Carbamic acid esters of glycols

40 H. ISBELL & T. L. CHRUSCIEL CARBAMIC ACID ESTERS OF GLYCOLS Of the drugs listed in Table VI, carisoprodol (S 103), emylcamate (S 104), mebutamate (S 107) and phenprobamate (S 110) are not used primarily as central nervous system depressants but are recommended either for hypertension (S 107) or as " muscle relaxants " (S 103, S 104 and S 110). Some newly introduced drugs, buramate (S 102) and pentabamate (S 109), have been marketed as " tran- quillizers" and hexapropymate (S 105) and oxy- fenamate (S 106) are used as sedatives. All these are weak drugs and have not been abused or shown to have abuse potential in animal or human experi- ments. Tybamate (S 111) used as a sedative has had an especially good animal and experimental work-up for abuse potential. 167, 170, 174, 187 It appears to be a very weak, short-acting drug of no or very low dependence liability. Meprobamate (S 108) is an entirely different case. It is a fairly potent central nervous system depressant which, pharmacologically, is similar to the barbitu- rates. Cases of dependence of the barbiturate- alcohol type were reported shortly after the drug was marketed and are still occumng. 168' 1699 172, 173, 175, 177-182, 185 Meprobamate has been shown to pro- duce physical dependence in the dog 171 manifest by convulsions and canine " delirium " on with- drawal. Meprobamate has also been shown to suppress abstinence from barbital in dogs. An extensive illicit traffic in meprobamate devel- oped in the United States of America which was supplied by diversion from legal channels. Accordingly meprobamate must be rated as hav- ing moderate to high potential for dependence of the barbiturate-alcohol type. REFERENCES 165. Anderson, E. G. (1965) In: DiPalma, J. R., ed., Drill's pharmacology in medicine, 3rd ed., pp. 559-566, McGraw-Hill, New York (Chap- ter 35: Skeletal-muscle relaxants) 166. Barsa, J. A. & Kline, N. S. (1956) Amer. J. Psychiat., 112, 1023 (Use of meprobamate in the treatnment of psychotic patients) 167. Berger, F.-M., Kletzkin, M. & Margolin, S. (1964) Med. exp. (Basel), 10, 327 (Pharmacologic properties of a new tranquilizing agent, 2-methyl- 2-propyl-trimethylene butylcarbamate carbamate (tybamrate)) 168. Bulla, J. D., Ewing, J. A. & Buffaloe, W. J. (1959) Amer. Practit., 10, 1961 (Further controlled studies of meprobamate) 169. Czerwenka-Wenkstetten, H., Hofmann, G. & Kryspin-Exner, K. (1965) Wien. med. Wschr., 115, 1012-1016 (Tranquillizersucht und Miss- brauch) 170. Domino, E. F. (1965) In: DiPalma, J. R., ed., Drill's pharmacology in medicine, 3rd ed., pp. 356-364, McGraw-Hill, New York (Chap- ter 24: Psychosedative drugs. II. Meprobamnate, chlordiazepoxide and miscellaneous agents) 171. Essig, C. F. (1958) Arch. Neurol. Psychiat. (Chic.), 80, 414-417 (Withdrawal convulsions in dog following chronic meprobamate intoxication) 172. Essig, C. F. & Ainslie, J. D. (1957) J. Amer. med. Ass., 164, 1382 (Addiction to meprobamate) 173. Ewing, J. A. & Haizlip, T. M. (1958) Amer. J. Psychiat., 114, 835-836 (A controlled study of the habit forming propensities of meprobamate) 174. Feldman, H. S. & Mulinos, M. G. (1966) J. New Drugs, 6, 354 (Lack of addiction from high doses of tybamate) 175. Frangipane, M. (1963) Friuli med., 18, 737-741 (A case of toxicomania caused by meprobamate) 176. Fraser, H. F., Essig, C. F. & Wolbach, A. B. (1961) Bull. Narcot., 13, No. 4, 3-7 (Evaluation of carisoprodol and phenyramidol for addictiveness) 177. Haizlip, T. M. & Ewing, J. A. (1958) New Engl. J. Med., 258, 1181 (Meprobamate habituation. A controlled clinical study) 178. Held, H. & Oldershausen, H. F. V. (1969) Klin. Wschr., 47, 78-80 (Zur Pharmakokinetik von Meprobamat bei chronischer Hepatopatien und Arzneimittelsucht) 179. Hollister, L. E. & Glazener, F. S. (1960) Psycho- pharmacologia (Berl.), 1, 336 (Withdrawal reactions from meprobamate alone and combined with promazine) 180. Lemere, F. (1956) Arch. Neurol. Psychiat. (Chic), 76, 205 (Habit forming properties of meproba- mate) 181. Phillips, R. M., Judy, F. R. & Judy, H. E. (1957) Northw. Med. (Seattle), 56, 453 (Meprobamate addiction) 182. Retterstol, N. & Sund, A. (1963) Nord. med. Ark., 69, 722-724 (Meprobamate, habituation and addiction) 183. Shelton, J. & Hollister, L. E. (1967) J. Amer. med. Ass., 199, 338 (Simulated abuse of Tybamate in man. Failure to demonstrate withdrawal reac- tions) C-D- 0 a) 0 0 ._4,o C] 0 a)- a) cn 0 = x C 0 C 0C Co D ca 0 0 a) -5 V 0 c 0.1 0 Q Co0 co 010-0 IZ' Iz ZIr 0 I I C., CD U- W Un 0 LI- U) co '.5 oH O x 'O 0 C to v0oO - c a. 0 >a 0 0 0- z .E a) cr W Q), 4Ms a)a) u 0 0 >a 0 0 a) ,o ;; C -- - a)0o -u "" toa- : a) a)>(n= 0 ) 5,c E a) 0 - - z 0 C 0 >a C 0 E 0 z .5 a) ._4 C co a0 0-.- Z .5 co E 0 Z C 0 0 0-. Z .5 0 0 3 ,o o '-a) x E a) ,,1I. 0 ao 0-.- z.ECo Co0 3: ,o a) a) E co eDE 11 m ._ 0) 0 *- Eco (0 E - c u >u ~-°Qa) Q1 c >a Co E o X - O)C.) 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D 0 0 0 C .a 0 0 ._ aQ 0 0 .0 0 0 < 0 .0 S to -0 O.nto > E CDEe .0 0~~~~~. 9o IZ s 0 ED *0 CC) C.)C~~~~~~C 1-. o0 C)~0 0. - 43 - 0 U C Cl<d a)0' 0) 0.-- .0 c.0 C <0" O C: L- c .,O = mto °vo- s- 0 sUO0CC 0 -0 , aE 0 0._C *0 0 _ C :2 0 U) c C00C 0 *0 U C Iw- 0 20a 0 0 mCO 0o.2 >, 0 C) C (a :) -J 0 LU -J m c a U) l- 0 C , CL cn I- z C,) UJ z 4 co uJ 0 uJ i- C' C, 0 z -J z Lu LU -J I- co0- 2E0 , C o0 'OC 0 0Eso 6 z 44 H. ISBELL & T. L. CHRUSCIEL 184. Swanson, L. A. & Okada, T. (1963) J. Amer. med. Ass., 184, 780 (Death after withdrawal of mepro- bamate) 185. Taddei, J. & Parmi, E. (1959) Boll. Soc. ital. Biol. sper., 35, 211-214 (Pharmacological observation on the meprobamate habit) 186. Wilson, J. C. (1963) Amer. J. Psychiat., 120, 600-601 (Status epilepticus associated with withdrawal from deprol (meprobamate and benactyzine)) 187. Veress, F., Major, V., Fink, M. & Freedman, A. M. (1969) J. clin. Pharmacol., 9, 232-238 (High dose tybamate therapy of heroin dependence) PIPERIDINEDIONE DERIVATIVES Of the seven drugs listed (Table VII), glutethimide (S 116) and methyprylon (S 117) have been marketed for the longest time. Originally, both glutethimide and methyprylon were advertised as being " non- barbiturate" hypnotics. Actually both drugs are pharmacologically quite similar to barbiturates and glutethimide is more toxic than barbiturates when taken in large doses. Shortly after both glutethimide and methyprylon became available, case reports began to appear in the literature indicating that the two drugs caused dependence of the barbiturate- alcohol type in man.1881l95 Glutethimide has been shown to induce dependence in dogs and monkeys and to suppress abstinence from barbital in physically dependent dogs and monkeys. Accordingly, glute- thimide must be judged to have dependence potential of high degree equal to that of the barbiturate hypnotics. Although less well documented, methy- prylon must be rated as having moderate or high abuse liability. The potential for dependence of aminoglutethimide (S 112), and cinperene (S 113) may, by chemical and pharmacological analogy, be assessed as being equal to that of methyprylon. Aminoglutethimide has been withdrawn from the market in the United States of America because of serious side-effects. REFERENCES 188. Berger, H. (1961) J. Amer. med. Ass.. 177, 63 (Addiction to methyprylon) 189. Horn, M. H. (1968) Fortschr. Neurol. Psychiat.. 36, 310-316 (Einige Aspekte der Methyprylonsucht) 190. Jensen, R. (1960) N. Z. med. J., 59, 431 (Addiction to Nodular. A report of 2 cases) 191. Johnson, F. A. & VanBuren, H. C. (1962) J. Amer. med. Ass., 180, 1024 (Abstinence syndrome following glutethimide intoxication) 192. Lloyd, E. A. & Clark, L. D. (1959) Dis. nerr. Syst., 20, 1 (Convulsions and delirium incident to glutethimide (Doriden) withdrawal) 193. Luby, E. D. & Domino, E. F. (1962) J. Amer. med. Ass., 181, 46 (Additional evidence of addiction liability of glutethimide) 194. Ossenfort, W. F. (1957) Dallas med. J., 43. 229 (Drug addictions) 195. Sadwin, A. & Glen, R. S. (1958) Amer. J. Psychiat., 115, 469 (Addiction to glutethimide-Doriden) 196. World Health Organization (1966) Drug Informa- tion No. 56, Geneva (unpublished document)