US 2003O232890A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0232890 A1 Epstein et al. (43) Pub. Date: Dec. 18, 2003 (54) METHODS FOR TREATING AN (60) Provisional application No. 60/245,323, filed on Nov. IMPAIRMENT IN MEMORY 1, 2000. CONSOLIDATION (30) Foreign Application Priority Data (75) Inventors: Mel H. Epstein, Bristol, RI (US); Kjesten A. Wiig, Providence, RI (US) Oct. 31, 2001 (WO)........................... PCT/US01/45793 Correspondence Address: Publication Classification HAMILTON, BROOK, SMITH & REYNOLDS, P.C. 530 VIRGINA ROAD (51) Int. Cl. ................................................ A61K 31/137 P.O. BOX 91.33 (52) U.S. Cl. .............................................................. 514/649 CONCORD, MA 01742-9133 (US) (73) Assignee: Sention, Inc., Providence, RI (US) (57) ABSTRACT (21) Appl. No.: 10/444,970 Impairments in memory consolidation are treated with an (22) Filed: May 23, 2003 amphetamine compound. In one embodiment, the method includes administering an 1-amphetamine compound. In Related U.S. Application Data another embodiment, the method includes administering an (63) Continuation-in-part of application No. 10/139,606, 1-methamphetamine compound. The method can include filed on May 2, 2002, which is a continuation-in-part determining memory consolidation before, during and/or of application No. 10/003,740, filed on Oct. 31, 2001. after administering the amphetamine compound. Patent Application Publication Dec. 18, 2003. Sheet 1 of 19 US 2003/0232890 A1 Figure 1 a . 2. .9 () Y Saline 0.25 0.5 1,0) 2.0 Dose (mg/kg) Figure 2 400 300 2 5 200 s * 100 O saline S-(+)-amphetamine Group Patent Application Publication Dec. 18, 2003 Sheet 2 of 19 US 2003/0232890 A1 Figure 3 a 9 2 9 A. Saline 2 hr. 1 hr 0.5 hr 0hr Injection Time (hours) Figure 4 400 300 One-way analysis of variance 200 F value - P value summary 2 Are means signif, different? (P & 0.05) 00 Number of groups F R squared Saline 2 hr 1 hr 0.5 hr 0hr Injection Time (Hours) Figure 5 300 2 0 0. 100 s 2 i Patent Application Publication Dec. 18, 2003 Sheet 3 of 19 US 2003/0232890 A1 Figure 6 300 250 15 O Saline S-(+)-amphetamine Patent Application Publication Dec. 18, 2003 Sheet 4 of 19 US 2003/0232890 A1 FIG. 7A FIG. 7B Number of Movements Total Distance so GOO As -o-control 40 -- control 500 --S-(+)-amphetsreic t- --S-(+)-unphetamine 5 400 30 300 20 se C a 200 2 O t) O o 2 4. 6 8 C 0. 2 4. 6 8 0. Time (min) Timc (min) F G. 7 C Number of Rears Movement Tine so 5 a -o-Control -o-contre 4U - --S-(+)-amphetamine -e-S-(+)-amphetamine 3D 3s 0 -- e 20 e lo 2. 0. ( 2 3 4 5 6 7 8 9 2 4 8 8 () Time (min) Time (min) FIG. 7E FIG. 7F Time Spent Resting Number of Stereotyped Movements 15 - 50 -- Control g --d- cott \ 40 --S-(+)-amphetamine -e-S-(+)-amphetamine g pa in 20 4. O 0. --- 0. t 2 4 s 6 8 9 2 4. 6 8 13 Time (min) Time (min) Patent Application Publication Dec. 18, 2003. Sheet 5 of 19 US 2003/0232890 A1 Figure 8 500 34. OO OO 2 O O 100 5 Figure 9 500 34. OO OO 2 O O 100 Saline C105 Patent Application Publication Dec. 18, 2003 Sheet 6 of 19 US 2003/0232890 A1 Figure 10 400 3 O O 200 100 Control C105 Patent Application Publication Dec. 18, 2003 Sheet 7 of 19 US 2003/0232890 A1 Figure 11 300 2 O O 10 O Saline C105 Figure 12 300 2 O O 10 O Saline C105 Patent Application Publication Dec. 18, 2003 Sheet 8 of 19 US 2003/0232890 A1 FIG. 13A Fig. 13B Discrimination Index (D1) - Discrimination Index (D2)- Controls Controls 1. 5 5 0 s x 10 40 30 .9 9 is 20 E 5 t :- 3 10 O 0. Saline ClO5. Saline COS Group Group FIG. 13C FIG. 13D Discrimination Index (D1) - Fornix Discrimination Index (D2) - Fornix Lesion Rats Lesion Rats 5 S 0 4 0. 0 3. O 5 2 () 0. 0 Forlaix + Saline Fornix + C 05 Fornix Saline Fornix + C05 Group Group Patent Application Publication Dec. 18, 2003 Sheet 9 of 19 US 2003/0232890 A1 FIG. 14A FIG. 4B Total Distance Number of Movements 50 20 s w-- Sairie -- Saline d 500 -o-C05 -o-C05 2 400 d - s 3 soo 's 10 s s 200 s 100 Z 0 O 0 2 3 4 5 & 7 8 9 lo 0 1 2 3 4 5 s 7 8 9 10 Time (min) Tine (min) FIG. 4D Movement Time Number of Rears 40 Sali -a -Sale 10 -o-C105 -HSainte st 30 -o-C05 AaE 20 s s 8 3 to 2. O 0. O 2 3 4 5 - 6 8 9 IO 0 1 2 3 4 5 6 7 8 9 O Time (min) Time (min) FIG. 14E Number of Stereotyped Movements Time Spent Resting 50 -- Saline 50 -o-C105 4. O 230. to 0 1 2 3 4 5 6 7 8 9 0 0 1 2 3 4 S 6 8 9 O Time (min) - Time (min) Patent Application Publication Dec. 18, 2003 Sheet 10 of 19 US 2003/0232890 A1 FIG. 15A FIG. 15B Number of Movements Total Distance t ----sulfil -- contre S 500 --0-s-(+)-mphetamine --St-amphetamine. -- s 3. ) 300 . a 20 f 2 s s t 6 8 Tirne (min) Timc (min) FIG. 15C FIG. 15D Number of Rears Movement Time 50 ar -- Control -- Ili 340 -o-S-(+)-amphetamine -0-S-(+)-amphetamins e 30 - 5 20 g d to 0 1 2 3 4 5 6 8 s 10 Time (min) FIG. 5E FIG. 5F Number of Stereotyped Movements Time Spent Resting s 5 e -- Citro ar -- control -o-anphetamine v. 3 -o-S-(+)-amphetamire ex p 0. 's 30 i A. s 2 a. E 10 2 3 4 5 6 9 0. 2 4. 6 Tint (in) Time (min) Patent Application Publication Dec. 18, 2003 Sheet 11 of 19 US 2003/0232890 A1 Figure 16 12 2. 3. 10 > 2 8 d) - 6 M .2 4 is 2 - 5 g g H en r ca Figure 17 Patent Application Publication Dec. 18, 2003 Sheet 12 of 19 US 2003/0232890 A1 M 2 O CMO c5 itis 3 A -- san EO) C c e C C C C C N \o bf S ef. N - uope.I]uaouOO papalpad Patent Application Publication Dec. 18, 2003 Sheet 13 of 19 US 2003/0232890 A1 o vu O CN CO N vm vm (SL = Xeu) IIeoop.IOM Patent Application Publication Dec. 18, 2003 Sheet 14 of 19 US 2003/0232890 A1 600 500 400 3OO 2OO 1 OO O % -- veh 1.0 2.0 0.5 1.0 0.25 0.5 d-amph C 105 SN522 Dose (mg/kg) FIG. 20 Patent Application Publication Dec. 18, 2003 Sheet 15 of 19 US 2003/0232890 A1 500 234OOO OOO 10 O O 0.1 0.25 0.50 0.75 1.0 Dose of l-methanphetamine (mg/kg) FIG 21 Patent Application Publication Dec. 18, 2003 Sheet 16 of 19 US 2003/0232890 A1 -- Saline 60 -O- SN522 (0.25 mg/kg) -a- SN522 (0.5 mg/kg) 50 40 30 10 Trials FIG. 22 Patent Application Publication Dec. 18, 2003 Sheet 17 of 19 US 2003/0232890 A1 1200 -O- SN522 (0.25 mg/kg) -A-SN522 (0.5 mg/kg) 1000 -O- SN522 (2.5 mg/kg) -A- SN522 (5.0 mg/kg) 800 800 400 200 Time After injection (min) FIG. 23 1200 -O- d-amph (0.25 mg/kg) -A- d-amph (0.5 mg/kg) 1 1 O O -- d-Amph (2.5 mg/kg) 1000 -A-d-Amph (5.0 mg/kg) 900 800 700 600 500 400 300 200 100 is 9 & S. $ is 8 & Time After injection FIG. 24 Patent Application Publication Dec. 18, 2003 Sheet 18 of 19 US 2003/0232890 A1 30 min 24 hr Recall Time * P<0.05 vs. placebo (0 mg) F.G. 25 Patent Application Publication Dec. 18, 2003 Sheet 19 of 19 US 2003/0232890A1 Placebo C105 individual RAVLT Scores for Volunteers 0 21-49 Years Old o 60-72 Years Old FIG. 26 US 2003/0232890 A1 Dec. 18, 2003 METHODS FOR TREATING AN IMPAIRMENT IN 0006 Accordingly, methods and compositions that MEMORY CONSOLIDATION enhance long-term memory function and/or performance, or prophylactically (e.g., as a neuroprotective treatment) pre RELATED APPLICATIONS vent or slow degradation of long-term memory function and/or performance would be desirable. Similarly, methods 0001. This application is a continuation-in-part of U.S. and compositions for restoring long-term memory function application Ser. No. 10/139,606, filed May 2, 2002, which is and/or performance are needed. a continuation-in-part of U.S. application Ser. No. 10/003, 740 filed Oct. 31, 2001, which claims the benefit of U.S. 0007 Impairments in memory consolidation in a human Provisional Application No. 60/245,323 filed on Nov. 1, can occur in a number of conditions or diseases, Such as 2000 and claims priority to International Application PCT/ age-related memory loSS, Alzheimer's disease, Multiple US01/45793, filed Oct. 31, 2001, which designates the Sclerosis, brain injury, brain aneurysm, Stroke, Schizophre United States and was published in English. The teachings nia and epilepsy. Clinical management Strategies currently of the above applications are incorporated herein by refer provide minimal, if any, improvement in memory.