DANTROLENE-ASSOCIATED HEPATIC INJURY. Incidence and character RICCARDO UTILI, M.D., JOHN K. BOITNOTT, M.D., AND HYMAN J. ZIMMERMAN, M.D.

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1 GASTROENTEROLOGY 72: , 1977 Cpyright 1977 by the American Gastrenterlgical Assciatin Vl. 72, N.4, Part 1 Printed in U.S.A. DANTROLENE-ASSOCIATED HEPATIC INJURY Incidence and character RICCARDO UTILI, M.D., JOHN K. BOITNOTT, M.D., AND HYMAN J. ZIMMERMAN, M.D. Veterans Administratin Hspital, Medical Service and Department f Medicine, Gerge Washingtn University, Schl f Medicine, Washingtn, D. C., and the Department f Pathlgy, Jhns Hpkins University, Schl f Medicine, Baltimre, Maryland Hepatic injury during lng term dantrlene sdium therapy ccurred in 19 f 1044 patients (1.8%) mnitred fr at least 60 days. Six had icteric hepatitis (0.6%) and 3 died (0.3%). After the marketing f the drug, an additinal 31 cases f dantrlene-assciated liver disease were available fr analysis. Of these 16 had icteric hepatitis with a favrable utcme, whereas 11 died. The injury was mainly hepatcellular with a pattern f acute r subacute hepatic disease r chrnic active hepatitis. Analysis f a ttal f 50 cases shwed a 28% case fatality rate. All the fatalities ccurred in patients abve 30 years f age and after at least 2 mnths f therapy, with 57% cases expsed fr at least 6 mnths. Eleven f the 14 fatalities ccurred in females (P < 0.05). N cases f hepatic disease ccurred in patients expsed fr less than 1 mnth r under the age f 10. The majrity f adverse reactins (71 %) ccurred between 1 and 6 mnths f therapy. Daily dsage f 300 mg r mre is assciated with higher incidence f hepattxic reactins and with the majrity (85%) f the fatalities. This idisyncratic hepatic injury des nt appear t invlve hypersensitivity t the drug. A careful assessment f the benefit-risk rati in the therapeutic use f dantrlene sdium is prpsed. Dantrlene sdium 1-{[5-(p-nitrphenyl)- furfurylidene]amin}hydantin (hereafter referred t as dantrlene) is a lng acting skeletal-muscle relaxant which has been successfully used t cntrl muscle spasticity in patients with varius neurlgical disrders. I - 7 Its site f actin is within the muscle where it inhibits the release f calcium frm the sarcplasmic reticulum, therby uncupling excitatin and cntractin. 8 Spradic reprts f hepatic adverse reactin attributable t dantrlene include mderate elevatin f serum levels f glutamic xalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), alkaline phsphatase, and bilirubin,2-5 and descriptin f 2 patients with clinically vert hepatcellular injury. 9, 10 In sme instances the abnrmalities f liver functin tests were nly transient and did nt require interruptin f the treatment. 3, 5 In thers, the bichemical tests returned t nrmal nly after discntinuatin f the drug;2, 4, 9,10 reinstitutin f the drug therapy in 2 patients led again Received August 11, Accepted Octber 30, Address requests fr reprints t: Hyman J. Zimmerman, M.D., Medical Service, Veterans Administratin Hspital, 50 Irving Street, N.W., Washingtn, D. C This study was supprted by Veterans Administratin research funds and by a grant frm Eatn Labratries, Nrwich, New Yrk. Dr. Utili is n leave f absence frm the Clinic f Infectius Diseases, First Medical Schl, University f Naples, Naples, Italy. The authrs wish t thank Dr. M. L. Hrne and Mrs. M. E. Klb frm Eatn Labratries fr prviding the data, and assistance in the preparatin f this reprt. t abnrmal values which necessitated definitive withdrawal f the drug. 4,9 In additin, cases f fulminant hepatic failure assciated with dantrlene therapy were brught t the attentin f the physician by the manufacturer. The purpse f this cmmunicatin is t describe the incidence and character f the hepatic injury that has been attributed t dantrlene. The data presented in this paper are derived frm 50 cases f liver injury reprted t the manufacturer r t the United States Fd and Drug Administratin, and cnstitute the ttal f all f the recrded cases wrldwide. Thus the authrs have been affrded the unique pprtunity f analyzing all f the knwn cases. Methds The patient surces fr the data presented may be categrized as fllws: Categry 1. Cntrlled efficacy and safety studies, including lng term fllw-up f apprpriate patients. Sme f these studies were instituted as early as 1968 and by nw include patients wh have been fllwed as lng as 7 years n dantrlene treatment. This categry encmpasses 2191 patients studied in clinical trials during the premarketing perid by experienced investigatrs in cllabratin with the Clinical Research Divisin f Eatn Labratries. The data frm these studies have been reviewed by the authrs. Categry 2. Patients taking the drug after marketing. This ppulatin has been estimated by the manufacturer t number 30,000 peple taking dantrlene sdium n a lng term basis. Figures indicate that ver 200,000 patients with spasticity 610

2 April 1977 DANTROLENE-ASSOCIATED HEPATIC INJURY 611 have taken dantrlene fr varying perids f time since marketing f the drug in The data derived frm patients in categry 1 were, as may be expected, well dcumented and generally cmplete. On the ther hand, the data reprted by individual physicians (categry 2) were ften incmplete. Of a ttal f 2191 patients in categry 1, 1044 (grup A f categry 1) cnstitute the main study ppulatin. These patients had been n placeb fr apprximately 1 mnth befre starting dantrlene treatment and base line data had been cllected. After initiatin f treatment, they were carefully mnitred fr bichemical and clinical evidence f hepatic injury fr at least 60 days, and as lng as 7 years. These patients had varying types f chrnic neurlgical diseases, f which a prminent and disturbing manifestatin was muscle spasticity, and very ften necessitated intermittent hspitalizatin. The mst frequent diagnses were cerebral palsy (37%), spinal crd injury (22%), and multiple sclersis (15%). Abut 67% f the ppulatin cnsisted f utpatients with nly limited perids in the hspital, whereas the ther 33% were ldged in hspitals, hspital schls fr crippled children, r ther institutins. The remaining 1147 patients (grup B f categry 1) were mnitred fr less than 60 days. Many f these finished the study and cntinued n dantrlene fr varying perids f time, but withut systematic mnitring. The lack f a sufficient fllw-up f these patients des nt permit their inclusin in the statistical analysis. Hwever, amng these, 10 patients develped single SGOT elevatins with values always belw 200 Karmen units. Only 1 patient had a cncmitant slight elevatin f serum bilirubin (1.4 mg per 100 ml). At the time f preparatin f this reprt, within grup A, recrds were available fr a ttal f 719 patients wh had been taking dantrlene cntinuusly fr ver 6 mnths; 488 wh had been n the drug fr ver 1 year; 97 fr ver 3 years; and 15 fr ver 4 years. There were 200 patients belw the age f 10, the thers were almst equally distributed thrughut all age grups, up t the age f 60. Amng these patients there were 637 males and 395 females (sex nt reprted fr 12 patients). All patients received dantrlene in dses ranging frm 50 t 800 mg per day. Tw patients frm the study ppulatin (grup A, categry 1) were excluded frm analysis. One had a past histry f drug abuse, cnfirmed by the presence f talc crystals in liver sectins,11 and alchlism. The ther had had an elevated SGOT level n base line data, which remained minimally elevated during the year he tk dantrlene. Tw additinal patients frm categry 2 were als excluded. One patient with severe jaundice accmpanied by a rash and fever was subsequently diagnsed at a University Center as hepattxicity attributable t diphenylhydantin therapy. Anther had tw cnsecutive psitive tests fr HBsAg during the clinical manifestatins f acute hepatitis. With these exclusins, a ttal f 50 patients (19 frm categry 1 and 31 frm categry 2) wh develped liver injury during dantrlene therapy were analyzed. The hepatic adverse reactins bserved in these patients were categrized int the fllwing fur grups: (1) transaminase elevatin nly; (2) transaminase elevatin assciated with mild hyperbilirubinemia (frm 1 t 2.5 mg per 100 ml); (3) icteric hepatitis (serum bilirubin abve 2.5 mg per 100 ml) with subsequent recvery; and (4) fatalities caused by acute r subacute hepatic failure. Bichemical testing f the patients included measurement f SGOT, serum bilirubin, alkaline phsphatase and, in sme instances, SGPT. Values shwn in the figures represent the mst abnrmal levels bserved fr the respective test in each patient. Because f differences in units in which alkaline phsphatase values were expressed, the levels fr this enzyme are given as percentage f nrmal fr the methd used. Sectins f hepatic tissue frm 9 patients (4 frm the study ppulatin and 5 frm the pstmarketing perid) were available t us fr study. In 6 patients the material was btained by liver bipsy during the curse f acute illness and in 3 the material was btained at autpsy. One patient had tw liver bipsies 2 years apart. Statistical analysis f nnparametric data was dne using the X2 test with Yates' crrectin. 12 Results Study ppulatin. The incidence f hepatic adverse reactin in 1044 patients (grup A categry 1) taking dantrlene fr at least 60 days is shwn in table 1. Evidence f hepatic injury was present in 19 patients (1.8%); 6 f them develped jaundice (0.6%) and 3 f this grup died (0.3%). One patient wh develped jaundice was a resident in a schl fr mentally retarded children. One f the fatalities ccurred in a patient wh had recieved bld transfusins (4 units) 3 mnths earlier. Results f the test fr HhsAg are nt available in either case. Amng the 19 patents, 3 shwed nly fluctuating bichemical abnrmalities withut vert clinical manifestatins f hepatic injury, despite cntinuatin ftherapy with the drug. In 13 patients (5 with SGOT elevatin nly, 5 with SGOT elevatin and hyperbilirubinemia, <2.5 mg per 100 ml, and 3 with icteric hepatitis), the hepatic injury required discntinuatin f the therapy. Reinstitutin f the drug was undertaken in 5 f these 13 patients. It led t a return f enzyme elevatin in 2 patients after 1 mnth (1 patient at the same dse level, and the ther at ne-fifth f the initial dse). The ther 3 were again n the drug withut bichemical abnrmalities fr a perid frm 1 mnth t 1 year, at dsage ranging frm the riginal t ne-sixth f the riginal. The time fr bichemical tests t return t nrmal values varied between 1 and 12 mnths (median 3 mnths). The incidence f hepatic injury was twice as high in females as in males amng the study ppulatin, but the difference was nt statistically significant (table 1). Hepatic injury reprted after marketing f drug (categry 2). Individual physicians reprted 31 cases f apparent dantrlene-assciated hepatxicity amng an estimated number f 30,000 peple taking the drug n a lng term basis (0.1%). Of these cases, 2 shwed nly enzyme elevatins; in 2 thers, enzyme elevatins were TABLE 1. Incidence and sex distributin f hepatic adverse reactins in patients f the study ppulatin Parame- N.fpa- Ttal n. f N. f cases N. f fataladverse re- with icteric ter tients actins" hepatitis" ities Q Ttal (1.8) 6 (0.6) 3 (0.3) Male (1.4) 2 (0.3) 0 Female (2.5) 4 (1.0) 3 (0.8) Unknwn a Values in parentheses, percentage relative t the number f patients fr each sex grup.

3 612 UTILI ET AL. Vl. 72, N.4, Part 1 accmpanied by mild hyperbilirubinemia (less than 2.5 mg per 100 ml); 16 patients had vert "hepatitis" with jaundice and a favrable utcme, and 11 patients died. Amng the 16 patients with icteric hepatitis and subsequent recvery, there were 2 reprted with t little infrmatin fr further analysis. Analysis f hepatic injury: sex and age. The distributin f the character f the hepatic reactin accrding t the sex and the age f 48 patients analyzed is shwn in figures 1 and 2, respectively. Nne f the 200 patients fthe study ppulatin belw the age f 10 develped hepatic injury. These patients presented a distributin f duratin ftreatment cmparable t the lder patients. The difference in incidence f injury, amng these tw age grups is significant (P < 0.01). Severity f the disease seemed t be age related. The 14 fatal cases were abve 30 years f age (fig. 2). Eleven f these were female (P < 0.05, fig. 1). Duratin f treatment. Duratin f dantrlene administratin at the time f the nset f hepattxicity is shwn in figure 3. N adverse hepatic reactins have been recrded during the first mnth f therapy. N fatal cases ccurred during the first 2 mnths. The majrity f patients (34 cases, 71%) develped hepatic injury between 1 and 6 mnths. The remaining 29% f the patients (14 cases) develped hepattxicity after the sixth mnth f therapy. Of these, 57% (8 cases) died. Seven f the 14 fatalities had a rapid curse f hepatic E "'. ~ 20 /: E z " L- "'--_ Male Sex Female ENZYME ELEVATION ENZYME ELEVATION WITH MILD HYPER BlliR. «2.Smg%J D JAUNDICE FATALITY FIG. 1. Sex distributin and type f reactin in 48 patients with dantrlene-assciated hepattxicity. "' c: Q) ~ n- ~ ~ 5 z 15 I'Z2I JAUNDICE _ FATALITY ENZYME ELEVATION ENZYME ELEVATION WITH MN.D HYPER BlliR. «2.5mg%) FIG. 2. Age distributin f 48 patients with dantrlene-assciated hepattxicity. >70 15 ENZYME ELEVATION ENZYME ELEVATION WITH MILD HYPER BlliR. «Z.5mg%) I2Zl JAUNDICE FATALITY FIG. 3. Duratin f treatment with dantrlene at the time f the ccurrence f hepatic injury. failure and died within 20 days frm the time f the first symptm. Dsage. The relatinship between hepatic adverse reactin and the daily dsage f dantrlene is shwn in table 2 fr the patients f the study ppulatin, and in table 3 fr all f the 48 patients wh develped dantrlene-assciated hepattxicity. All f the fatalities ccurred in patients n a daily dsage abve 200 mg. Bichemical changes. The peak levels f SGOT and alkaline phsphatase in the patients with txic reactins are shwn in figure 4. Only 7 cases (14%) shwed alkaline phsphatase values that were increased t mre than 3 times the nrmal. In nly ne instance was there a marked elevatin. One patient shwed a bichemical pattern strikingly different frm the thers. He was a 67-year-ld male with nrmal SGOT and serum bilirubin, nrmal intravenus chlangigram, wh, 6 days after dantrlene sdium (300 mg daily fr 40 days) was stpped, had a 900% increase in alkaline phsphatase and a slight elevatin f SGPT (169 Karmen units). These values returned t nrmal within 2 mnths. The distributin f peak levels f serum bilirubin amng the 48 patients with adverse reactin is shwn in figure 5. Marked hyperbilirubinemia (greater than 20 mg per 100 ml) was seen in nly 8 cases (16%) and des nt seem t have assciated with higher mrtality. In general, there appears t be n crrelatin between the degree f jaundice and the fatality rate. HBsAg was specifically reprted t be negative in the serum f 22 patients (2 in the grup f mild hyperbilirubinemia, 12 in the grup f icteric hepatitis and recvery, and 8 in the grup f fatalities). Antinuclear antibdies were investigated in nly 1 patient with mild hyperbilirubinemia and fund t be psitive. Leukcytsis was present in 15% f patients f categry 1. One patient had marked esinphilia (21 %). Clinical data. Apprximately 60% f the patients f categry 1 had variable degrees f nausea, anrexia, vmiting,' and abdminal discmfrt, which preceded the nset f the disease; 40% f the patients, hwever, were asymptmatic. Fever and rash were specifically nted t be absent. Physical examinatin shwed hepatmegaly in 30% f cases; in 1 case it was assciated with splenmegaly.

4 April 1977 DANTROLENE-ASSOCIATED HEPATIC INJURY 613 TABLE 2. Incidence f hepatic adverse reactin related t the daily dsage f dantrlene in 1044 patients f the study ppulatin (categry 1, grup A ) Dsage N. f patients Ttal n. f he- N. with nly N. with SGOT elevatin patic injury and mild hyperbilirubine- (%) SGOT elevatin mia «2.5 mg/loo ml) N. with icteric hepatitis (recvered) N. f fatalities mglday < (1.4)a (2.4) (3.5) r mre 72 2 (2.8) 2 a The percentage values are referred t the ttal number f patients in each grup f dsage. TABLE 3. Relatinship between type f reactin and daily dsage in 48 patients with hepatic injury assciated with dantrlene (categries I and IlJ Dsage Ttal n. f hepatic injurvatlon N. with nl>, SGOT ele- N. with SGOT elevatin and N. with icteric hepatimild hyperbilir. «2.5 mg/loo N. f fatalities ml) tis (recvered) mglday < r mre Alkaline Phsphatase (Percent f Nrmal) FIG. 4. SGOT and alkaline phsphatase elevatins in all patients with dantrlene-assciated hepatic injury. Serum enzyme levels are analyzed accrding t the fllwing grup: transaminase elevatin nly (x); transaminase elevatin with hyperbilirubinemia less than 2.5 mg per 100 ml (..); icteric hepatitis (0); fatality (e). living _ FATAlITIES FIG. 5. Distributin f values f serum bilirubin in all f the patients with elevated SGOT. Histpathlgy. Of the 9 cases available t us fr review, 8 shwed significant features f hepatic parenchymal injury (table 4). Six f these shwed clearly "aggressive" disease with prminent prtal inflammatin and fibrsis, piecemeal necrsis, rsette frmatin, bile duct prliferatin, and mderate hepatcellular abnrmalities (fig. 6). Marked bile stasis was seen in 4 cases. Cirrhsis was present in 3 f 4 fatal cases (fig. 7). One patient (54-year-ld female), had tw liver bipsies perfrmed 2 years apart. The first was btained 5 mnths after she mistakenly tk 1600 mg per day fr 13 days; subsequently she tk 600 mg per day. The first bipsy shwed a picture f "chrnic aggressive hepatitis" with prminent piecemeal necrsis. At that time, the SGOT was 195 Karmen units, alkaline phsphatase was 4-fld elevated, and the serum bilirubin was 1 mg per 100 ml. A liver bipsy 2 years later, while the patient was still n dantrlene, shwed marked increase in fibrsis with lss f nrmal lbular architecture, piecemeal necrsis, and active parenchymal cell necrsis ("active" cirrhsis); at that time SGOT was 290 Karmen units, and alkaline phsphatase was still 4-fld elevated. The patient died 3 mnths later; at autpsy, cirrhsis was fund. The bipsy in 1 patient shwed submassive necrsis. The necrsis was mainly centrlbular and was accmpanied by marked prtal fibrsis, bile duct prliferatin with bile stasis, and early cirrhsis. Anther patient shwed massive necrsis. One patient, published elsewhere,9 had a picture f acute hepatcellular damage and marked prtal inflammatin with numerus esinphils. These findings were cnsistent with either viral r drug-induced hepatitis. The presence f talc crystals in these sectins favrs the hypthesis f viral hepatitis in a drug addict,!i hwever,

5 614 UTILI ET AL. Vl. 72, N. 4, Part 1 the patient had a secnd episde f hepatitis clearly related, temprally, t the resumptin f dantrlene administratin. In 1 patient there was mild, fcal, nnspecific inflammatin, predminantly prtal. This was in agreement with very mild serum enzyme elevatins. Three additinal patients f categry 2 were reprted at autpsy t have liver damage cnsistent with severe chrnic active hepatitis (2 cases) and subacute hepatitis with bridging (1 case). These sectins, hwever, were nt reviewed by us and were nt included in table 4. After withdrawal f drug, clinical reslutin f the liver disease was seen in 3 patients with chrnic active hepatitis and in the 1 patient with mild prtal inflammatin. Marked imprvement f bichemical data ccurred in the patient with acute hepatcellular disease (table 4). Discussin Mst instances f drug-induced hepatic injury are described as single cases r small grups f cases. A TABLE 4. Histpathlgy Type f injury N. f cases Chrnic active hepatitis Submassive necrsis with early cirrhsis Massive necrsis Acute hepatcellular Mild, nnspecific prtal inflammatin Analysis grup 5 b Icteric hepatitis (3 cases) Fatality (2 cases) 1 Fatality Fatality 1" Icteric hepatitis 1 Enzyme elevatin " Fr analysis grups see Methds. b A reprt cncerning ne f these patients has been published elsewhere (Ref. 10). C Published elsewhere (Ref. 9); talc crystals were seen in these sectins. series such as the ne available t the authrs f this reprt can prvide a useful estimate f incidence and f the characteristics f the injury. These bservatins are essential if the usefulness f the agent is t be balanced against adverse effects. The presumed relatinship f the liver damage t the dantrlene therapy may be questined fr sme patients f this reprt. This may apply t 3 patients in the cntrl study ppulatin wh had fluctuating serum transaminase levels despite cntinuing therapy with dantrlene. Furthermre, 2 additinal patients had alternative causes fr the hepatic injury, such as hspitalizatin in a state institutin fr retarded children where viral hepatitis is endemic, and repeated bld transfusins, respectively. Anther patient with nrmal bilirubin and very high alkaline phsphatase levels may well have had biliary tree disease, rather than drug injury. Likewise, patients wh tlerated readministratin f the drug withut recurrence f liver damage may have had anther etilgy. Hwever, in the absence f cnclusive data permitting their exclusin, these patients were included amng thse presumed t have dantrlenerelated disease. In additin, many patients, particularly amng the cases f the pstmarketing perid (categry 2), were n a multiple drug regimen. This included drugs with hepattxic ptential; hwever, dantrlene was the cmmn denminatr. The additinal drugs may have, in individual instances, been respnsible fr r cntributed t the ccurence f hepatic injury r t its severity. Indeed, drug-induced hepatic injury appears t be mre frequent amng patients taking multiple drugs than in thse taking a single drug. 13 In assessing the relatinship between expsure t a drug and the develpment f hepattxicity, the cnsist- FIG. 6. Liver bipsy shwing prtal inflammatin, piecemeal necrsis, and marked rsette frmatin, a picture cnsistent with chrnic active hepatitis (H & E, x 250).

6 April 1977 DANTROLENE-ASSOCIATED HEPATIC INJURY 615 FIG. 7. Liver bipsy shwing subacute hepatic necrsis with cirrhsis (H & E, x 120). ency f the hepatic injury bserved is useful. Althugh each case may be cmplicated by the underlying disease and by the cncmitant administratin f ther drugs, the pattern f injury in all but 1 patient was hepatcellular, as shwn by the bichemical and histlgical features. In the majrity f patients, hwever, the lesin appeared t be subacute r even chrnic rather than vertly acute hepatcellular injury. Transaminase levels were rarely in the range suggestive f acute disease. Mst values were between 100 and 600 Karmen units (fig. 4). The histlgical features were thse f subacute hepatic necrsis r chrnic active hepatitis. There was, hwever, marked intracanalicular chlestasis with bile duct prliferatin as a cncmitant feature in 4 cases; and 14% f the patients had alkaline phsphatase values in the chlestatic range. 14 Indeed, 1 f these patients initially presented a clinical aspect suggestive f "bstructive jaundice."io Distinctin f an individual instance f drug-induced hepattcellular injury frm viral hepatitis is difficult. The histlgy f drug-induced hepatcellular injury indeed resembles that f viral hepatitis s clsely, that this frm f drug-induced injury is ften referred t as "hepatitic."15 This difficulty applies t the cases f the present study. Nevertheless, the high incidence and character f chrnic active liver disease, and the early cirrhsis in ur patients, despite a clinical histry f acute disease, wuld be mst unusual in an rdinary series f cases f viral hepatitis. Rather, it is similar t that bserved in recipients f xyphenisatin,16, 17 a methyldpa,17-19 isniazid,20, 21 and has been recgnized as ne f the imprtant frms f drug-induced liver disease. 22 Furthermre, the gravity f the syndrme that develped in patients wh had been taking the drug fr 6 mnths r lnger wuld als be extremely unusual in viral hepatitis. A similar phenmenn has been bserved in patients wh develped jaundice after having taken isniazid fr 2 mnths r 10nger.21 Like ther drug-induced hepatcellular disease, the lesin is a serius ne with a high case fatality rate (28%). The incidence f hepatic injury can be estimated frm the 1044 patients in the study ppulatin. The percentage f hepatic adverse reactin as reflected by elevatin f serum transaminase levels with r withut jaundice, was 1.8%. The incidence f vert hepatitis, manifested by jaundice and bichemical evidence f hepatic injury was 0.6% (table 1). Sme f the factrs assciated with develpment f the injury may be useful in guiding the therapeutic use f dantrlene sdium. Duratin f the expsure seems imprtant. N instances f hepatic injury were bserved amng patients expsed fr less than 1 mnth, and n fatalities ccurred amng thse expsed fr less than 2 mnths. Indeed, 8 f the 14 fatal cases had been expsed fr at least 6 mnths (fig. 3). Age als seemed t have sme influence; n cases f hepatic injury ccurred under the age f 10 (fig. 2), althugh there were 200 persns in this age grup wh were carefully mnitred during the "study perid." There was n significant difference between sexes in develpment f the injury (table 1), but there was a difference in prgnsis. Of the 14 patients wh died, 11 were female, a significant (P < 0.05) sex difference (fig. 1). There appeared t be a crrelatin between daily dse and the ccurrence f liver damage. It was mre frequent (P < 0.05) amng patients fthe study ppulatin taking 300 mg r mre per day than amng thse taking lwer dses (table 2). Furthermre, amng the entire grup f patients with hepatic injury, fatal cases were almst restricted t patients taking 300 mg r mre per day (table 6). N fatal cases ccurred amng thse tak-

7 616 UTILI ET AL. Vl. 72, N.4, Part 1 ing less than 200 mg f dantrlene per day (tables 2 and 3). The mechanism fr injury remains bscure. Hallmarks f hypersensitivity such as drug fever r rash were nt apparent. Furthermre, the lng perid f expsure befre the develpment f bichemical r clinical evidence f hepatic damage militates against drug hypersensitivity as the mechanism fr injury.22 In the case f injury which depends n drug allergy, the perid f expsure t the cmpund is usually fairly cnsistent and ranges frm 1 t 4 weeks. 22 In nne f the patients reviewed was expsure that brief, and sme patients had been taking the drug fr many mnths befre the develpment f manifest liver damage. Hepatic injury attributable t an idisyncratic reactin t a drug, but nt accmpanied by clinical features suggestive f hypersensitivity, may be the result f metablic aberratin with the prductin f txic metablites. 22 Despite these arguments, hwever, the character f the injury, namely a pattern cnsistent with chrnic active hepatitis des bring t mind a syndrme f presumed "autimmune" pathgenesis. In the autimmune type f chrnic active hepatitis f unknwn etilgy, r that secndary t xyphenisatin and a methyldpa, abnrmal hst immune respnse has been invked. 23 Cnceivably txic metablites might lead t subtle injury which in turn triggers hst immune respnse leading t chrnic autimmune hepatic injury.23 Hwever, there is n evidence at this time t supprt this view. In the nly patient in whm serlgical markers were sught, antinuclear antibdies were fund in the serum. Cmments The hepatic injury described in this reprt, althugh it is f lw incidence, is a serius ne. It may be frtunate that the nset f hepatic injury, when it has ccurred, has been delayed in all but rare instances fr at least 45 days after starting the drug. Serius hepatic injury is even mre delayed, inasmuch as n fatal cases ccurred in persns expsed less than 2 mnths. Accrdingly it may prve practical t evaluate carefully the therapeutic respnse t dantrlene during the first 4 t 6 weeks f therapy. In thse patients wh shw mdest r n therapeutic benefit, the use f the drug shuld be abandned after 45 days. Only thse patients wh shw imprtant benefit shuld be permitted t take the drug beynd the 45-day perid. Only the lwest dsage cmpatible with maximum benefit shuld be used. It seems clear that vert hepatic disease rarely ccurs in patients taking less than 200 mg per day. Clearly, the patients wh receive this drug shuld have regular testing f the SGOT-SGPT levels. If liver dysfunctin develps, the drug shuld be stpped and the clinical situatin reassessed. If, n readministratin f the drug, the dysfunctin recurs, it shuld nt be given further, even if it had seemed f benefit. REFERENCES 1. Dykes MHM: Evaluatin f a muscle relaxant: dantrlene sdium (Dantrium). JAMA 231: , Chipman M, Kaul S, Lambie M: Efficacy f dantrlene sdium in the treatment f spasticity. Dis Nerv Syst 35: , Chyatte SB, Basmajian JV: Dantrlene sdium: lng-term effects in severe spasticity. Arch Phys Med Rehabil 54: , Mayer N, Mecmber A, Herman R: Treatment f spasticity with dantrlene sdium. Am J Phys Med 52:18-29, Gelenberg AJ, Pskanzer DC: The effect f dantrlene sdium n spasticity in multiple sclersis. Neurlgy 23: , Haslam RHA, Walcher JR, Lietman PS, et al: Dantrlene sdium in children with spasticity. Arch Phys Med RehabiI55: , Denhff E, Feldman S, Smith MG, et al: Treatment f spastic cerebral-palsied children with sdium dantrlene. Dev Med Child NeurI17: , Ellis KO, Bryant SH: Excitatin-cntractin uncupling in skeletal muscle by dantrlene sdium. 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