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(12) United States Patent (10) Patent No.: US 7,074,961 B2 Wang Et Al

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(12) United States Patent (10) Patent No.: US 7,074,961 B2 Wang Et Al US007074961B2 (12) United States Patent (10) Patent No.: US 7,074,961 B2 Wang et al. (45) Date of Patent: Jul. 11, 2006 (54) ANTIDEPRESSANTS AND THEIR 6.211,171 B1 4/2001 Sawynok et al. ANALOGUES AS LONG-ACTING LOCAL 6,545,057 B1 4/2003 Wang et al. ANESTHETCS AND ANALGESCS 2001/0036943 A1 11/2001 Coe et al. (75) Inventors: Ging Kuo Wang, Westwood, MA (US); FOREIGN PATENT DOCUMENTS Peter Gerner, Weston, MA (US); Donald K. Verrecchia, Winchester, MA CH 534124 A 2, 1973 (US) WO WO95/17903 A1 7, 1995 WO WO95/1818.6 A1 7, 1995 (73) Assignee: The Brigham and Women's Hospital, WO WO 99.59.598 A1 11, 1999 Inc., Boston, MA (US) WO WO O2/060870 A2 8, 2002 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 451 days. Luo et al., Xenobiotica, vol. 25, No. 3, pp. 291-301, 1995.* (21) Appl. No.: 10/117,708 Ehlert et al., The Interaction of Amitriptyline, Doxepin, Imipramine and Their N-Methyl Quaternary Ammonium (22) Filed: Apr. 4, 2002 Derivatives with Subtypes of Muscarinic Receptors in Brain (65) Prior Publication Data and Heart, The Journal of Pharmacology and Experimental Therapeutics, Apr. 1990, vol. 253, No. 1, pp. 13–19. US 2003/00968.05 A1 May 22, 2003 Gerner, P., et al., Anesthesiology (2002) 96:1435–42. Related U.S. Application Dat e pplication Uata Khan, M.A., et al., Anesthesiology (2002) 96:109–16. (63) stripps'965,138, filed on Sep. ABDI et al. “The anti-allodynic effects of amitriptyline, (60) Provisional application No. 60/235.432, filed on Sep. 26. gabapentin, and lidocaine in a rat model of neuropathic 2000. pain.” Anesth Analg Dec. 1998:87: 1306–6. (51) Int. Cl. CD7C 2 II/00 (2006.01) (Continued) (52) U.S. Cl. ....................... 564/281: 564/336; s Primary Examiner Deborah D. Carr (58)58) FieldField of Classification SearchS h ................. 564/281 s P.C.(74) Attorney, Agent, or Firm Wolf, Greenfield & Sacks, 564/336, 338; 540/455 See application file for complete search history. (57) ABSTRACT (56) References Cited Methods and compositions of antidepressants and analogs thereof for inducing local long-lasting anesthesia and anal U.S. PATENT DOCUMENTS gesia are provided. The methods and compositions are 2,554,736 A 5/1951 Haefliger et al. useful for alleviating acute and chronic pain, particularly 3,576,853. A 4, 1971 Kaiser et al. useful for treating a localized pain. 3,998,810 A 12/1976 Wiedemann et al. 5,860,950 A 1/1999 Demopulos et al. 32 Claims, 13 Drawing Sheets -- MOTOR 5.4 mm (0.5%bupivocaine -- PROPROCEPTION -a- NOCEPON 80 so 40 2. so 90 2O 50 180 time nir US 7,074,961 B2 Page 2 OTHER PUBLICATIONS Elden, et al., “Zur Analyse von Psychopharmaka: Lofepramin (Gamonil (R) Pharmazaulische Zeitung 123 Barber et al., “Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin' Circulation (1978) 1796–1801 and English language abstract. Research vol. 69, No. 3 Sep. 1991: 677–696. Fomenko, et al., “Chemical heterogeneity of Himi Cerda et al., “A Physiologic Assessment of Intrathecal pramine binding sites on human platelet membranes' Euro Amitriptyline in Sheep.” Anesthesiology, May 1997: 86(5): pean Journal of Pharmacol.--Molecular Pharmocology Sec 1094-1103. tion 189 (1990) 175-183. Esser et al., “Acute amitriptyline in a rat model of neuro Li, et al., “Hexamethonium. Type Allosteric Modulators of pathic pain: differential symptom and route effects.” Pain 80 the Muscarinic Receptors Bearing Lateral Dibenzazepine (1999) 643-653. Moieties.” Arch. Pharm. Pharm. Med. Chem. 334, (2001) Esser et al., “Local Peripheral Action of Antidepressants in 121-124. Rat Models of Neuropathic Pain And Inflammation.” Pre Enlund, A. M., et al., “Capillary electrochromatography of sented Nov. 26, 1998, Supported by the Medical Research tricyclic antidepressants on strong cation exchangers with Council of Canada. different pore sizes.' Journal of Chromatography A 918 Heughan et al., “Peripheral Amitriptyline Suppresses For (2001)211-220. malin-Induced Fos Expression in the Rat Spinal Cord.” Maxwell, R.A., et al., “ Molecular Features Affecting The Anesth Analg, 2002, 94: 427–431. Potency of Tricyclic Antidepressants and Structurally Max et al., “Effects of desipramine, amitriptyline, and Related Compounds as Inhibitors of The Uptake of Tritiated fluoxetine on pain in diabetic neuropathy, New England J Norepinephrine by Rabbit Aortic Strips'. The Journal of Med 326:1250–6, 1992. Pharmacology and Experimental Therapeutics, 166 (2) Pancrazio et al., “Inhibition of Neuronal Na' Channels by (1969) 320329. Antidepressant Drugs' The Journal of Pharmacology and Experimental Therapeutics, 1998, 284; 208-214. * cited by examiner U.S. Patent Jul. 11, 2006 Sheet 1 of 13 US 7,074,961 B2 Z O - Z O O 9 cy 9- ga U 9 5 S. O 9is S2 C2 2 O SN O O O O O O O O c O O r CO O w N % MAXIMAL POSSIBLE EFFECT U.S. Patent US 7,074,961 B2 NOLldBOIOON–W7– % NWAXIMAL POSSIBLE EFFECT U.S. Patent Jul. 11, 2006 Sheet 3 of 13 US 7,074,961 B2 O O Z CO O - 2 Ho2 9 Sas S2 S is 52 O7 n O CO ge O to Y d) - E l9 O O D w . i 2 9 o st as SN E O O ve wer - QO -co v on O O O O 92 oC 3 S. S. % MAXIMALPOSSIBLE EFFECT U.S. Patent Jul. 11, 2006 Sheet 4 of 13 US 7,074,961 B2 . H. H. | | N s . N TIME (MINUTES) U.S. Patent Jul. 11, 2006 Sheet S of 13 US 7,074,961 B2 I s | i N O. O. O. O. O. O. O. O. O. O. O. O. O. C. N. s r. s. c. c. TIME (MINUTES) U.S. Patent Jul. 11, 2006 Sheet 6 of 13 US 7,074,961 B2 4.4 mS -5OmV OS 3OmV -18OmV 1OOms Epp = -150m.V CONTROL 1.O :10M BUPIVACAINE O.8 10.M AMITRIPTYLINE O6 O4 O.2 O.O TIME (ms) Epp = -6OmV 1.O CONTROL 0.8 0.6 1ms 1OuMBUPIVACAINE O.4 O.2 1OuMAMITRIPTYLINE O.O TIME (ms) Fig. 4A U.S. Patent NORMALIZED CURRENT U.S. Patent Jul. 11, 2006 Sheet 8 of 13 US 7,074,961 B2 (aomy- 2ams n-60/SH: 2000 PAL lms CONTROL 3M BUPIVACAINE 3 MAMITRIPTYLINE Fig. 5A U.S. Patent Jul. 11, 2006 Sheet 9 of 13 US 7,074,961 B2 i i SS.8 S E. 92 S. 2 A 2 ------------ I - C o o N co r c vm O O O O O O RELATIVE PEAK Not CURRENT U.S. Patent Jul. 11, 2006 Sheet 10 of 13 US 7,074,961 B2 (/\u09]-)ENITALJIHLIWWe (/\u09-)ENTTIA1dIHLIWWO (/\u009]-)ENIVOVAldng? (Au09-)ENIWOWAld|ngo |Wri]NOLIVNINGONOO ZTO OTO NORMALIZED CURRENT U.S. Patent Jul. 11, 2006 Sheet 12 of 13 US 7,074,961 B2 |-08 09 0,2 oey eqSSO euxeW% U.S. Patent Jul. 11, 2006 Sheet 13 of 13 a td v c d v (unou.) eUUL US 7,074,961 B2 1. 2 ANTIDEPRESSANTS AND THEIR agement. Preferably such local long-acting anesthetics also ANALOGUES AS LONG-ACTING LOCAL will exhibit reversible effects. Such drugs would be useful ANESTHETCS AND ANALGESCS and desirable, for example, in postoperative analgesia, and for treating acute and chronic pain. Preferably, such agents RELATED APPLICATIONS would have sufficient potency to permit administration of a This application claims priority to and is a continuation in single, relatively low dosage of the agent, thereby minimiz part of U.S. application Ser. No. 09/965,138 filed on Sep. 26, ing the likelihood of side effects that have been attributed to 2001, now U.S. Pat. No. 6,545,057, which claims priority to the existing local long-acting anesthetic agents. U.S. application Ser. No. 60/235,432 filed on Sep. 26, 2000. Antidepressants are frequently used as analgesics in pain 10 management but only when administered systemically. GOVERNMENT SUPPORT Among them, amitriptyline has been used orally for the analgesic therapy of chronic pain. Amitriptyline's sites of This work was funded in part by grant number GM48090 action are both central and peripheral. Despite the numerous from the National Institutes of Health. Accordingly, the reports on amitriptyline's analgesic effect on reducing pain Government may have certain rights to this invention. 15 when administered systemically, the exact mechanism of this effect remains unknown. To our knowledge, tricyclic FIELD OF THE INVENTION and tetracyclic antidepressants have not been used as local This invention relates to the use of antidepressants and analgesics. Likewise, they have not been used at all as analogs thereof to produce local long-acting relief of differ anesthetics either locally or systemically. ent varieties of pain. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION The invention involves in one respect the Surprising To provide a better understanding of the invention it is discovery that antidepressants act as long-acting local anes necessary to distinguish between the two terms analgesia thetics and analgesics that are useful for alleviating pain. and anesthesia. Analgesia is defined as a condition in which 25 These antidepressants exhibit unexpected anesthetic and nociceptive stimuli are sensed but are not interpreted as pain. analgesic properties compared to related compounds that Anesthesia is a state characterized by total loss of sensation, previously have been used for pain management. The avail the result of pharmacologic depression of nerve function. ability of compounds with strong local long-acting anes Thus, analgesia does not produce anesthesia whereas anes thetic properties.
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