Blindness and Neuropathy From
Diiodohydroxyquin-Like Drugs
Committee on Drugs
The halogenated hydnoxyquinolines-iodochlo- eases is outweighed by the serious and often irre- rhydroxyqumn, diiodohydroxyquin, bnoxyquino- versible damage that can insidiously occur with line, and chlorquinaldol (Table 1)-were long chronic treatment of a child. thought to have little toxicity, but it is now clear Villarejos et studied the long-term use of io- that these compounds can cause serious and inre- dochlorhydroxyquin (10 mg/kg/day, six days a versible damage to the nervous system.’ Toxicity week for 16 weeks) in children from an area of is a function of dose and duration of therapy. Sin- Honduras where there was a highendemic level of gle, lange doses cause cerebral dysfunctions, char- diarrhea. Treated children had lower rates of diar- actenized by disorientation and retrograde amne- rhea than placebo or nonplacebo controls. No sia. Optic atrophy and peripheral neunopathy can neuropathy was noted even though the home of occur when moderate doses are used for more than each study subject was visited six days a week by three weeks. nurse’s aides. Because infantile diarrhea is a major Neunopathy has been reported in 12 children212 problem in many countries, the results of this and we know of three others who had taken halo- study could lead to widespread, chronic use of hal- genated hydroxyquinolines in high doses (at least ogenated hydroxyquinolines. We would be con- adult doses) and/on for more than three weeks. cerned that in such a less-controlled clinical situa- Fourteen of the 15 had loss of visual acuity; 13 had tion increases of dose and/on length of therapy permanent optic atrophy. Dysethesia, weakness would occur and cause a large number of cases of and other manifestations of peripheral neuropa- permanent neuropathy. Such a change, from an thy, reported so commonly in adults, were noted apparently safe dose of diiodohydroxyquin used to in less than half. Perhaps the reporting was un- treat cases of nonspecific diarrhea in a formal din- common because the majority of cases were treat- ical triaP4 to a larger, toxic dose in the day-to-day ed before the age of 4 when it is difficult to diag- practice situation, has been responsible for neu- nose such findings. Broxyquinoline was the drug in 10 We believe that the risk of neuropathy two cases; the remaining patients had taken either offsets possible benefits from the chronic use of iodochlorhydroxyquin or diiodohydroxyquin. Al- these drugs as a chemoprophylactic agent against though the reason for therapy in the earlier cases diarrhea. was acrodenmatitis entenopathica, a rare disease, Although the halogenated hydroxyquinolines the more recent cases reported from the United have been used in an attempt to prevent and to States have included children treated for a more cure “traveler’s diarrhea,” they have not been common problem, chronic nonspecific diarrhea. shown to be effective. Children should not be Because of concern that the few cases of this seri- given halogenated hydroxyquinolines for the pre- ous adverse effect of which we are aware may rep- vention or treatment of this symptom complex. resent only the “tip of the iceberg,” it seemed ap- Readers should know that these drugs are sold pnopniate to call attention to the toxicity of these under many trade names (Table I) around the drugs and to make recommendations for their use world and are often available over-the-counter. in hopes of preventing new cases. Diiodohydroxyquin (Diodoquin) is approved These drugs have been recommended and (package labeling in the United States) only for widely used for the treatment of chronic nonspeci- the treatment of intestinal amebiasis (30 mg/kg/ fic diarrhea, even though efficacy has not been day for 20 days). It is recommended by some au- fully established. Any value that they may have in thorities’5 only for the treatment of the asympto- the treatment of this heterogeneous group of dis- matic passers of the cyst form of E. histolytica in
378 BLINDNESS ANDDownloaded NEUROPATHY from www.aappublications.org/news FROM DIIODOHYDROXYQUIN by guest on October 1, 2021 nonendemic areas. No neuropathy has been re- TABLE I ported when diiodohydnoxyquin is used in this PROPRIETARY NAMES#{176} OF Foun HALOGENATED dosage schedule. Metronidazole is an alternate HyDnoxyQulNouNEst drug available for amebiasis that is unassociated Iodochlorohydroxyquin: Aichioquin, Amebil, Amoenol, with such serious neuropathy. Bactol, Barquinol, Budoformin, Chinoform, Acrodenmatitis entenopathica is a serious, rare Clioquinol, Cliquinol, Eczecidin, Enteroquinol, disorder. There are anecdotal reports that these Enterozol, Entero-Septol, Entero-Vioform, Entrokin, halogenated hydroxyquinolines in high, chronic Hi-Enterol, Jodoenterol, Nioform, Quinambicide, Rometin, Vioform dosages are effective in the treatment of this disor- Diiodohydroxyquin: Dinoleine, Diodoquin, Diodoxylin, den. There are also treatment failures. No appro- Direxiode, Disoquin, Di-Quinol, Dyodin, pniately controlled trial has been done to evaluate Embequin, Enterosept, Floraquin, loquin, effectiveness. Until such a study is done, the physi- Moebiquin, Quinadome, Rafamebin, Searlequin, SS cian caring for such children will have to decide 578, Stanquinate, Yodoxin, Zoaquin for on against treatment based on his clinical judg- Broxyquinoline (5, 7-dibromo-8-quinolinol): Broxykinolin, Colepur, Colipar, Fenilor, Intestopan, ment. Should he decide to treat, he should use as Paramibe low a dose and as short a course as possible. It Chlorquinaldol (5, 7-dichloro-2-methyl-8-quinolinol): seems unlikely that courses of therapy less than Gynotherax, Gyno-Sterosan, Saprosan, Siogeno, three weeks will cause neuropathy provided the Siosteran, Slosteran, Sterosan, Steroxin. doses do not exceed 10 mg/kg/day for broxyquin- #{176}Prepared from The Merck Index and a report from Aus- oline and iodochlorhydnoxyquin, 30 mg/kg/day tralia (Australian Drug Evaluation Committee: Subacute for diiodohydnoxyquin, and 3 mg/kg/day for myelo-optic-neuropathy and the halogenated hydroxyquino- chionquinaldol. Most of these estimates of safe dos- lines. Med. J. Aust., 2:1090, 1971). age and length of therapy are based on inferences tThese drugs are available over-the-counter in many countries. and not on observational data and should only be considered as guidelines subject to change. Any REFERENCES physician using these drugs must, with the help of 1. Oakley, G. P., Jr.: The neurotoxicity of the halogenated parents and child, diligently search for signs on hydroxyquinolines. JAMA, 225:395, 1973. symptoms suggesting a loss of visual acuity or 2. Berggren, L., and Hansson, 0. : Treating acrodermatitis enteropathica. Lancet, 1:52, 1966. other neunologic abnormality. 3. Etheridge, J. E., Jr., and Stewart, G. T.: Treating acro- dermatitis enteropathica. Lancet, 1:261, 1966. CONCLUSIONS 4. Strandvik, B., and Zetterstrom, R.: Amaurosis after The halogenated hydroxyquinolines can cause broxyquinoline. Lancet, 1:922, 1968. serious, permanent neuropathy. Optic atrophy, 5. van Balen, A. T. M.: Toxic damage to the optic nerve causing permanent blindness, is the most com- caused by iodochorhydroxyquinoline (Entero-vio- form). Ophthalmologica, 163:8, 1971. monly reported neunopathy in children. In young 6. Drukker, J., and Lindenburg, P. A. W.: Beiderzijdse op- children, the onset of neuropathy is insidious and ticusatrofie bij een kind van anderhalf jaar die wel- hard to diagnose. We, therefore, recommend that licht een gevolg is van toediening van joodchloo- these drugs not be used in children, with two pos- rhydroxychinoline (Enterovioform). Nederl. T. Geneesk., 116:1618, 1972. sible exceptions: the treatment of the asympto- 7. Reich, J. A., and Billson, F. A.: Toxic optic neuritis: Cli- matic cyst passer of E. histolytica in a person not oquinal ingestion in a child. Med. J. Aust., 2:593, living in an endemic area and the treatment of 1973 acrodermatitis enteropathica. If used, parents 8. Garcia-Perez, A., et a!.: A case of optic atrophy possibly should be informed of the possible toxicity. Par- induced by quinoline in acrodermatitis entero- pathica. Brit. J. Derm., 90:453, 1974. ents, child, and physician should diligently search 9. Idriss, Z. H., and Kaloustian, V. M. D.: Acrodermatitis for the first indication of neunopathy. These drugs enteropathica. Clin. Pediat., 12:393, 1973. are contraindicated in the treatment of nonspeci- 10. Behrens, M. M.: Optic atrophy in children after duo- fic, chronic diarrhea, and “traveler’s diarrhea.” dohydroxyquin therapy. JAMA, 228:693, 1974. Co IIrrEE ON DRUGS 11. Pittman, F. E., and Westphal, M. C.: Optic atrophy fol- lowing treatment with diiodohydroxyquun. Pediat- SUMNER J. YAFFE, M.D., Chairman rics, 54:81, 1974. WARREN BIERMAN, C. M.D. 12. Fleisher, D. I., Hepler, R. S., and Landau, J. W.: Blind- HOWARD M. CANN, M.D. ness during diuodohydroxyquin (Duodoquin) thera- SANFORD COHEN, M.D. py. Pediatrics, 54: 106, 1974. J OLIN FREEMAN, M.D. 13. Villarejos, V. M., et al.: Chemoprophylaxis of diarrhea. Amer. J. Trop. Med., 20:602, 1971. SYDNEY SEGAL, M.D. 14. Cohlan, S. Q.: Chronic nonspecific diarrhea in infants LESTER F. Soyx , M.D. treated with duiodohydroxyquinoline. Pediatrics CHARLES F. 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GODFREY P. OAKLEY, JR., M.D., Consultant 15. Drugs for parasitic infections. Med. Lett., 16:5, 1974.
Downloaded from www.aappublications.org/news by guest on October 1, 2021 AMERICAN ACADEMY OF PEDIATRICS 379 Blindness and Neuropathy From Diiodohydroxyquin-Like Drugs: Committee on Drugs Sumner J. Yaffe, C. Warren Bierman, Howard M. Cann, Sanford Cohen, John Freeman, Sydney Segal, Lester F. Soyka, Charles F. Weiss and Godfrey P. Oakley, Jr. Pediatrics 1974;54;378
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Downloaded from www.aappublications.org/news by guest on October 1, 2021 Blindness and Neuropathy From Diiodohydroxyquin-Like Drugs: Committee on Drugs Sumner J. Yaffe, C. Warren Bierman, Howard M. Cann, Sanford Cohen, John Freeman, Sydney Segal, Lester F. Soyka, Charles F. Weiss and Godfrey P. Oakley, Jr. Pediatrics 1974;54;378
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1974 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
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