THE QUALITY OF INDIAN-MADE SYNTHETIC DRUGS. II

EXAMINATION OF IODOCHLORHYDROXY-

QUINOLINE (ENTEROVIOFORM) OF

INDIAN MANUFACTURE 11

Laboratory Study By J. C. PAL, m.sc.

and

B. MUKERJI, d.sc., m.d., p.n.x.

(Biochemical Standardization Laboratory, Government oj India, Calcutta/Kasaidi)

Clinical Study By J. C. GUPTA, m.b.

and

M. L. CHATTERJEE, m.b.

(School of Tropical Medicine and Carmichael Hospital for Tropical Diseases, Calcutta)

In the course of a comprehensive survey of the chemotherapy of amcebiasis, Leake (1932) studied the properties of iodochlorhydroxy- quinoline (enterovioform or vioform, N.N.R.) in comparison to chiniofon, N.N.R. (sodium iodohydroxyquinoline sulphonate) and certain other derivatives of hydroxyquinoline from the standpoint of oral toxicity in guinea-pigs and cats, amcebicidal action in vitro, and balanti- dicidal effect in naturally infested guinea-pigs. His observations, later confirmed in a joint report by David, Johnstone, Reed and Leake

(1933), definitely indicated that this compound was an effective anti-dysenteric remedy with a superior curative rate in non-toxic doses over

chiniofon (trade marked names : ' Yatren'

'

Anayodin ', etc.). The compound was marketed for the first time by the Ciba Company and has since earned a fair amount of popularity particularly in the treatment of refractory cases of chronic amcebic infections. In India, this

synthetic drug was already in demand when the war broke out, and the gradually developing shortage of emetine coupled with the newer

knowledge about its toxicity to the myocardium made the medical profession turn to this and similar other synthetic anti-dysenteric remedies, e.g. carbarsone, etc., more and more enthusiastically. The supply of this drug was entirely imported until recently, when a few Indian manufacturers have synthesized the

compound. This laboratory had the opportu- nity of examining most of these brands even before these were released into the market, and the present paper embodies a collaborative study of the laboratory and clinical evaluation of Indian-made

' Vioform ' powders and tablets.

Experimental A. Analytical data. As in case of the

chemical examination of carbarsone (Mukerii et al, 1944), the object of this study was to compare critically the Indian-made compound with iodochlorhydroxyquinoline manufactured and marketed by Ciba Company. All the

470 THE INDIAN MEDICAL GAZETTE [Oct., 1944

tests recommended by the N.N.R., 1941, were therefore followed side by side with the standard product of Ciba Company.

(t) Physical characters and solubility.?The Indian-made

1 Vioform' is a greyish-yellow powder, having a very faint aromatic odour, almost insoluble in water, sparingly soluble in

alcohol, soluble in hot glacial acetic acid. These tests compare favourably with the Ciba '

Vioform

Table I

Analysis of iodochlorhydroxyquinoline powders

Number

1 2 3 4 5 6 7 8 9 10

Name Sender J Melting-point

Ambisyd Enterovioform Quinambicide Vioform Quinambicide Enterovioform

Do. Enterochin Iodochloroxyquinoline Enterovioform crystallized from ' Ciba' brand tablets.

N.N.R. standard

S. P. P. ; 176 I. R. I. 174 B. R. I. S. P. P. B. R. I. I. R. I. I. R. I.

I I. R. I. P.C.P.W.

176 178 178 176.5 177 178 172 1775

178-180

Percentage of iodine

41.83 39.26 40.06 40.63 40.73 40.42 38.66 38.83 39.76 40.93

37.5^1.5

Percentage of chlorine

14.30 16.83 15.16 16.20 15.20 17.06 16.40 15.91 10.99 15.10

11.5-12.2

Table II

Analysis of iodochloroxyquinoline tablets

Number

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16

Name

Quinambicide Iodochloroxyquinoline Quinambicide Iodoch loroxyquinoline Iodochloroxyquinoline Quinambicide Iodochloroxyquinoline Iodochloroxyquinoline Iodochloroxyquinoljne Iodochloroxyquinoline Iodochloroxyquinoline Quinambicide Iodochloroxyquinoline Iodochlorhydroxyquinoline Iodochlorhydroxyquinoline Enterovioform, 'Ciba' brand

N.N.R. standard ..

Sender

B. R. I. M. S. I. D. B. R. I.

M. S. I. D. M. S. I. D. B. R. I.

M. S. I. D. M. S. I. D. M. S. I. D. M. S. I. D. M. S. I. D. B. R. I.

M. S. I. D. M. S. I. D. M. S. I. D. M. S. I. D.

* Iodine in gm. per tablet

0.103 0.083 0.112 0.115 0.080 0.076 0.076 0.080 0.085 0.086 0.088 0.099 0.094 0.106 0.094 0.080

(37.5% to 41.5%) 0.0937 to 0.1037

* Chlorine in gm. per tablet

0.041 0.041 0.041 0.038 0.036 0.062 0.041 0.024 0.045 0.043 0.043 0.043 0.042 0.043 0.048 0.038

(11.5% to 12.2%) 0.0287 to 0.0305

* Claim in each of the above sample = 0.25 g. enterovioform per tablet.

(ii) Chemical analysis.?Pal and Guha

(1943) have already shown that the N.N.R.

(Amer. Med. Assoc., 1941) method for the esti- mation of iodochlorhydroxyquinoline. requires modification in certain important/ff^pects in order to get dependable results. Irivthis inves- tigation, the modified method of estimation was therefore followed. The results are shown, for

'

Vioform ' powders in table I and for ' Vioform '

tablets in table II. A glance at the tables will indicate that in the

case of the Indian-made ' Vioform' powders (table I), the melting-points of almost all the

samples examined come close to or within the N.N.R. range. The percentage of iodine in all the samples is within the N.N.R. standards but the percentage of chlorine in all the cases (with the exception of no. 9) is invariably above the

N.N.R. specifications. It has not yet been

possible for us to explain this difference.

Crystals obtained from ' Ciba' brand tablets of iodochlorhydroxyquinoline (as 'Ciba' brand powder is not available in India), after repeated recrystallization from hot glacial acetic acid, were analysed several times for chlorine content, employing the same method as previously. In

Oct., 1944] INDIAN-MADE SYNTHETIC DRUGS : PAL & OTHERS 471

these cases also, the percentage of chlorine was found to be higher than the N.N.R. figure. As our study is essentially a comparative one, with the ' Ciba ' product as the

' standard ', we have only recorded this observation without attempt- ing to offer any satisfactory explanation.

In the case of iodochlorhydroxyquinoline tablets (table II), we have determined the

quantities of iodine and chlorine present in the average weight of a tablet claimed to contain 0.25 g. of ' enterovioform' per tablet. When these iodine and chlorine contents are converted to their respective percentages, taking 0.25 g. of enterovioform to be constant in every case, chlorine content is found to be higher than, but iodine content almost within the limit of, the N.N.R. specification. This agrees closely with the analytical figures of the

' Ciba ' brand

tablets, and therefore the conclusion seems justi- fiable, as far as laboratory data are concerned, that the locally synthesized brands of

' entero-

vioform ' are almost identical with the ' Ciba '

compound as available for sale in the Indian market. B. Clinical trials. These were conducted

in hospitalized patients with proved cases of vegetative and/or cystic forms of E. histolytica present in stool examination at the time of ad- mission. A regular follow-up was made in

every case for a period varying from 3 to 6 months. No case was pronounced as cured where repeated stool examinations were not made by sigmoidoscopic control before and after the treatment. Twenty-four cases of human amcebiasis

were so far treated with two locally synthesized brands of iodochlorhydroxyquinoline tablets m doses of 0.25 g. thrice daily for 10 days. Of these, 19 patients were completely cured. Three cases showed clinical improvement but stool examination gave positive findings and an- other two had inconclusive results. In spite of the comparatively high chlorine content as determined by us (over N.N.R. standard), gastro-intestinal irritation, referable directly to the effect of the drug in the dosage employed, was not complained of. The possibility of iodism in sensitive individuals with a compound of this type containing so much iodine was kept in view, but no symptoms pointing to this con- dition were noticed in any case. David et al. (1933) tried the drug in human

amcebiasis in the same dosage and under similar controlled conditions in America. They reported that out of 47 unselected cases, 38 cases were cured ; in 6, recurrences were found in contacts and 3 patients could not be followed. This is a

parallel record to what has been obtained by us with locally made ' Enterovioform \

Comments

Judging from the evidence at our disposal (chemical analysis and clinical trials), it seems

justifiable to state that the locally synthesized

iodochlorhydroxyquinoline compares very favourably with the

' Ciba ' brand ' Yioform and may be considered as a worth while equiva- lent of the imported product. None of the brands agree with the standards of chlorine content mentioned in N.N.R., but this is offset

by the fact that the ' Ciba' tablet also gives a

higher chlorine content by the same method of analysis. In any event, it may be recorded that the few brands of iodochlorhydroxy- quinoline synthesized in India and examined by us are more or less equivalent to the ' Ciba '

product and can be accepted by the medical profession as suitable for wider clinical trial in amcebiasis cases. The median toxicity in

guinea-pigs on single oral administration with one brand of the local product came to about 180 mg./kg. (observation for 3 days), which is more or less similar to the toxicity (200 mg./kg. kills 13/20 pigs in 4 days) obtained

by David et al. (loc. ext.). There is therefore no cause for anxiety in giving trial to any of the Indian products.

Summary Indian-made iodochlorhydroxyquinoline differs

slightly in chlorine content from the standard product of the same name in N.N.R. 1941, but agrees closely in melting-point, physical charac- teristics, solubility, iodine and chlorine per- centages with the ' Ciba' brand

1 Entero- vioform \ Its toxicity (one brand only tested) is within safe limits in therapeutic dosages. In clinical trials in controlled cases of amoebiasis in hospitalized patients, it has given compar- able satisfactory results. The Indian-made synthetic product is there-

fore likely to be of the proper standard, and wider clinical trial to these brands can be given by the Indian medical profession in suitable

cases without any risk to their patients when employed in therapeutic doses.

Acknowledgment

The authors wish to thank Lieut-Colonel F. W.

Griffin, Chief Inspector of Medical Stores, C.G.I.

(M.G.O. Branch), G.H.Q.(I.), New Delhi, for making available many of the above samples for purposes of analytical work.

REFERENCES

American Medical Asso- New and Non-Official ciation (i941). Remedies. American Medi-

cal Association, Chicago. David, N. A., John- J. Amer. Med. Assoc., 100,

stone, H. G., Reed, 1658. A. C., and Leake, C. D. (1933).

Leake, C. D. (1932) .. Ibid., 98, 195.

Mukerji, B., Pal, J. C., Indian Med. Gaz., 79, 220. Gupta, J. C., and Chatterjee, M. L. (1944).

Pal, J. C., and Guha, Sci. and Culture, 8, 496 R. C. (1943).