Effect of Desacetylmethylcolchiicine (Colcemide) in Acute Gouty Arthritis By DAVID H. NEUSTADT Desacetylmethylcolchicine (Colcemide) compared favorably with colchicine in the treatment of acute gout in 17 patients. Although gastrointestinal s y m p toms were avoided, other more serious undesirable effects such as bone-marrow depression a n d alopecia are cited. Disacetylmethylcolchicina IColcemide) esseva favorabile in comparation con colchicina in le tractamento de gutta acute in 17 patientes. Ben q u e symptomas gastrointestinal esseva evitate, altere plus sene effectos adverse, per exemplo depression del medulla ossee e alopecia, es citate. T HE PURPOSE of this study is to evaluate the clinical and biochemical effects of desacetylmethylcolchicine ( Colcemide ) in acute gouty arthritis. An attempt is made to compare the therapeutic properties and side effects of desacetylmethylcolchicine with those of colchicine in patients treated with both agents. Desacetylmethylcolchicine (hereafter referred to as Colcemide ) is a natural alkaloid which has been isolated from the plant Colchicum autumnale.’ The compound differs chemically from colchicine in that a methyl group replaces an acetyl group at the nitrogen position of the colchicine molecule. CLINICAL MATERL4L AND METHODS Clinical Material Observations are derived from a series of 22 acute attacks of gouty arthritis occurring in 17 patients. Only patients with unequivocal acute gouty arthritis have been selected for inclusion in this series. In three patients, two separate acute episodes were treated. One patient afforded the opportunity of treating three distinct attacks. All other patients were given one course of the drug for a single attack. The average known duration of gout was 4.6 years. The age distribution of these patients ranged from 27 to 68 years. There were 13 males and four females. Ten of these patients had previously received colchicine for acute attacks. The majority of the patients also had received probenecid. Method3 and Dosage Criteria to determine clinical effects included a critical assessinent of pain and all measurable indices of inflammatory articular involvement. Side effects with special regard to any gastrointestinal manifestations were diligently sought and recorded. Patients were requested to report any itching or changes in the skin, mucous membranes or hair. Certain laboratory information was obtained in 1.5 of the 17 patients, both before and after therapy. These studies included: hemoglobin, total white blood cell count and differential count, sedimentation rate, platelet count and serum iiric acid. From the Department of Medicine, Utiiversity of Louisville School o f Medicine, Louis- oille, Ky. Presented in part before the International Congress of Rheumtic Diseases, Toronto, Ontario, Canada, on June 26, 1957. 91 92 DAVID €1. NEUSTADT Colcemide’ was supplied as an oral preparation in the form of a scored tablet containing 1 mg. of the substance. Treatment was initiated as soon as possible in every instance. The medication was started within twelve hours of the attack in the majority and within twenty-four hours in a few. In two cases there was a delay of 48 and 72 hours, respectively. Initially, the medication was given with instructions to take one tablet every hour until either relief of pain or occnrrence of gastrointestinal symptoms, or a total of fifteen tablets had been taken. Late in the study, four patients were given an initial dose of 4 mg., and then 1 mg. cvcry hour. RFSUI~TS Clinical Results Striking subjective improvement occurred in 15 patients with 17 aciite attacks within 5 to 24 hours. Objective improvement took place more slowly but was observed within 12 to 72 hours. Table 1 lists the total dosage in mg., the therapeutic response, any side effects, previous response to colchicine if taken and occurrence of side efiects from colchicine. Response is graded as “Excellent,” “Good,” “Fair” or “No effect.”An “Excellent” response indicates complete resolution of all evidence of inflammatory articular features in 72 hours or less. “Good” is defined as greatly improved in 73 hours with complete resolution within one week. “Fair” described moderate improvement with partial amelioration of signs and symptoms with full recovery within two weeks. There was an “excellent” response in a total of 14 acute episodes in 11 patients. A “good“ response w a s obtained in 3 acute attacks in the same number of patients. There were two “fair” results, one of which occurred in a patient who had obtained an “excellent” response in a previous attack; the medication in the more recent instance was given 48 hours after the onset of the attack. No effect occurred in two patients, in one of whom two separate attacks were treated. All patients who derived excellent results required a total dosage of 8 mg. or less, with an average of 6.5 mg. The highest dosage given to obtain a “good“ response was 10 mg. In those with “fair” results or “no effect,” dosage ranged from 7 to 15 mg., with an average dosage of 10.8 mg. It is to be noted that gastrointestinal symptoms occurred only in those patients who had received the higher dosages. Patients 13, 14, 16 and 17 (table 1 ) received 4 mg. stat doses, and all obtained excellent results with treatment. These individuals required therapy over a very short period of time, varying from 1 to 3 hours to achieve maximum benefit. Table 2 is a summary of therapeutic responses and gastrointestinal side effects of Colcemide, compared with those from colchicine. A comparison of the therapeutic responses reveals no significant superiority of either drug. However, there is an impressive difference in the frequency of occurrence of gastrointestinal manifestations. No patient who attained an “excellent” response with colcemide displayed ~~ - ~.... . “Colcenlide used in this investigation was supplied through the courtesy of Ilr. C. Sullivan, Ciba Pharmaceutical Co., Summit, N.J. H. 93 E F F E C T OF COLCEMlDE I N ACUTE GOUTY ARTHRITIS TABLE1.-Results with Desacetylmethylcolchicine in 22 Attacks Arthritis in 17 Subjects Total Patient Dosage No. (mg.) Response Side Effects Previous Response to Colchicine 2* 8 4. 6 Excellent Excellent - Excellent Excellent 3* 10.12 NoEffect No Effect I* 8. 7 ill I . 6. 6 lhcellent & Fair Excellent Mild Diarrhea None, Nausea 1 , 9 EzreUent Good 8 10 Good 9 10 11 8 7 15 Excellent Excellent NoEffect 12 13 14 5 51 6+ EzceUent Excellent Good G B 16 10 16 17 7 # 7t Fair Excellent Excellent Side EffecF with Colchicine Nausea & Diarrhea Nausea. Vomitina & Diarrhea Never Given ~.. Excellent Diarrhea - Not Givrn Good Diarrhea Excellent Nausea & Diarrhea Slight Nausea - Mild Diarrhea - - Nausea - Never Given Never Given Fair Not Given Never Given Good to Excellent Good in Past Not Given Good - of Acute Gouty Remarks N o advantage Equal (without side effecta) Refractory t o both Started 48 hrn. late in 2nd attack Equal (without side effects) Equal (without side effects) Colchicine superior - - Nausea. Vomiting & Diarrhea Recently n o effect with Colchicine Nausea & Cramps, Equal (without side effects) Colchicine slightly better: not taken in two years - Slight Diarrhea Nausea, Vomiting & Diarrhea Nausea & Vomitina Colcemide superior (without side effects) ‘ 2 attacks t 3 attacks # Including S t a t Dose 4 mu. any discernible untoward reactions. One patient with a “good response developed mild nausea. Diarrhea occurred in only 3 treated attacks in two patients, neither of whom responded to treatment. Nausea occurred in two other patients who achieved “fair” results. Of the 10 patients who had Colchicine in the past only one reported equivalent response without developing side effects. Some form of gastrointestinal effect occurred in all others having an equivalent or satisfactory response. Laboratoy Results There were no appreciable alterations in white blood cell counts or differential counts. No significant change was found in sodium urate levels. Hemoglobulin and platelet counts also were unchanged. Untoward Effects There were no undesirable effects encountered in this series, other than the occasional gastrointestinal complaints. However, a woman with chronic tophaceous gout, not a member of this study group, was given Colcemide for an acute exacerbation. Approximately three weeks after receiving 7 mg. of the preparation she developed almost complete loss of scalp hair. She had also 94 DAVID H. NEUSTADT TABLE2.-Summury of Eflects Agents of Desucetylmethylcolchicine Compared with Colchicine ISide Effects) Vomiting Diarrhea Responae No. of Attackb Excellent 14 - 63.6'$0) 0 0 0 3 - 13.6v0 2 - 9.2% 1 0 2 0 0 -3 - 13.6% 22 100.04'; 0 3 0 0 0 3 3 85 - 50r/,) 3 0 4 1 1 1 1 1 2 1 1 8 Nauaea ~ 1)esacetylniethylcolchicine (17 Patients) Good Fair No Efiect Total Excdent ) 80% Colchicinc ( 10 Patients) Good Fair No Effect Total 3 - 30%J 1 - 107; 1 - 10% 10 1cw;;, 6 1 3 taken large amounts of Colchicine just before the onset of depilation. Previous coiirses of Colchicine had been taken without any loss of hair. The patient's hair gradually returned. DISCUSSION Any accurate appraisal of a new agent in acute gouty arthritis must be based on its relative merits and risks as compared with drugs currently available. These special considerations include: ( 1) effectiveness in combating acute attacks; ( 2 ) convenience of use for both doctor and patient; and (3) undesirable side effects and potential toxicity. Colchicine, the traditional measure, is undoubtedly the agent that must be challenged. Although colchicine is an effective agent in the majority of acute attacks of gouty arthritis, a high percentage of patients develop gastrointestinal symptoms.*J In some of these, the associated nausea, vomiting and diarrhea is of an extreme nature, which outweighs or at least markedly compromises the benefits derived. In a few, in whom gastrointestinal intolerance is very severe, and in some patients with gastrointestinal disease, oral colchicine cannot be used. Colsky and co-workers' first called attention to Colcemide as an effective oral preparation that did not cause gastrointestinal side effects in the treatment of acute gout. Levin and others5 also reported that the oral preparation produced favorable response without undesirable reactions in a small number of patients with acute gout. The present preliminary study confirms these previous reports that Colcemide is an effective agent in combating the acute attack and rarely produces gastrointestinal disturbances which frequently occur after colchicine. Colcemide demonstrated certain definite advantages over colchicine. An equivalent response was obtained more rapidly than with colchicine. This reduced length of time for recovery from the acute arthritis was even more impressive in those patients given larger initial doses. The lack of troublesome gastrointestinal disturbances also favorably influenced the length of time for recovery. Two patients obtained prompt relief from acute attacks EFFECT OF OLCEMIDE IN ACUTE GOUTY ARTHRITIS 9.5 with colchicine but were prevented from returning to work for a minimum period of 7 to 10 days because of residual gastrointestinal symptoms difficult to control. After treatment with Colcemide, they were able to return to work in 3 and 5 days, respectively. In one patient with chronic peptic ulcer disease, small doses of colchicine orally caused nausea and violent vomiting, and on one occasion provoked gastrointestinal bleeding. This patient was given Colcemide with an excellent response, without any evident aggravation of his underlying gastrointestinal disorder. The most important of the potential disadvantages of Colcemide, as compared with colchicine, is the possible effect on the blood picture. Experimental studies in animals, as well as studies conducted with this drug in patients with leukemia and related blood disorders, have definitely established that this agent possesses a potent bone marrow action, if it is given in large enough dosage."-" Although no cases have been formally reported, I have been advised of two patients with gout who developed granulocytopenia with anemia after receiving frequent courses of relatively high doses of Colcemide.12 However, the possibility of any bone marrow suppression from Colcemide in ordinary clinical usage for an acute gouty attack would seem remote. The second potentially serious side reaction worthy of comment is the question of loss of hair. Mikkelsen and othersI3 reported a case of total alopecia in a man following therapy with 14 mg. of Colcemide. Although hair subsequently regrew, the experience was understandably an alarming one. It is noteworthy that this patient also received colchicine, prednisone and probenecid. Alopecia has not been observed, to my knowledge, after prednisone or probenecid in clinical dosage. However, alopecia is listed in Goodman and Gilman as a rare side reaction of c~lchicine.'~*'~ Others have observed loss of hair in patients taking Colcemide, but this occurred in patients with leukemic disorders.6J'**1Loss of hair in leukemia is not considered an uncommon clinical feature, when no drug can be invoked as an etiologic agent. The manufacturers of Colceinide state that as of June 10, 1947, they have been informed of a total of four cases of alopecia occurring after use of the drug.12 The preparation, according to their records, has been administered to more than 250 patients with gout. The four patients in whom alopecia developed received a dose of 10 mg. daily or more. In each instance, hair regrew when the drug was discontinued or the dosage reduced. It is possible that the use of smaller doses, which seem wholly effective for acute gout in this series, would reduce the frequency of this undesirable effect. However, in view of the patient who developed alopecia after only 7 mg. of Colcemide and considering the usual delay in onset of loss of hair following the ingestion of the substance, I believe that this complication may represent a form of hypersensitivity to the drug. Then, of course, the reaction would be unrelated to the amount of the drug, and its occurrence completely unpredictable. SUMMARY 1. Desacetylmethylcolchicine ( Colcemide ), a natural alkaloid, chemically 96 DAVID H. NEUSTADT similar to colchicine, was administered orally to 17 patients in a series of 22 attacks of acute gouty arthritis. 2. Response to Colcemide was comparable to that with therapeutic doses of colchicine, without the undesirable gastrointestinal symptoms, which frequently occur after colchicine. 3. Continued cautious investigation with this agent is necessary to determine the frequency of such serious reactions as bone marrow depression and alopecia, which would markedly limit its useflilness. REFERENCES I. Santavy, F. and Reichstein, T.: Isolierung nener Stoffe aus dcn Samen der Herbstzeitlose Colchicuin antumnale L. Substanzen der Herhstzeitlose imd ihre Derivate, Helvet, Chim acta. 33:1606, 1950. 2. Gutman, A. B. and Yii, T. F.: Current principles of inanagement in gout. Am. J. hled. 1.3~744,1952. 3. Steinbrocker, O., Neustadt, D. H. and Ehrlich, M.: Rutazolidin in treatment of gout with comparison with other agents. M. Clin. N. America ,38:611, 1954. 4. Colsky, J., Wallace, S. and Ranowitch, M. hl.: Dcsacetylmethylcolchicine in acutc Gouty arthritis. New England J. Rfcd. 253~730,1955. 5. Levin, hl. H., Marcus, S., Strangt:, D. and Sweezey, A. L.: Therapeutic trials in acute gouty arthritis. Ann. Rheiimat. Dis. 15233, 19.56. 0. Hock, H. E. and Gross, R.: Colchicinwirkungen u n d Granulocytopoese: Klinesche und Experimentelle Beobachtw~genmit Substnnz Flaw Colchicum autumnale. Klin. Wchnschr. 31~816,1953. 7. Lichtman, A.: Effect of Ikmecolchin ( desmcthylcolchicine ) on peripheral blood and bone marrow in rabbit and cat. Thesis. Zurich, 1954. 8. .Iloe\chlin, S., Meyer, H. and Lichtman, A.: Ein news Colchicium-Nehenidkaloid (Demecolin Ciba) als Cytostaticiim i n y e l o i s c h e r leukamen. Schweig. med. Wchnschr. 8.3~990, 1953. 9. Leonard, B. J. and Wilkinson, J. F.: Iksacetylmethylcolchicine in treatment of inyeloid leukemia. Brti. Med. J. 1:874, 1955. 10. Sheehy, T. \V. and Ransone, J. W.: D c m e c o l c i n e (Colceinid) toxicity. Arch. Int. Med. 100~85,1957. 11. Piney, A.: Treatment of chronic myrloid lcilkaemia with a colchicum derivitive. Acta Haemat. 14~83,1955. 12. Siilliwin, C. H.: Personal conmimication. 1.7. hlikkelsen, W. M., Salin, R. W. and I h f f , I. F.: Alopecia totalis after tles.icetyliiiethylco1chicine therapy of acute gout. New England J. llctl. 2.55769, 1956. 14. Goodman, L. and Gilman, A.: Thr P1iarm:icological Basis of Therapeutics. New York, The Macmillan Co., 195.5. 15. Brown, W. 0. and Seed, L.: Effect of colcliicine on human tissues. Am. J. Clin. Path. 15189, 1945. Dcrzjitl H . Neustndt, M.D., lnstrrictor in Medicine, University of Lorcisvillc, Louisville, Ky.