|Year : 1953 | Volume
| Issue : 4 | Page : 113-118
Use of isonicotinic acid hydrazide in ocular-tuberculosis
Dept. of Ophthalmology, Medical College, Nagpur, India
|Date of Web Publication||12-May-2008|
K R Kesavachar
Dept. of Ophthalmology, Medical College, Nagpur
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kesavachar K R. Use of isonicotinic acid hydrazide in ocular-tuberculosis. Indian J Ophthalmol 1953;1:113-8
Early in 1952 a spectacular announcement was made in the press about the discovery of a new and potent drug against tuberculosis, namely Isonicotinic Acid Hydrazide. Since that time a large number of articles have appeared on the use of this drug, its limitations and side effects.
The fact that lsonicotinic Acid Hydrazide has a very marked effect on Tubercle bacilli was discovered simultaneously by workers of Messrs. Squibbs and Hoffman La Roche. This drug is an intermediary product of the combination of thio-semiCarbazones ( derivatives of Sulfonamides ) and nicotinamide. The accepted generic name is " Isoniazid."
It has been shown by Edward H. Robitzek and Irving J. Selikoff ( 1952) that the drug is absorbed easily and maximal concentrations obtained in the blood between one and six hours after oral administration. This concentration persists for 6-24 hours. The drug is excreted in the urine. The cerebo-spinal fluid of patients show appreciable quantities of the drug about three hours after an oral dose.
The Medical Research Council in Great Britain appointed a Tuberculosis Chenmotherapy Trials Committee ( 1952 ). Isonicotinic Acid Hydrazide was given extensive trials from June 1952. The report said "Toxicity with this drug has been a very minor problem. At the end of three months there was rather more improvement in the general condition of the patients on Isoniazid than in the other patients on Streptomycine and PAS, but the differences were not great."
The Committee came to the conclusion that given alone this drug is not more effective than Streptomycine and PAS.
Evidence is accumulating to the fact that resistance to the drug develops in quite a number of cases. ( Grofton 1953 ).
Lattimer of Columbia University ( 1953 ) states that Isoniazid is effective in Streptomycine resistant cases. It does not exert any toxic action on the kidney, but is a convulsant and as such should be given to epileptics with caution. He is also of the opinion that given along with PAS. resistance to the drug does not develop so easily. The dosage that has been recommended generally is 4 mgm. per kg. of body weight.
Gordon M. Meade ( 1953 ) mentions that it is distinctly favourable in miliary tuberculosis and tuberculous meningitis. The side effects that have been described are minimal and usually of no consequence though varied. Constipation, vertigo. muscular twitching, euphoria, drowsiness, insomnia, retention of urine, and dermatitis have all been noticed after administration of lsoniazids.
Tuberculous manifestations in the eye are, in the vast majority of cases, secondary. These manifestations are probably more allergic in nature than due to organismal infections. As has been recognised for years, ocular tuberculosis almost never occurs in persons who have a patent tuberculous infection. The majority of cases occurs in apparently healthy young persons particularly women, in whom the search for the primary focus is difficult and often impossible to detect. Roentgenograms, estimation of erythrocytic sedimentation rate, intradermal tuberculin tests. etc., are quite inconclusive in the majority of cases. The severity of the eye manifestation often stands in inverse proportion to the primary focus. The main primary foci are the trachxo-bronchial and abdominal glands --Semadeni ( 1950 ). A certain percentage of these people show a large " healed primary focus in the lung itself.
The following clinical reports of four cases is intended, as far as its limited scope goes, to draw attention towards the use of Isonicotinic acid hydrazide in ocular tuberculosis. Admittedly it is not possible to draw definite conclusions on the basis of only four cases, but the good results thus far obtained prompt continued experimentation with this drug. The four cases reported were in young women and all of them showed at the time of discharge the clinical picture of an almost healed Interstitial Keratitis.
| Case Reports|| |
Case-1 -- M as. M. G.
Hindu female 30 years old. First seen on 5-11-52, with a complaint of shooting pain in the left eye and dimness of vision: duration six months. No other complaint.
Examination revealed a normal right eye with a vision of 6/6. The left eye showed the following features:
There was deep annular scleritis, with the cornea at the periphery very hazy all round. Slit lamp examination showed a small deep corneal opacity just outside and above the pupil. Subacute iridocyclitis was present with plenty of keratic precipitates. Blood vessels were seen invading the deeper parts of cornea from all round, grouped together in bunches. The eye was very tender. Fundus appeared normal apart from a thin vitreous haze. Vision was 6/24. Systemic examination did not reveal any abnormality apart from a few enlarged posterior cervical glands.
Special Investigations :
Urine: No abnormality except for a few epithelial cells.
Blood: for Kahn's test repeatedly negative.
Differential count for white blood corpuscles showed 10% eosinophils.
E.S.R.: 17 m.m. during first hour by Westergreen method.
X-Ray of chest showed no abnormality.
Stools: No ova or cysts of any kind detected.
Mantoux test ( 1 in 10,000 ) showed a reaction 11 m.m. in diameter after 48 hours.
Atropine ointment 1% b.d. Pad and bandage.
Parenteral Streptomycine ½ gm, daily and PAS 4 gins. t.d.s. orally .
After live days the patient showed no improvement though the pupil was widely dilated. Iridocyclitis was very active with a large number of K.P.s Deep vascularization appeared to have increased. The same treatment was persisted with, for a week more, Then streptomycine was stopped and the patient was put on Isoniazid ( I.N.H.-Brand of Tibizide ) 150 mgm. daily in three divided doses. PAS was continued as before. Four days later the eye was very much quieter: K.P.s were disappearing and so also the deep blood vessels. This treatment was continued for 20 clays and the patient was discharged a month and five days after admission with a quiet eye.
Slit Lamp examination at that time revealed a large thin deep opacity just outside the pupil and only a few deep blood vessels on the temporal side of the cornea. There was no sign of deep annular scleritis. Fundus was almost clear.
The patient was seen 2 months later with a quiet eye. The deep opacity was persisting and the deep vessels appeared empty. The patient was again seen 6 months later. The deep opacity was as before. Eve was quiet; a few shining yellow crystals were seen in the area of the opacity in the cornea (2 Cholesterol crystals). Otherwise the eve was quiet and has remained so since then.
Case- -2- Miss. J. B.
Hindu female, aged 20 years, was first seen on 9-10-52 with multiple phlyctenes just outside the limbus of the right eye and what looked like a phlyctenular keratitis. The eve was very irritable with severe photophobia and blepharospasm. Patient was treated with calomel dusting, atropine ointment and Sulfathiozole 5% ointment. The condition did not subside, and she was admitted as an inpatient on 20-10-52. There was no history of any other complaint apart from this eye trouble.
Examination of the eye on 20-10-52 showed an extremely irritable eye; pupil would not dilate in spite of using 2% atropine ointment. Phlyctenes were still present; Cornea showed no staining with fluoresciene. Slit lamp examination revealed, multiple deep opacities with plenty of deep blood vessels, with very little branching and anastomosis.
Special Investigations :
Systemic examination revealed nothing abnormal. A pelvic examination by the Gynaecologist showed no abnormality. Blood for Kahn was repeatedly negative. Skiagram of the chest revealed clear lung fields. E.S.R. was normal. Urine and stools examination also did not show any abnormality. Mantoux test was not done.
The patient was put on atropine 1% ointment right eye twice daily, and calomel dusting once daily. Streptomycine ½ gm. daily intramuscularly, and PAS 4 gm. three times a day' orally were ordered. The eye was bandaged.
With this treatment it was noticed that the eye would quieten down for a few days and flare up again and become as irritable as before. The pupil would not dilate at all even with Mydricaine injections though there were no posterior-synechiae.
The same treatment was persisted with for 20 days. at the end of which time slit lamp examination revealed further deep involvement of the cornea. Systemic Penicillin was also tried with no avail.
Then the parenteral streptomycine was stopped and was replaced by sub-conjunctival injection of the same drug, 10 mgm. daily. A very interesting feature was noticed with these injections. The pupil which would not dilate even with Mydricaine, dilated widely when Streptomycine was given suh-coniunctivally. The corneal irritability subsided considerably. But as soon as the Streptomycine was withdrawn the eye became irritable and the pupil contracted again, even though mydricaine was continued.
Though the eye became less irritable with sub-conjunctival Streptomycine, the deep opacities and deep vessels persisted. So on 20-11-52, a month after admission, Isoniazid was started, 150 mgm. a day in three divided doses-and sub-conjunctival Streptomycine and PAS orally were continued. After the administration of Isoniazid, there was flaring up of the eye four times during a period of a month and ten days. But it was noticed that the general tendency of the eye was to quieten down.
On 20-12-52, the eye settled down completely and from that day a rapid regression of the opacities and deep blood vessels was noticed. I he patient was discharged on 3-1-53. with an absolutely quiet eye. Slit lamp examination at that time revealed only a few deep blood vessels and deep opacities. 'Fen daps later the patient cane back with a flared up eve and was readmitted. The same treatment was continued namely Isoniazid 150 mgm. daily, sub-conjunctival Streplomycine 10 mgm. and PAS 4 gm. daily. Locally atropine ointment was used. The redness rapidly subsided and patient was discharged on 22-1-53 with a quiet eye. The patient was seen three months later. The eye was quiet. There were no deep blood vessels but a few thin deep opacities persisted.
Case - -3 -Miss S.
A young girl aged 13 years was first seen on 20-2-53 with the complaint of pain. redness and discharge is the right eye: duration 4 months. Examination of the eye revealed a highly edematous tipper lid. Eversion of the lid which was very difficult did not reveal anything abnormal apart from the injection. When the lids were pulled apart, a large " ulcer size 10 mm. diameter, was seen at the 12 o'clock position of the Iimbos tending to encroach on the cornea.
The edges of the ulcer were everted. The floor of the ulcer was covered with mucopurulent debris. The conjunctiva was slightly chemotic all round the ulcer. The cornea near the ulcer showed a superficial and deep haze. No blood vessels were seen invading the cornea. Left eve was normal.
Systemic examination showed enlarged preauricular and submandibular lymph glands on the right side. The tonsils were large and appeared inflamed.
A smear from the conjunctiva and ulcer revealed the presence of pus cells and staphylococi. Blood for Kahn was repeatedly negative. Chest X-Rap showed nothing abnormal.
The case was diagnosed provisionally as chronic tuberculous conjunctival ulcer. The patient was kept on sub-conjunctival penicillin 50,000 units, infiltrated all round the ulcer, sulfathiocole 5% ointment and atropine drops daily.
On 27-2-53 a hit of the edge of the ulcer was excised and sent up for pathological examination. The report came up as "Chronic granulation tissue. So the same treatment was persisted with.
On 10-3-53, it was noticed that the ciliary injection had increased. A deep paracentral corneal opacity appeared with deep blood vessels in that area. In view of this, the subconjunctival penicillin was replaced by sub-conjunctival streptomycine 10 mgm., along with PAS 3 gm. t.d.s. Locally atropine ointment was used and the ulcer was painted with lactic acid daily for three days. Painting with lactic acid increased the irritation and so was discontinued.
On 16-3-53 the biopsy was repeated and the report of the Pathologist stated " Histology very suggestive of tubercular granulation tissue, as two typical tubercles are seen in a mass of lymphoid tissue -pathological diagnosis-tubercular granulation tissue."
The sub-conjunctival streptomycine was continued but as the eye continued irritable, Isoniazid was also started 150 mgm, in three divided closes daily along with PAS 3 gm. daily. During the month of this treatment the eye showed intermission and remissions. But on 18-4-53 it was noticed that the ulcer was definitely healing and the irritability, of the eye was subsiding. The oedema of the lids subsided and by 24-4-53 the eye had more or less quietened down. Ten dass later the ulcer had healed completely though the ciliars injection persisted to sonic extent. So Isoniazid and PAS were continued but streptomycine was stopped. This went on for nearly a month and on 28-5-53 the eye was absolutely quiet. Patient was discharged on 30-5-53. Slit lamp examination at that time showed the presence of a thin deep para central opacity with a few deep blood vessels. The patient was seen regularly for three months after that. The eye did not flare up again. The deep opacity did not disappear completely, though the blood vessels mostly regressed. Here again, as in case I. were seen the shining yellow crystals in the area of the corneal opacity( ? Cholesterol crystals ).
Case- - 4 -- Mrs. T.
Hindu female aged 28 years was first seen in the outdoor department on 9-6-53 with deep annular scleritis both eyes and corneal opacities near the limbus. On 22-6-53 she was admitted as an in-patient.
Slit lamp examination of the eves on 25-6-53 showed the presence of deep scleritis in both eves, more in the left eye, and the presence of deep opacities and deep blood vessels in both the eyes.
Systemic examination revealed nothing abnormal. The patient was a young well built woman, but the posterior cervical Imph glands were found considerably enlarged.
Urine and stools examined showed nothing abnormal.
E.S.R. was 6 m.m. during first hour.
X-Ray of the chest showed a healed primary focus.
No active Tuberculous lesion.
Blood for Kahn was repeatedly negative.
Blood Urea 30.7 mgm. per 100 c.c.
Blood uric acid 3.33 mgm. per 100 c.c.
Mantoux test was negative.
Examination of the teeth and car, nose and throat revealed nothing abnormal.
1% atropine ointment was used in the eyes b.d. Streptomycine parenteral ½ gm. daily.
lsoniazid 150 mgm. daily in three divided doses.
PAS 4 gm. daily t.d.s.
Four days after this treatment, the eyes started quieting down, the right eye more rapidly than the left. A month later it was noticed that the eyes were almost quiet but the left eve continued to be slightly irritable. The deep opacities persisted, though thinning out, but the deep blood vessels were definitely regressing.
On the basis of the opinion that these cases of clinical ocular tuberculosis are allergic manifestations to tuberculous protein, Cortisone ointment was administered locally for a week thrice daily along with the other drugs. The inflammation in the left eye rapidly subsided and Cortisone was withdrawn. The patient was kept on Isoniazid and PAS only for a few more days. Local atropine ointment was continued. The patient was discharged on 5-8-53 with both eyes completely quiet.
Slit Lamp examination at the time of discharge showed that the deep opacities and deep blood vessels though present, were definite) disappearing. She was seen a month later. There was no flare up. The deep opacities were very thin and there were only a few deep blood vessels.
| Conclusions|| |
Reflecting on the effect of treatment in these four cases we find that tuberculous annular scleritis, which ordinarily is a very resistant form of ocular condition yielded to the combined effect of the modern antibiotic and chemotherapeutic agents, and resulted in a complete and lasting cure.
As in none of these cases isoniazid was used solely, it would not be logical to put down all the improvement to this new chemotherapeutic drug against tuberculosis. This much can he said that improvement began to show itself and recurrences became less in cases 1, 2 and 3 only when treatment with isonialzid was started. In case 4 when treatment was begun with isoniazid along with PAS and streptomycine the eye became quiet in the shortest time as compared with the other three cases.
This does not mean an absolute triumph for isoniazid but these cases give sufficient ground to record the usefulness of this new chemotherapeutic measure in the treatment of ocular tuberculosis either of the granulomatous or non-granulomatous variety. Its absolute evaluation will have to be done against proper controls. Its evaluation by local subconjunctival injections or applications also needs a proper study. since in case 2 it is noteworthy that when PAS and streptomycin were given orally and parenterally for twenty days, we could not get the pupil to dilate under atropin, whereas it readily dilated when streptomycin was given subconjunctivally in a much smaller dose (1/100th of the parenteral dose ) It may be possible for isoniazid to act better and in smaller doses when given locally in the form of eye applications or subconjunctival injections reducing the chances of developing drug resistance as is feared with this preparation, although toxicity toxicity does not form a major bogy.
The dosage used was less than the recommended dosage since it was used along with PAS and streptomycin. In the dosage used in these four cases no side effects of the drug were seen.
| Summary|| |
A report on 4 cases of clinical ocular tuberculosis, two of scleritis, one of tuberculous conjunctival ulcer and one of keratitis profunda, treated with Isonicotinic Acid Hydrazide -Isoniazid- along with PAS orally and streptomycin parenterally and subconjunctivally is given.
The value of Isoniazid in these cases is discussed.
The pharmacology of this new preparation is briefly stated.
| References|| |
Grafton J.: 1953 Modern Treatment Yearbook Ch. 31, pp. 290-291.
Lattimer J. K.: 1953 Current Therapy. Ed. H. F. Conn. Ch. Renal. Tuberculosis, p. 427. W. B. Saunders & Co., Philadelphia and London.
Meade G, M.: 1953 Current Therapy, Ed. H. F. Conn. Ch. Pulmonary Tuberculosis, p. 109, W. B. Saunders & Co., Philadelphia and London.
Report of Tuberculosis Chemotherapy Trials Committee. 1952. BBrit. Med. Jour. Vol. 11, 735-746.
Robitzek E. H. and Setikoff I. J. (1952 ) Am. Rev. Tubercl. 65, 402-428.
Semadeni B.: 1949 The Eye and its Diseases, Ed. Conrad Berens, Ch. Tuberculosis of that eye, p. 681, W. B. Saunders & Co.. Philadelphia and London.