all the children of school age, and to "contacts" of patients undergoing regular treatment (for example, children of preschool and postschool age * From the Ophthalmic Clinic, University of Rome.
and adults in the families of children under treatment at school). Mass treatment, more over, requires that the whole population should be treated alike, partly because of the risk of reinfection among children who have been cured by antibiotic or sulfonamide treatment and have left school. This risk, due to the weakness of the immunity con ferred by cured trachoma, has been con firmed by Bietti and Ferraris De Gespare 1 in cured patients living in a superendemic environment. It occurred to us to use "repository" (slowly-absorbed or slowly-eliminated) sub-
REPOSITORY DRUGS TN TRACHOMA
221
studies, and the research of T'ang 4 and his co-workers and of Collier5 on culture of the trachoma virus, which failed when the sam ple was treated with penicillin but not with streptomycin. All this work proves beyond doubt that penicillin acts on the trachoma virus. My first experiments were performed BENZATHINE PENICILLIN with my co-worker Pannarale 6 on 35 pa The first substance we used was a peni tients, mostly school children, who all had cillin with a prolonged action, N,N dibenzyl- well-established trachoma. ethylenediamine dipenicillin G (benzathine Eighteen of these patients received an penicillin), which has an exceptionally long- intramuscular injection of DBEP every 14 continued action and is absorbed gradually. days, 10 every 20 days, and seven every 30 The blood levels are at first low, but ther- days. In the first group only eight, in the apeutically active concentrations of peni second only six, and in the third only four cillin are maintained in the serum and tis injections were given. The treatment there sues for a very long time (fig. 1). This fore took about three months, and the use of penicillin is based on Bietti's2 ob dosage was calculated to give about 2,000 to servations since 1944 on its effects on the 2,500 units per kg. of body weight intra trachoma virus (degeneration and disap muscularly per day. For instance, a child pearance of inclusions, clinical cure of tra weighing 20 kg. received 900,000 units every choma). These observations have unfortu two weeks or 1,200,000 every 20 days. nately remained unnoticed for a long time. The results obtained four months after I should like, however, to mention Poleff's3 the start of treatment were: and Gilkes' and co-workers3b inclusions a. Of the 18 patients treated every 14 days, 12 were completely cured and two almost completely cured. oo/cc b. Of the 10 patients treated every three 2weeks, seven were completely and two nearly cured. c. Of the seven patients treated every 0.5 30 days, three were completely and two 0.25nearly cured. Two years after the start of treatment the 0.12results were even better. Not only had all 00.6' the patients considered cured four months 003 after the start of treatment remained so, but others had been completely cured. Thus 0Q1conjunctival hypertrophy had completely dis appeared in 16 of the first group of 18 DAYS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 patients (one case was not cured but im THE CORRESPONDING DOSAGE FOR TREATMENT GIVEN EVERY-14 DAYS proved, and another could not be found) ; nine patients out of the second group of 10 IDEM EVERY-20 DAYS (one case was treated elsewhere by other fDEM EVERY-30 DAYS means), and out of the third group of Fig. 1 (Bietti). Concentration of penicillin in seven those five patients who could be seen blood after injection of 2,500 units/kg. in subjects again, were completely cured. of 25 to 35 kg. body weight.
stances in an attempt to solve the problem of giving as full a treatment as possible to communities whose members will not collab orate well and cannot be altogether trusted to treat themselves. They can do so very easily, however, by using antibiotic eyedrops or ointment over a long enough period.
222
G. B. B I E T T I
% OF CURES 9080-
//
70 60
*'
,•
SO
7/
/
40-
fa /
y%3
/
°71
Ay
30-
y 20 B ft1
0
3
lla
MONTHS MONTHS TIME ELAPSED FROM END OF TREATMENT
-•
u
\\
n
20 w
Fig. 2 (Bietti). Percentage of patients cured with benzathine penicillin according to the schedule of ad ministration and the time elapsed from end of treat ment.
Inclusion bodies had already disappeared after the first shot of benzathine penicillin. Benzathine penicillin was used again by my co-worker Pannarale on four groups comprising 198 patients, showing an ac tive trachoma generally of average sever ity who received the same doses as in the first experiment every seven, 14, 20, and 30 days. After three months' treatment there was complete cure in 53 percent of the cases treated every seven days, in 41 percent of the cases treated every 14 days, in 24 per cent of those treated every 20 days, and in 21 percent of those treated every 30 days. Between one and two months after the end of the treatment the residual hyper trophy had resolved and complete cure could be observed in 82 percent of the cases treated every seven days, in 80 percent of the cases treated every 14 days, in 64 per cent of those treated every 20 days, and in 43 percent of those treated every 30 days. Between three and five months after the end of treatment there was complete cure in 89 percent of the cases treated every seven days, in 81 percent of those treated every 14 days, in 83 percent of those treated
every 20 days, and in 71 percent of the cases treated every 30 days. The most active treatment thus proved to be that given at intervals of seven to 20 days (fig. 2 ) . We are also exploring the possibility of treatment by spaced doses of benzathine penicillin per os. Milano7 and Brignola8 and Rende8b have also obtained satisfactory results with ben zathine penicillin. Yap 9 approves of its use but has not formed a precise opinion con cerning its action on the virus, considering its antibacterial action more important. In spite of these good results, however, benzathine penicillin treatment has the un deniable disadvantages of being costly and of requiring the injection of large doses of suspended antibiotic (especially when the patient has a high body weight). It also causes a certain amount of local discomfort at the site of injection, and sometimes a fever reaction after heavy doses (for ex ample, those given at 30-day intervals). There is also the theoretic possibility of al lergy and penicillin anaphylactic shock, though we have never seen them in patients treated with benzathine penicillin. Moreover, if kept in a hot climate, the present prepara tions of benzathine penicillin G are not absolutely certain to be stable. SULFONAMIDES
These considerations induced us to under take further research, especially since peni cillin treatment is certainly useless for the seasonal conjunctivitis of Koch-Weeks as sociated with trachoma in certain countries. We therefore used a sulfonamide of slow elimination, sulfamethoxypyridazine (Kynex, Cl 13.494, or Lederkyn, fig. 3), kindly put at our disposal by Lederle Laboratories.
H -S02N
( 3 SUIPHANILAMIOO - 6 -
ME T H O X V P Y R I O A Z I N E )
Fig. 3 (Bietti). Sulfamethoxypyridazine (Kyne orx Cl 13.494 or Lederkyn).
R E P O S I T O R Y DRUGS IN TRACHOMA
Our first experiments were carried out on 57' patients, mostly children of school age, suffering from trachoma II of average severity.10 They showed that sulfamethoxypyridazine given in doses of about 8.0 to 12 eg. per kg. of body weight every seven or 10 (sometimes 15) days for three months led to complete cure in 45 cases and to con siderable improvement, almost to cure, in the others. These results were noted three months after the end of the treatment; that is to say, spontaneous improvement of in completely cured cases was still possible. Actually 15 to 18 months after the end of treatment 50 cases were cured and the other seven were improved (table 1). Inclu sions usually cannot be found after the sec ond shot of the drug. I desire to point out that the dosage we used cannot be regarded as final. Good re sults would quite probably be obtained with still smaller doses.* We believe that for the * Further research still in progress conducted by my co-workers B. Latte and M. Lanzieri on 180 trachomatous individuals (mostly stage I I ) from Sardinia has actually shown that: 1. The administration of 8.0 eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be ex pected to become cured during the next months) in 48 out of 60 patients; 2. The administration of S.O eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be ex pected to become cured during the next months) in 42 out of 60 patients; 3. The administration of 3.0 eg. of Lederkyn per kg. of body weight every seven to 10 days for three months produced complete or almost com plete cure or marked improvement (to be expected to become cure during the next months) in 18 out of 60 patients. These provisional results await further con firmation at another examination to be done after six months. The results obtained by another group of my coworkers ( P . F. Ferraris De Gaspare and M. Montaldi) among 750 individuals (plus 90 untreated controls) from Tripoli (Libia) affected by tra choma II or I I I lead to similar conclusions. Their work (still in progress and awaiting further check-ups) on groups of 30 patients each, has shown so far that:
223
time being 8.0 to 10 eg. per kg. of body weight every seven to 10 days for three months might be considered an active and practically nontoxic dose. We desire to em phasize that no incident worth noting has resulted from the administration of sulfamethoxypyridazine. Blood counts have shown excellent tolerance, since the only change observed was a certain decrease, be tween 36.4 and 10 percent, in the number of white cells. This leukopenia is most marked after the two first administrations; it then levels out at an average of 10 to 12 percent. The white cell count returns to normal a few weeks after the end of the 1. The administration of sulfamethoxypyridazine every seven days for three months was followed, three months after the end of treatment, by ( a ) 66 percent of cures, when 8.0 eg. per kg. body weight were given; (b) 60 percent of cures, when 5.0 eg. per kg. body weight were given; (c) 30 per cent of cures, when 3.0 eg. per kg. body weight were given. 2. The administration of sulfamethoxypiridazine every 10 days for three months was followed, three months after the end of treatment, by ( a ) 67 per cent of cures, when 8.0 eg. per kg. body weight were given; (b) 50 percent of cures, when 5.0 eg. per kg. body weight were given; ( c ) 24 percent of cures, when 3.0 eg. per kg. body weight were given. 3. The administration of sulfamethoxypyridazine every 12 days for three months was followed, three months after the end of treatment, by (a) 50 per cent of cures, when 8.0 eg. per kg. body weight were given; (b) 40 percent of cures, when 5.0 eg. per kg. body weight were given; ( C ) 2 0 percent of cures, when 3.0 eg. per kg. body weight were given. By adding aureomycin ointment (one percent, four times a day), the percentage of cures jumped to roughly 70 percent among the patients receiving the lowest dosage of sulfamethoxypyridazine (3.0 eg. every seven to 12 days) and almost to 90 per cent among those receiving 8.0 eg. Aureomycin ointment (one percent) if given alone for three months four times a day, was fol lowed by 60 percent of cures; if given for only four days a month during six months was followed by 30 percent of cures. The results obtained with sulfamethoxypyridazine correspond very closely to those observed after daily administration of 5.0 eg. per kg. body weight of Gantrisin. When the administration of Gantrisin took place only every seven days, the percentage of cures dropped to 23 percent. Among the 90 untreated patients only 10 percent improved consistently during the period of observa tion of six months.
224
G. B. B I E T T I TABLE 1 THERAPY WITH K Y N E X FOR THREE MONTHS
(Results obtained IS to 18 months after the end of the treatment) Number of Patients
Recovered
Almost Recovered
Much Improved
Slightly Improved
Unchanged
7
7
—
—
—
—
Group I I : Sect. A—2 gr. every 7 da., 10-11 eg. per kg. body weight
6
6
—
—
—
Group I I : Sect. B—3 gr. every 7 da.; 8.1-13 eg. per kg. body weight
10
9
1
—
—
Group I I : Sect. C—4 gr. every 7 da., 6.4-10.2 eg. per kg. body weight
8
6
2
—
—
—
Group I I I : Sect. A—2 gr. every 10 da., 9-11.8 eg. per kg. body weight
7
6
1
—
—
—
Group I I I : Sect. B—2.5 gr. every 10 da., 8.8-11 eg. per kg. body weight
5
4
1
—
—
—
Group I I I : Sect. C—3 gr. every 10 da., 9-11 eg. per kg. body weight
8
7
1
—
—
—
Group IV: 3 gr. every 15 da., 9-15 eg. per kg. body weight
6
5
1
—
—
—
57
50
7
—
—
—
Group I: 2 gr. every 5 da., 8-9 eg. per kg. body weight
TOTAL
treatment. Because of this finding we did not feel that we should continue the treat ment beyond three months in the more re sistant cases, though another course of treat ment might perhaps be considered after a two-month rest period. We also examined our patients' blood sulfonamide level, and noted that a dose of 8.0 to 10 eg. per kg. of body weight of sulfamethoxypyridazine per os gives a maxi mum concentration of about 17 mg, percent cc. at the 20th hour, and that the figure drops thereafter until on the fifth day it is very low (1.0 to 2.0 mg. percent), which may suggest that the effect on trachoma virus is then very weak (figs. 4 and 5). A more constant level of the sulfonamides in the blood can, of course, be obtained by giving every day, or every second or third
day respectively 0.5, 1.0 and 1.5 gr. of sulfamethoxypyridazine. But these dosages, which have proved in our hands fully effec tive in trachoma, can only have the aim to reduce the amount of sulfas to be given, while the purpose of using a sulfonamide of slow elimination (given periodically at regu lar intervals) is to reduce as much as pos sible the attendance of the patient to the dis pensary. In connection with the inconstant level of sulfas obtained with an intermittent ad ministration of Kynex, we wondered whether the good clinical effects which we have observed could not have been obtained by simply giving ordinary sulfonamide at periodic intervals, and whether it was nec essary to maintain any particular concen tration in the blood during the succeeding
225
R E P O S I T O R Y DRUGS IN TRACHOMA
days. Indeed, during the joint Unicef-WHO campaigns in Morocco and Egypt, Maxwell Lyons11 and Reinhards 12 noted a beneficial effect on the trachoma when spaced doses of antibiotics (for example, aureomycin oint ment twice a day on three or four consecu tive days monthly for six or seven months) were applied to the conjunctiva. To verify this finding we gave two or three gm. (according to weight) of sulfathyazol every seven days for three months to a group of eight children of body weight be tween 21 and 31.6 kg. Ten days after the end of the course no change was observed in four, little change in two others, but in the remaining two a well-marked improvement. The reduction of the hypertrophy was not comparable to that obtained in the patients treated with Kynex, but three months after the end of the treat ment we noted a later improvement which in two cases proceeded to cure. Thus, although the administration at periodic intervals of ordinary sulfonamides has a certain effect on the clinical picture of trachoma, this is less marked than the
IBS.
t
17 IS
is-l 1* 13 12 II10 9'
a ?■
6 54'
3
'
2 1HO URS
Fig. 4 (Bietti). Concentration of sulfonamide in blood after administration of 8.0 eg. of sulfamethoxypyridazine/kg. body weight. Solid line: free sulfonamide. Broken line: total.
mg. A
HOURS
20
44
68
92
116
140
i&4
tEe
ili
236~
Fig. 5 (Bietti). Concentration of sulfonamide in blood after administration of 10 eg. of sulfamethoxypyridazineAg- body weight. Solid line: free sulfonamide. Broken line: total.
effect of the same dose of a slowly-elimi nated sulfonamide which maintains after five to seven days' administration a bacteriostatic concentration in the blood and tis sues which, even though minimal, persists much longer than that produced by ordinary sulfonamides If it could be confirmed that the local intermittent antibiotic treatment (Maxwell Lyons-Reinhards) is equally effective in trachoma without bacterial contamination, the conclusion could be drawn that, since the same results cannot be obtained with spaced doses of ordinary sulfonamides, therefore antibiotics and Kynex act on the trachoma in a slightly different way: the antibiotics are active even if the action is limited to three days a month, but the sul fonamides must be present in the blood for longer in order to be fully active. We may have to do more research in order to arrive at a dosage which will be more suitable, economical, practical, effec tive, and of minimal toxicity, and in order to study the influence of sulfonamide ther apy with Kynex on the pathogenic bacterial flora associated with the trachoma (chiefly the Koch-Weeks bacillus). Nevertheless, it seems possible to state at present that slowly eliminated sulfonamides promise to be very
G. B. B I E T T I
226
useful in the mass treatment of trachoma especially in antibiotic-resistant cases (10 to 30 percent according to Reinhards). This has been recently confirmed by Rochat.13 They may sometimes be combined with local intermittent antibiotic treatment, es pecially in regions where associated bacterial conjunctivitis is a major problem. Other slowly eliminated sulfonamides (mainly sulfaphenazol) are now being tested. It may be that they will be as effective as sulfamethoxypyridazine has been shown to be. SUMMARY
The results of the clinical use in tra choma of "repository drugs" (slowly ab sorbed or eliminated substances: benzathine penicillin and sulfamethoxypyridazine) are reported. The administration of benzathine penicil lin as intramuscular injections for three months every seven to 14 to 20 days (2,500 to 2,000 units per kg. body weight per day) resulted in clinical cure of over 80 percent
of patients (89 percent every seven days). Also the administration of sulfamethoxy pyridazine at the dosage of 8.0 to 10 cg./kg. body weight every seven to 10 days for three months proved equally effective. The results have to be checked at about six months after the end of treatment, since a spontaneous improvement takes place after cessation of therapy. This intermittent schedule of treatment, especially with sulfamethoxypyridazine, which, from the practical point of view, has several advantages over penicillin, is par ticularly to be recommended for mass treat ment to communities whose members will not or cannot collaborate with the ordinary way of treatment with antibiotics. Sulfamethoxy pyridazine, moreover, offers the advantage of reducing the dosage in the ordinary therapy schedule of trachoma, as well as of other ophthalmic infectious diseases. It may also be used with benzathine penicillin and local anti biotics in special cases. University of Rome.
REFERENCES 1. Bietti, G. B., and Ferraris De Gaspare, P. F.: Rev. int. Trach., 31:47, 1954. 2. Bietti, G. B.: Policlinico Sez. Pratica, 52:36, 1945. 3. Poieff, L.: Rev. int. Trach., 31:434, 1954; Maroc Med., No. 243, 1953. 3b. Gilkes, M. J., Smith, C. H., and Sowa, J.: Brit. J. Ophth., 42:478, 1958., 4. T'ang, F. F., et al.: Scientia Sinica, Nos. 4, 5, 1956. 5. Collier, I. H.: Brit. M. J. in press; personal communication, X V I I I Cone, ophthalmologicum, 1958, Brussels. 6. Bietti, G. B , and Pannarale, M. R.: Rev. int. Trach., 32:354, 1955. 7. Milano: Rev. int. Trach., 33:515, 1956. 8. Brignola: Personal communication. 8b. Rende, S.: Rev. Ital. Tracoma, 8:134, 1956. 9. Yap: Communication to W H O . 10. Bietti, G. B., and Lanzieri, M.: Rev. int. Trach., 34:270, 1957. 11. Maxwell-Lyons, F . : W H O , Euro-158, 1/8, 1958. 12. Reinhards, J.: W H O , Euro-158, 1/11, 1958. 13. Rochat, G. F . : Excerpta Med., X V I I I Cone, ophthalmologicum, Brussels, 1958.