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Ineffectiveness of Isoniazid as an Appetite-Stimulator
Ineffectiveness of Isoniazid as an Appetite-Stimulator" A. GERSON HOLLANDER, M.D., F.C.C.P. Oakland, California
In 1952 the clinical use of isoniazid in the treatment of pulmonary tuberculosis was described by Robitzek and Selikoff',' and by McDermott and his associates.s Although both groups of workers were primarily interested in the therapeutic effects of the drug on the clinical course of the disease, one of the outstanding subjective responses of the patient was the marked increase of appetite. As Robitzek and Selikoff" put it: "The most descriptive stock expression is 'ravenous.''' Weight gains ranging up to 59 pounds were recorded over a period of four to 15 weeks, and the average weight gain was 19.7 pounds in 8.8 weeks of therapy. They noted that the weight gains usually became evident in the second or third weeks. It seemed possible that the appetite-stimulating effect of the drug might not be entirely dependent on the reduction in toxicity of the tuberculous process, and it was felt that this possibility should be investigated.
Plan of Investigation The 20 patients chosen for study were all adult males without evidence of pulmonary tuberculosis or tuberculous infection. They were long-term patients who were being treated on the Neurological and Orthopedic Services for a variety of disorders such as residuals of poliomyelitis, hemiplegia, paraplegia, fracture dislocation of the cervical vertebrae, multiple sclerosis, etc. Tuberculosis had been carefully excluded on the basis of history, complete physical examination and x-ray film of the chest. Blood urea nitrogens were obtained prior to starting the drugs and were within normal limits. Weights were obtained at weekly intervals, and the weight curve was constant for three weeks prior to testing. All selected had either "poor" or "fair" appetites, confirmed by the physician and nurse. The only information given to the patients was that they were being given a vitamin tablet. The same nurse made a notation as to the status of their appetite prior to the initiation of the experiment, and weekly thereafter. Objectively, a note was made as to whether the patient consumed an increasing quantity of food. One tablet was given three times a day for a period of 14 days. A rest period of 10 to 14 days was allowed before the patient was submitted to retesting with another preparation. Twenty were placed on each of the preparations for a period of two weeks. Weight and appetite changes were recorded weekly. In no instance were untoward effects noted except for flushing when preparation "M" was used . Chief, Tuberculosis Service, Veterans Administration Hospital, Oakland, California. *From the Veterans Administration Hospital, Oakland, California. 674
675
INEFFECTIVENESS OF ISONIAZID
Vol. XXVII
Preparations: Four tablets were used, all identical in size, shape and color, but consisting of (1) 100 mg. of isonicotinic acid hydrazid, (2) 100 mg . of the isopropyl derivative of isonicotinic acid hydrazid, (3) 50 mg . of nicotinic acid, (4) lactose. These preparations were labeled "K," "L," "M," and "N," the code being kept under seal so that neither the staff nor the investigator was aware of the identity of the preparation being given. Results The results (table) were uniform in that no significant weight change was noted in any of the groups nor was there any change in appetite. One preparation ("M") had to be discontinued because of the flushing reaction which was obtained immediately after its use. It became apparent that this was nicotinic acid, and the probabilities are it would have been wiser to have used a 25 mg. dose. Drugs
"K" (Lactose) "L" (Isoniazid)
* "M" (Nicotinic Acid) "N" (Iproniazid)
No . Pts.
20 20 20 20
Pre-T est Appetite Change in Appetite Fair Poor
12 14 17 15
8 6 3
5
0 0 0
':' React ions occurred a nd necessitated discontinuing drug before completing experiment. ACKNOWLEDGEMENTS The author is indebted to Dr. H. Corwin Hinshaw for suggestions in conducting this st ud y, to Dr. J . K. Smith, Dr. C. S. Ushiro and the nurses of the Neurological Service for their aid in the study, and to Dr. Lawrence B. Hobson and the E. R. Squibb and Sons Company who made these preparations available. CONCLUSIONS
In 20 patients who were not suffering from tuberculosis and whose weight had been constant for a period of weeks, but whose appetites were "poor" or "fair," no appetite-stimulating properties were demonstrated by the administration of 300 mg. of isonicotinic acid hydrazid daily, or 300 mg . of the isopropyl derivative of isonicotinic acid hydrazide daily. It is therefore probable that the effect on appetite and weight gain as reported by Robitzek and Selikoff;' as well as McDermott and others," was secondary to the suppression of toxicity and not an independent effect of the isonicotinic acid hydrazide derivatives on the appetite. RESUMEN
Se trat6 de encontrar si era posible obtener un efecto estimulante del apetito en 20 enfermos que no padecian tuberculosis, dando en estos enfermos que tenian un peso constante, 300 miligrams de hidracida del acido isonicotinico 0 de su derivado isopropilico en la misma dosis diariamente y no se comprob6 propiedad estimulante del apetito. Por tanto, es probable que el efecto sobre el apetito y sobre elpeso tal como 10 relatan Robitzek y Selikoff" asi como por McDermott y otros" sea secundario a la supresi6n de la toxicidad y no un efecto independiente de la isoniacida y derivados sobre el apetito.
676
A. GERSON HOLLANDER
June, 1956
RESUME
Les auteurs ont etudie 20 malades non tuberculeux, dont Ie poids etait reste constant depuis plusieurs semaines, mais qui avaient un mauvais appetit, On leur administra 300 mmg. par jour d'hydrazide d'acide isonicotinique ou 300 mmg. de son derive isopropyle. L'appetit ne fut nullement stimule par ce traitement. L'explication probable en est que le gain d'appetit et de poids dfl it l'isoniazide (et tel qu'il a ete rapporte par Robitzek et Selikoff, ainsi que par McDermott et ses collaborateurs) est secondaire a la suppression de la toxicite de Ia maladie et non pas consecutif it I'effet particulier de derives de l'acide isonicotinique sur l'appetit, REFERENCES 1 Robitzek, E . H., and Selikotf, I. J.: Hydrazine Derivatives of Isonicotinic Acid (Rimifon, Marsilid) in the Treatment of Active Progressive Caseous-Pneumonic Tuberculosis, Am. R ev. Tube rc., 1952, 65, 402. 2 Elmendortf, D. F., Jr., Cawthorn, W. U., Muschenheim, C., and McDermott, W.: The Absorption, Distribution, Excretion, and Short-Term Toxicity of Isonicotinic Acid Hydrazide (Nydrazid) in Man , Am. R ev. Tllb erc. , 1952, 65, 429.
In 1952 the clinical use of isoniazid in the treatment of pulmonary tuberculosis was described by Robitzek and Selikoff',' and by McDermott and his associates.s Although both groups of workers were primarily interested in the therapeutic effects of the drug on the clinical course of the disease, one of the outstanding subjective responses of the patient was the marked increase of appetite. As Robitzek and Selikoff" put it: "The most descriptive stock expression is 'ravenous.''' Weight gains ranging up to 59 pounds were recorded over a period of four to 15 weeks, and the average weight gain was 19.7 pounds in 8.8 weeks of therapy. They noted that the weight gains usually became evident in the second or third weeks. It seemed possible that the appetite-stimulating effect of the drug might not be entirely dependent on the reduction in toxicity of the tuberculous process, and it was felt that this possibility should be investigated.
Plan of Investigation The 20 patients chosen for study were all adult males without evidence of pulmonary tuberculosis or tuberculous infection. They were long-term patients who were being treated on the Neurological and Orthopedic Services for a variety of disorders such as residuals of poliomyelitis, hemiplegia, paraplegia, fracture dislocation of the cervical vertebrae, multiple sclerosis, etc. Tuberculosis had been carefully excluded on the basis of history, complete physical examination and x-ray film of the chest. Blood urea nitrogens were obtained prior to starting the drugs and were within normal limits. Weights were obtained at weekly intervals, and the weight curve was constant for three weeks prior to testing. All selected had either "poor" or "fair" appetites, confirmed by the physician and nurse. The only information given to the patients was that they were being given a vitamin tablet. The same nurse made a notation as to the status of their appetite prior to the initiation of the experiment, and weekly thereafter. Objectively, a note was made as to whether the patient consumed an increasing quantity of food. One tablet was given three times a day for a period of 14 days. A rest period of 10 to 14 days was allowed before the patient was submitted to retesting with another preparation. Twenty were placed on each of the preparations for a period of two weeks. Weight and appetite changes were recorded weekly. In no instance were untoward effects noted except for flushing when preparation "M" was used . Chief, Tuberculosis Service, Veterans Administration Hospital, Oakland, California. *From the Veterans Administration Hospital, Oakland, California. 674
675
INEFFECTIVENESS OF ISONIAZID
Vol. XXVII
Preparations: Four tablets were used, all identical in size, shape and color, but consisting of (1) 100 mg. of isonicotinic acid hydrazid, (2) 100 mg . of the isopropyl derivative of isonicotinic acid hydrazid, (3) 50 mg . of nicotinic acid, (4) lactose. These preparations were labeled "K," "L," "M," and "N," the code being kept under seal so that neither the staff nor the investigator was aware of the identity of the preparation being given. Results The results (table) were uniform in that no significant weight change was noted in any of the groups nor was there any change in appetite. One preparation ("M") had to be discontinued because of the flushing reaction which was obtained immediately after its use. It became apparent that this was nicotinic acid, and the probabilities are it would have been wiser to have used a 25 mg. dose. Drugs
"K" (Lactose) "L" (Isoniazid)
* "M" (Nicotinic Acid) "N" (Iproniazid)
No . Pts.
20 20 20 20
Pre-T est Appetite Change in Appetite Fair Poor
12 14 17 15
8 6 3
5
0 0 0
':' React ions occurred a nd necessitated discontinuing drug before completing experiment. ACKNOWLEDGEMENTS The author is indebted to Dr. H. Corwin Hinshaw for suggestions in conducting this st ud y, to Dr. J . K. Smith, Dr. C. S. Ushiro and the nurses of the Neurological Service for their aid in the study, and to Dr. Lawrence B. Hobson and the E. R. Squibb and Sons Company who made these preparations available. CONCLUSIONS
In 20 patients who were not suffering from tuberculosis and whose weight had been constant for a period of weeks, but whose appetites were "poor" or "fair," no appetite-stimulating properties were demonstrated by the administration of 300 mg. of isonicotinic acid hydrazid daily, or 300 mg . of the isopropyl derivative of isonicotinic acid hydrazide daily. It is therefore probable that the effect on appetite and weight gain as reported by Robitzek and Selikoff;' as well as McDermott and others," was secondary to the suppression of toxicity and not an independent effect of the isonicotinic acid hydrazide derivatives on the appetite. RESUMEN
Se trat6 de encontrar si era posible obtener un efecto estimulante del apetito en 20 enfermos que no padecian tuberculosis, dando en estos enfermos que tenian un peso constante, 300 miligrams de hidracida del acido isonicotinico 0 de su derivado isopropilico en la misma dosis diariamente y no se comprob6 propiedad estimulante del apetito. Por tanto, es probable que el efecto sobre el apetito y sobre elpeso tal como 10 relatan Robitzek y Selikoff" asi como por McDermott y otros" sea secundario a la supresi6n de la toxicidad y no un efecto independiente de la isoniacida y derivados sobre el apetito.
676
A. GERSON HOLLANDER
June, 1956
RESUME
Les auteurs ont etudie 20 malades non tuberculeux, dont Ie poids etait reste constant depuis plusieurs semaines, mais qui avaient un mauvais appetit, On leur administra 300 mmg. par jour d'hydrazide d'acide isonicotinique ou 300 mmg. de son derive isopropyle. L'appetit ne fut nullement stimule par ce traitement. L'explication probable en est que le gain d'appetit et de poids dfl it l'isoniazide (et tel qu'il a ete rapporte par Robitzek et Selikoff, ainsi que par McDermott et ses collaborateurs) est secondaire a la suppression de la toxicite de Ia maladie et non pas consecutif it I'effet particulier de derives de l'acide isonicotinique sur l'appetit, REFERENCES 1 Robitzek, E . H., and Selikotf, I. J.: Hydrazine Derivatives of Isonicotinic Acid (Rimifon, Marsilid) in the Treatment of Active Progressive Caseous-Pneumonic Tuberculosis, Am. R ev. Tube rc., 1952, 65, 402. 2 Elmendortf, D. F., Jr., Cawthorn, W. U., Muschenheim, C., and McDermott, W.: The Absorption, Distribution, Excretion, and Short-Term Toxicity of Isonicotinic Acid Hydrazide (Nydrazid) in Man , Am. R ev. Tllb erc. , 1952, 65, 429.