Glutethimide Market in the United States of America Because of (S 116) and Methyprylon (S 117) Have Been Marketed Serious Side-Effects

44 H. ISBELL & T. L. CHRUSCIEL

184. Swanson, L. A. & Okada, T. (1963) J. Amer. med. 186. Wilson, J. C. (1963) Amer. J. Psychiat., 120, 600-601 Ass., 184, 780 (Death after withdrawal of mepro- (Status epilepticus associated with withdrawal bamate) from deprol (meprobamate and benactyzine)) 185. Taddei, J. & Parmi, E. (1959) Boll. Soc. ital. Biol. 187. Veress, F., Major, V., Fink, M. & Freedman, A. M. sper., 35, 211-214 (Pharmacological observation (1969) J. clin. Pharmacol., 9, 232-238 (High dose on the meprobamate habit) tybamate therapy of heroin dependence)

PIPERIDINEDIONE DERIVATIVES

Of the seven drugs listed (Table VII), glutethimide market in the United States of America because of (S 116) and methyprylon (S 117) have been marketed serious side-effects. for the longest time. Originally, both glutethimide and methyprylon were advertised as being " non- REFERENCES barbiturate" hypnotics. Actually both drugs are pharmacologically quite similar to barbiturates and 188. Berger, H. (1961) J. Amer. med. Ass.. 177, 63 glutethimide is more toxic than barbiturates when (Addiction to methyprylon) taken in large doses. Shortly after both glutethimide 189. Horn, M. H. (1968) Fortschr. Neurol. Psychiat.. 36, and methyprylon became available, case reports 310-316 (Einige Aspekte der Methyprylonsucht) began to appear in the literature indicating that the 190. Jensen, R. (1960) N. Z. med. J., 59, 431 (Addiction two drugs caused dependence of the barbiturate- to Nodular. A report of 2 cases) 191. Johnson, F. A. & VanBuren, H. C. (1962) J. Amer. alcohol type in man.1881l95 Glutethimide has been med. Ass., 180, 1024 (Abstinence syndrome shown to induce dependence in dogs and monkeys following glutethimide intoxication) and to suppress abstinence from barbital in physically 192. Lloyd, E. A. & Clark, L. D. (1959) Dis. nerr. Syst., dependent dogs and monkeys. Accordingly, glute- 20, 1 (Convulsions and delirium incident to thimide must be judged to have dependence potential glutethimide (Doriden) withdrawal) of high degree equal to that of the barbiturate 193. Luby, E. D. & Domino, E. F. (1962) J. Amer. med. hypnotics. Although less well documented, methy- Ass., 181, 46 (Additional evidence of addiction prylon must be rated as having moderate or high liability of glutethimide) 194. Ossenfort, W. F. (1957) Dallas med. J., 43. 229 abuse liability. The potential for dependence of (Drug addictions) aminoglutethimide (S 112), and cinperene (S 113) 195. Sadwin, A. & Glen, R. S. (1958) Amer. J. Psychiat., may, by chemical and pharmacological analogy, be 115, 469 (Addiction to glutethimide-Doriden) assessed as being equal to that of methyprylon. 196. World Health Organization (1966) Drug Informa- Aminoglutethimide has been withdrawn from the tion No. 56, Geneva (unpublished document) Un a) C 'C > U a)EC1 C a)a)) x co w 0) EZ(CZ

0) ) a) CC z CDa w0 c CL Q o 0 CO IF C z o 0 *30= w 0C a. M 0 ._ 00 CZ. C E ) a)*z¢t Ca a)-M C0a( .0 0 4a)a)CC C

E a) a a) C C.)o 0 oc co - s E .- " z.'Z.' Z: C - o ° 0 0~~~~~~~~~~~~~~ U(1 Da. o o o- o N° 0 .x CL Ua)D 0._ co c -c U a) 0". .0 ~.r0 N~~~~~~~~ -Ca > C E E E .C a) a a)co_ a)0Q a) - IZ >CC~~~~~~~~~~~~~~~~~~~~~~~~~C = M tn.-a4 -)zq0 .°- 0~ aasc)o U, o.0 Ca)C) Co (D Ca

.0 a).e 3 ~~ E a)a) ~~~~~~~3 U_ (U

a) a) a)

0 .0'al C--O.CO)t II CD~~~~~~~~~~~~~~ B ~~~~~~~~~EE .Cao° CCa0 0°c o) E .xo 0-. c .- E ~4c (n Oa) )n a 4D 03 z (n cn w Oto0 a o4 a) a. 04 E w C,)a z 4a) it w a) znj- o (- 0 >" c o .0 1 cn Ca- °cm D 0.7 I 0 E ao s "0 a) E) 0 Cq I 0 a)E.C~ ~ Z-I "Ua)0Q0> z 0 Q) -J -a ._ CIL -Z co@ 0=0) 0= C Q r aE ° a U z C~ ._ 0'-a LLJ a)E _w E H= C- z II E -0mE N E a5 C. ct 0CL I .3 00U 0_ Q 0 OVQ r- w 0. ._

-J ('4 C.) r mco m- ,_ 0) I)V. :5 I, = WU) U) L~ C

45 0 U) 0 0C) 0 C

C) - 0 U) LU

a 0- aLU 0 0~~~~~~~~~~~~~ z 0 a LU a ic~~~~~~~~~~~~~~~~~~~~~a. z 00~~~ C0 0~~~~~~-.C .0C 0.oE 0 0~~ .O0.CC 0 0..C-0

4.00 0 0 0CCCC C-0C C .0.0 0.

_ 02 0 C. ~~~~~~~>00 0 . !o 30I. 0 0'.- co C

C 0c 00 :E 0 $--0 ~ ~ ~ UC0 E ~ E O.0 0 0 0"- LU 0 CD IL

0 0 ~ ~ ~ ~ ~ ~ ~ ~ ~~00

co Z5 ZC0 o

0 00= oc tL

0 0 ~~~~~~~~~~~~~~~~00 0 0 0- 0 z z az C * LU) a LU)

0) LU

0 0 LU E2 C In 0 0 in ._ Ct m C E 0 .0 000 ._ 0 x x >% LU) coX I-Z O 3r 0 E y= \ O=X ,a a :2,IQ Z Q QL -) I I - 0= Z-I I t 0 011 00= 0 Co) U t 0 0o EM 0.b. / - 0 ICl)IC,) f C I I In O h- U I- ., 00U a) 6 Ct CL 0I z U- C.

E U) U)- U)~~~~~~~~~V

-46