US007619005B2
(12) United States Patent (10) Patent No.: US 7,619,005 B2 Epstein et al. (45) Date of Patent: *Nov. 17, 2009
(54) METHODS FORTREATING COGNITIVE 5,220,068 A 6/1993 Knoll et al. IMPAIRMENT INHUMANS WITH MULTIPLE 5,225,446 A 7/1993 Milgram SCLEROSIS 5,422,355 A 6/1995 White et al. 5,684,018 A 11/1997 Alexander 5,914, 129 A 6/1999 Mauskop (75) Inventors: Mel H. Epstein, Bristol, RI (US); 6,104,956 A 8, 2000 Naritoku et al. Kjesten A. Wiig, Providence, RI (US); 6,204.245 B1 3/2001 Siegel et al. Randall L. Carpenter, Waban, MA 6,228,875 B1 5, 2001 Tsai et al. (US) 6,251,938 B1 6/2001 Chorev et al. 6,284,760 B1 9, 2001 Marston et al. (73) Assignee: Cognition Pharmaceuticals LLC, New 6,451,806 B2 9, 2002 Farrar York, NY (US) 6,492.427 B2 12/2002 Shankar et al. 6,635,675 B2 10/2003 Kranzler et al. (*) Notice: Subject to any disclaimer, the term of this 6,699.495 B2 3/2004 Blume et al. patent is extended or adjusted under 35 6,828,351 B2 12/2004 Epstein et al. U.S.C. 154(b) by 157 days. 7,244,769 B2* 7/2007 Epstein et al...... 514,654 2002/0066457 A1 6/2002 Landfield et al. 2002fO115725 A1 8/2002 Epstein et al. This patent is Subject to a terminal dis 2007/0099999 A1* 5/2007 Epstein et al...... 514,649 claimer. 2007/0100000 A1* 5/2007 Epstein et al...... 514,649 (21) Appl. No.: 11/133,144 2007/01 17869 A1* 5/2007 Epstein et al...... 514,649 FOREIGN PATENT DOCUMENTS (22) Filed: May 19, 2005 EP 1743 641 A2 1 1707 (65) Prior Publication Data GB 2 122 617 1, 1984 WO WO97/17067 A1 5, 1997 US 2006/01 11448A1 May 25, 2006 WO WO 97.26871 A1 7/1997 WO WO99,16746 A1 4f1999 Related U.S. Application Data WO WOOO/O1379 A1 1, 2000 WO WOOO,32556 A1 6, 2000 (63) Continuation-in-part of application No. PCT/US2004/ WO WOOO,594.79 A1 10, 2000 015974, filed on May 21, 2004, which is a continua WO WOO1/O9897 A1 2, 2001 tion-in-part of application No. 10/791,223, filed on WO WOO2,39998 A2 5, 2002 Mar. 2, 2004, which is a continuation-in-part of appli WO WO O2/O53104 A2 T 2002 cation No. 10/444,970, filed on May 23, 2003, now abandoned, which is a continuation-in-part of applica OTHER PUBLICATIONS tion No. 10/139,606, filed on May 2, 2002, now aban doned, which is a continuation-in-part of application Chertkow, H., “Mild Cognitive Impairment.” Curr. Opin. in Neurol. 15:401–407 (2002). No. 10/003,740, filed on Oct. 31, 2001, now Pat. No. Clarke, A., “A New Formulation of Selegiline: Improved Bioavail 6,828,351. ability and Selectivity for MAO-B Inhibition.” J. Neural. Transm. (60) Provisional application No. 60/245,323, filed on Nov. 110: 1241-1255 (2003). 1, 2000, provisional application No. 60/473,168, filed Gauthier, S., et al., “Mild Cognitive Impairment.” The Lancet on May 23, 2003. 367: 1262-1270 (2006). Grundman, M., et al., “Mild Cognitive Impairment Can Be Distin guished From Alzheimer Disease and Normal Aging for Clinical (51) Int. Cl. Trials.” Arch. Neurol. 61:59-66 (2004). A6 IK3I/35 (2006.01) Halgren, E., et al., “Human Hippocampal Formation EEG A6 IK 3/445 (2006.01) Desynchronizes During Attentiveness and Movement.” (52) U.S. Cl...... 514/654; 514/317 Electroencephalography and Clinical Neurophysiology 44:778-781 (58) Field of Classification Search ...... None (1978). See application file for complete search history. (Continued) (56) References Cited Primary Examiner Brian-Yong S Kwon U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm—Hamilton, Brook, Smith & 2,828,343 A 3, 1958 Tindall Reynolds, P.C. 3,728.445 A 4, 1973 Bardani 3.996,381 A 12/1976 Florvallet al. (57) ABSTRACT 4,034,113 A 7/1977 Shulgin 4,105,695 A 8/1978 Partyka et al. Cognitive impairments in humans with multiple Sclerosis are 4,479,932 A 10, 1984 Bodor treated and cognition is improved with an amphetamine com 4,598,094. A 7, 1986 Wurtman et al. pound. In one embodiment, the method includes administer 4,636,494. A 1, 1987 Growdon et al. ing an 1-amphetamine compound. In another embodiment, 4,647,591 A 3, 1987 Cherkin et al. 5,019,594 A 5, 1991 Wurtman et al. the method includes administering an 1-methamphetamine 5,075,338 A 12/1991 Knoll et al. compound. 5,096,712 A 3, 1992 Wurtman 5,151,449 A 9/1992 Milgram 8 Claims, 55 Drawing Sheets US 7,619,005 B2 Page 2
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SO () . . . tasis Saline 0.25 C.5 O 2.0 Dose (mg/kg) 1. 2. 5 FG. 2 Y Saline S-(+)-amphetamine Group U.S. Patent Nov. 17, 2009 Sheet 2 of 55 US 7,619,005 B2 SOO - 400 d D J. 30 ge A 3. a is - p 5 200 t rama A. ... . r OO O 2 hr. ir Injection Time (hours) F.G. 3 U.S. Patent US 7,619,005 B2 U.S. Patent US 7,619,005 B2 (oos)tro?ualay? U.S. Patent Nov. 17, 2009 Sheet 5 of 55 US 7,619,005 B2 2 Saline S-(+)-amphetamine U.S. Patent Nov. 17, 2009 Sheet 6 of 55 US 7,619,005 B2 Total Distance " | -A W. -O- cort -S-S-(+)-gnpincarnine 400-500- - l--- | \ : ---, - 3()() - :- -- ?h so f {}{1- (4----- () 4 ( 8 Time (min) FIG 7A U.S. Patent Nov. 17, 2009 Sheet 7 Of SS US 7,619,005 B2 Number of Movements -- clic - -> C -- S-(+)-anpbcamine 2 g 30 | -i- -15 N -is: 9 () i o 2. 10 O 4 6 8 () Tirne (inin) F. G. 7B U.S. Patent Nov. 17, 2009 Sheet 8 Of 55 US 7,619,005 B2 Movement Time S O -o- Control -e-S-(+)-amphetainine O t 1 3 4. 5 6, 7 8 9 O Time (min) FIG 7C U.S. Patent Nov. 17, 2009 Sheet 9 Of SS US 7,619,005 B2 Nurnber of Rears -C-COrol --S-(+)-amphetamine Tinne firin) FIG 7) U.S. Patent Nov. 17, 2009 Sheet 10 Of 55 US 7,619,005 B2 Number of Stereotyped Movements 5 -- Control -e-S-(+)-amphetamine E) Tirne (min) FIG 7E U.S. Patent Nov. 17, 2009 Sheet 11 Of 55 US 7,619,005 B2 Time Spent Resting -- corol : -- S-(+)-amphetamine his------ Time (min) F.G. 7F U.S. Patent US 7,619,005 B2 FIG. 8 F.G. 9 U.S. Patent Nov. 17, 2009 Sheet 13 Of 55 US 7,619,005 B2 400 3 O O 2 O O 100 Control C105 FIG. O. U.S. Patent Nov. 17, 2009 Sheet 14 of 55 US 7,619,005 B2 FIG. 2 0. O OO Saline C105 FIG, 12 2 O O 1 O O Saline C05 U.S. Patent Nov. 17, 2009 Sheet 15 Of 55 US 7,619,005 B2 Discrimination Index (D1) - Controls r -a, s s O S. Saline ClO5 U.S. Patent Nov. 17, 2009 Sheet 16 of 55 US 7,619,005 B2 Discrimination Index (D2) - Controls p Safine ClO5 Group FIG 3B U.S. Patent Nov. 17, 2009 Sheet 17 of 55 US 7.619,005 B2 Discrimination Index (D1) - Fornix Lesion Rats 5 s O s' Y 2 10 9. 5 2 () O - Foix + Saline For Ilix -- ClO5 Group FIG. 3C U.S. Patent Nov. 17, 2009 Sheet 18 of 55 US 7.619,005 B2 Discrimination Index (D2) - Fornix Lesion Rats 5 O 4. O 3 2OO O Fornix + Saline Fornix -- C 05 Group FIG. 13) U.S. Patent Nov. 17, 2009 Sheet 19 of 55 US 7,619,005 B2 Total Distance 6 O O -- Salists 5. O O -- C 05 3. O O FIG. 14A U.S. Patent Nov. 17, 2009 Sheet 20 of 55 US 7.619,005 B2 Number of Movements 20 -- Salle -C-CO5 3. 2 S O a 2. O O 3 4 5 & 7 8 9 0 Jiline (min) F.G. 148 U.S. Patent Nov. 17, 2009 Sheet 21 of 55 US 7.619,005 B2 Movement Time 4 O -a-Saline ana 3 -o- ClO5 a a 30 - 20 5 c 10 4. 0 O 4 6 7 8 9 C. Time (min) FIG. 4C U.S. Patent Nov. 17, 2009 Sheet 22 of 55 US 7,619,005 B2 Number of Rears 10 -s-Saline -o- C105 o 2 3 4 5, 6 i 8, 9 () Time (min) F.G. 14 D U.S. Patent Nov. 17, 2009 Sheet 23 of 55 US 7,619,005 B2 Number of Stereotyped Movements -s-Saline -o- C105 ) 2 3 A. 5 -6 7 8 9 : ) Time (min) FIG. 4E U.S. Patent Nov. 17, 2009 Sheet 24 of 55 US 7.619,005 B2 Time Spent Resting -- Saline -o- C 05 S O Tinne (min) FG, 4F U.S. Patent Nov. 17, 2009 Sheet 25 of 55 US 7,619,005 B2 Total Distance e -E-control i 500 i- fi-- -- S-(+)-amphetamine U.S. Patent Nov. 17, 2009 Sheet 26 of 55 US 7.619,005 B2 NInber of Movements -- control -N 40 -O-S-(+)-arnphetanine E 30 -1 -1N g 20 C > Time (min) F.G. 15B U.S. Patent Nov. 17, 2009 Sheet 27 of 55 US 7.619,005 B2 Movement Time 50 -- Conito -C-S-(+)-amphetamine 3 O s 4 5 6 8 9 () Tine (min) F.G. 15C U.S. Patent Nov. 17, 2009 Sheet 28 of 55 US 7,619,005 B2 Number of Rears -e- control -C-S-(+)-anphetamine Time (min) F.G. 5D U.S. Patent Nov. 17, 2009 Sheet 29 Of 55 US 7,619,005 B2 Number of Stereotyped Movements 5 -O--d-amphetainine 9R : 10 2 a 2 - 5 E s Z. Time (min) FIG. 5E U.S. Patent Nov. 17, 2009 Sheet 30 of 55 US 7,619,005 B2 Time Spent Resting SG an -- cotto 2. AC) -O-S-(+)-amphetaininc-S---Y- E. P 3. 3C A4 M () t 4. 6 s (3 Tirne (min) FIG 5F U.S. Patent er, laer) laer) US 7,619,005 B2 FIG 16 Z(oos)KotlaneTXoII,IIeL F.G. 7 r<”r????????????????????????????????????????????????????|- U.S. Patent Nov. 17, 2009 Sheet 32 Of 55 US 7,619,005 B2 JLWTRICI (sºumoid) JLTAVYI||JLWA8{ 09. uotua buoo peoped U.S. Patent Nov. 17, 2009 Sheet 33 of 55 US 7.619,005 B2 w C CN CC N var w (SI = Xeu) IIeoe PIOAA U.S. Patent Nov. 17, 2009 Sheet 34 of 55 US 7,619,005 B2 600 S. NC 5OO > S. 400 f &SSS 5. 300 & C T & g 200 & t & 100 & O- & 92 : CO O & veh 10 2. O O.5. 10 O25 0.5 d-amph C 105 SN522 Dose (mg/kg) FIG. 20 U.S. Patent Nov. 17, 2009 Sheet 35 of 55 US 7,619,005 B2 500 234OOO OOO 10 O O k us O. 1 0.25 O5C) Dose off-methanphetamine (mg/kg) FIG. 2. U.S. Patent Nov. 17, 2009 Sheet 36 of 55 US 7,619,005 B2 -- Saline -- SN522 (0.25 mg/kg) -a- SN522 (0.5 mg/kg) 1 O F.G. 22 U.S. Patent Nov. 17, 2009 Sheet 37 Of 55 US 7,619,005 B2 200 a 522 (0.25 mg/kg) -4- SN522 (0.5 mg/kg) OOO -- SN522 (2.5 mg/kg) -a - SN522 (5.0 mg/kg) 6 O 400 200 S S & S eS S Time After injection (min) FIG. 23 200 -C- d-ariph (0.25 mg/kg i-A-d-amph (C.5 mg/kg) -- d-Airph (2.5 mg/kg) 1000 --- di-Amph (5.0 rig kg) /N S S &S & S S S & & Time After injection FIG. 24. U.S. Patent Nov. 17, 2009 Sheet 38 of 55 US 7,619,005 B2 1 1 ck O 30 ng 30 45 9 ng ring 15 ng 5 8 15 O g ing ng O mg - 3 O Inn 24 hr Recall Time * P < 0.05 vs. placebo (OIng) FIG. 25 U.S. Patent Nov. 17, 2009 Sheet 39 Of 55 US 7,619,005 B2 Pacebo C105 individual RAV. Scores for Volunteers e 21-49 Yeaf's Od a 60-72 Years Od FIG. 26 U.S. Patent US 7.619,005 B2 8ÓOIH ëõue).su])sa1 r N U.S. Patent US 7.619,005 B2 N. a to N re- C 3. U.S. Patent US 7.619,005 B2 ---- C e? C2 - Saicos fifty U.S. Patent Nov. 17, 2009 Sheet 44 of 55 US 7.619,005 B2 U.S. Patent Nov. 17, 2009 Sheet 45 of 55 US 7,619,005 B2 700 Scopolamine ( 0.75 mg/kg) (Oês)ÁouajeTufinol?L-days Sal O. 12 O.25 O.5 1.O SN522 (mg/kg) FIG. 32 U.S. Patent Nov. 17, 2009 Sheet 46 of 55 US 7,619,005 B2 Sal-Sal Sal 0.25 0.5 1.0 2.0 p C 105 (mg/kg) Scopolamine (0.75 mg/kg) Treatment Group FIG. 33 U.S. Patent Nov. 17, 2009 Sheet 47 of 55 US 7,619,005 B2 25 50 SN522 Dose FIG. 34 U.S. Patent Nov. 17, 2009 Sheet 48 of 55 US 7,619,005 B2 Total Speed 5 -400 5 9 s -300 O s -200 s CD $g -100 b 3 o E s O t CD O) Cs 100 d s 2 200 CO - placebo 25 mg 50 mg 100 mg 150 mg Treatment FIG. 35 U.S. Patent Nov. 17, 2009 Sheet 49 of 55 US 7,619,005 B2 Picture Recognition - Sensitivity Index d placebo 25 mg 50 mg 100 mg 150 mg Treatment FIG. 36 U.S. Patent Nov. 17, 2009 Sheet 50 of 55 US 7,619,005 B2 Information Processing - Targets Detected 30 20 10 s O placebo 25 mg 50 mg 100 mg 150 mg Treatment FIG. 37 U.S. Patent Nov. 17, 2009 Sheet 51 of 55 US 7,619,005 B2 Information Processing - False Alarms -10 " . 10 15 placebo 25 mg 50 mg 100 mg 150 mg Treatment FIG 38 U.S. Patent Nov. 17, 2009 Sheet 52 of 55 US 7,619,005 B2 FIG. 39 U.S. Patent Nov. 17, 2009 Sheet 53 of 55 US 7,619,005 B2 STMULUS () (4) (8) FIG. 40 U.S. Patent Nov. 17, 2009 Sheet 54 of 55 US 7,619,005 B2 FIG. 41A LP rh FIG. 41B U.S. Patent Nov. 17, 2009 Sheet 55 of 55 US 7,619,005 B2 Screening Day 1 (SD1) - Visit 1 Screening Day 2 (SD2 - Telephone Cat 6, + 7 days Day 1 - Visit 2 Day 2 - Telephone Call 2 6, it 1 Day Day 8 - Visit 3 Dav 9 - Telephone Cal 3 6, it 1 Day 1. Day 15 - Visit 4 Day 16 - Telephone Cal 4 6, it 1 Day ap Day 22 - Visit 5 Dav 23 - Telephone Call 5 4, it 2 Days 1. Day 27 - Telephone Call 6 FIG 42 US 7,619,005 B2 1. 2 METHODS FOR TREATING COGNITIVE Indeed, loss or impairment of long-term memory is a signifi IMPAIRMENT INHUMANS WITH MULTIPLE cant feature of such diseases, and no effective therapy for that SCLEROSIS effect has emerged. Short-term memory and working memory, are generally not significantly impaired in Such RELATED APPLICATIONS patients. Accordingly, methods and compositions that enhance This application is a continuation-in-part application of long-term memory function and/or performance, or prophy International Application PCT/US2004/015974, filed May lactically (e.g., as a neuroprotective treatment) prevent or 21, 2004, which designates the United States and was pub slow degradation of long-term memory function and/or per lished in English, which is a continuation-in-part of U.S. 10 formance would be desirable. Similarly, methods and com application Ser. No. 10/791,223, filed Mar. 2, 2004, which is positions for restoring long-term memory function and/or a continuation-in-part of U.S. application Ser. No. 10/444, performance are needed. 970, filed May 23, 2003 now abandoned, which is a continu Impairments in cognitive and memory processes in a ation-in-part of U.S. application Ser. No. 10/139,606, filed human can occur in a number of conditions or diseases. Such May 2, 2002, now abandoned which is a continuation-in-part 15 as age-related memory loss, Mild Cognitive Impairment, of U.S. application Ser. No. 10/003,740 filed Oct. 31, 2001, Alzheimer's disease, Multiple Sclerosis, brain injury, brain now U.S. Pat. No. 6,828,351, issued Dec. 7, 2004, which aneurysm, stroke, Schizophrenia, epilepsy, chronic fatigue claims the benefit of U.S. Provisional Application No. syndrome, fibromyalgia syndrome, chemotherapy (e.g., can 60/245,323, filed on Nov. 1, 2000, and claims priority to cer chemotherapy), traumatic brain injury, and Parkinson's International Application PCT/US01/45793, filed Oct. 31, disease. Following exposure to a muscarinic cholinergic 2001, which designates the United States and was published receptor antagonist, such as atropine or Scopolamine, humans in English. This application also claims the benefit of U.S. can experience impairment of cognitive and memory pro Provisional Application No. 60/473,168, filed May 23, 2003. cesses. Clinical management strategies currently provide The teachings of the above applications are incorporated minimal, if any, improvement in memory and cognitive func herein by reference in their entirety. 25 tion. Thus, there is a need to develop new, improved and effective methods for the treatment of a human suffering with BACKGROUND OF THE INVENTION an impairment in cognitive and memory processes. The term “memory' subsumes many different processes SUMMARY OF THE INVENTION and requires the function of many different brain areas. Over 30 all, human memory provides declarative recall, e.g., for facts and events accessible to conscious recollection, and non The present invention relates to methods of treating a declarative recall, e.g., procedural memory of skills and human having an impairment in memory and/or cognitive operations not stored regarding time and place. Research in function. recent years has provided information necessary to under 35 The human can have an impairment in memory consolida stand many of the various components of memory and has tion (the process of storing new information in long term identified associated brain regions. A newly acquired experi memory), an impairment in short term memory processes, an ence initially is susceptible to various forms of disruption. impairment in working memory, an impairment in long-term With time, however, the new experience becomes resistant to memory, an impairment in declarative memory or an impair disruption. This observation has been interpreted to indicate 40 ment in procedural memory. The humans are treated with the that a labile, working, short-term memory is consolidated into amphetamine class of compounds (collectively referred to a more stable, long-term memory. herein as "amphetamine compounds') to enhance, prevent Behavioral research has found that the human mind con and/or restore long-term memory function and performance, Solidates memory at certain key time intervals. The initial e.g., to improve the process of storing new information in phase of memory consolidation occurs in the first few minutes 45 long term memory in humans (memory consolidation) or to after an exposure to a new idea or learning experience. The improve short term memory or to improve working memory. next phase occurs over alonger period of time, such as during The human can have an impairment in memory and/or a sleep. If a learning experience has on-going meaning to us, cognition function as a consequence of exposure to a musca the next week or so serves as a further period of memory rinic cholinergic receptor antagonist. More particularly, the consolidation. In effect, in this phase, the memory moves 50 invention relates to the discovery that a particular enantiomer from short-term to long-term storage. of amphetamine compounds (R)-(-)-amphetamine (1-am Moreover, various mechanisms have been proposed to phetamine, levo-amphetamine) or (R)-(-)-methamphet account for the formation of long-term memory. A wide range amine (1-methamphetamine, levo-methamphetamine) is of observations Suggest an evolutionarily conserved molecu effective for treating humans having an impairment in lar mechanism involved with the formation of long-term 55 memory and an impairment in cognitive function. memory. These include increased release of synaptic trans In one embodiment, the invention includes a method of mitter, increased number of synaptic receptors, decreased K improving memory consolidation in a human, comprising the of receptors, synthesis of new memory factors either in the step of administering at least one member selected from the presynaptic or postsynaptic element, sprouting of new syn group consisting of 1-amphetamine and 1-methamphetamine aptic connections, increase of the active area in the presyn 60 to a human having an impairment in memory consolidation. aptic membrane and many others. Synaptic plasticity, the In another embodiment, the invention includes a method of change in the strength of neuronal connections in the brain, is improving memory consolidation in a human, comprising the thought to underlie long-term memory storage. step of administering at least one member selected from the Memory consolidation, the process of storing new infor group consisting of 1-amphetamine and 1-methamphetamine mation in long-term memory is also believed to play a crucial 65 to a human having an impairment in memory consolidation, role in a variety of neurological and mental disorders, includ wherein the 1-amphetamine is at least about 80 mole percent ing mental retardation, Alzheimer's disease and depression. 1-amphetamine relative to d-amphetamine and the 1-metham US 7,619,005 B2 3 4 phetamine is at least about 80 mole percent 1-methamphet In still another embodiment, the invention includes a amine relative to d-methamphetamine. method of improving memory consolidation in a human, In yet another embodiment, the invention includes a comprising the step of administering an amphetamine to a method of improving memory consolidation in a human, human having an impairment in memory consolidation in an comprising the step of administering at least one member 5 amount effective to improve memory consolidation in the selected from the group consisting of l-amphetamine and human, wherein the amphetamine is between about 80 mole 1-methamphetamine to a human having an impairment in percent 1-amphetamine to about 99 mole percent 1-amphet memory consolidation, wherein the 1-amphetamine is at least amine and the l-amphetamine is administered to the human in about 90 mole percent 1-amphetamine relative to d-amphet a dose at least about a 0.01 mg dose. amine and the 1-methamphetamine is at least about 90 mole 10 Another embodiment of the invention includes a method of percent 1-methamphetamine relative to d-methamphetamine. improving memory consolidation in a human comprising An additional embodiment of the invention includes a assessing the degree of impairment in memory consolidation method of improving memory consolidation in a human, in a human having an impairment in memory consolidation comprising the steps of assessing the degree of an impairment and administering an amphetamine to the human in an in memory consolidation in a human; administering at least 15 amount effective to improve memory consolidation in the one member selected from the group consisting of l-amphet human, wherein the amphetamine is at least about 80 mole amine and 1-methamphetamine to the human; and determin percent 1-amphetamine. The improvement in memory con ing the improvement in memory consolidation after admin Solidation after administering the amphetamine to the human istering the 1-amphetamine and 1-methamphetamine to the is determined. human. In an additional embodiment, the invention includes a In still another embodiment, the invention includes a method of improving memory consolidation in a human, method of improving memory consolidation in a human, comprising the step of administering an amphetamine to a comprising the step of administering an amphetamine to a human having an impairment in memory consolidation in an human having an impairment in memory consolidation in an amount effective to improve memory consolidation in the amount effective to improve memory consolidation in the 25 human, wherein the amphetamine is at least about 90 mole human, wherein the amphetamine is at least about 85 mole percent 1-amphetamine and has the structural formula: percent 1-amphetamine. In another embodiment, the invention includes a method of improving memory consolidation in a human, comprising the step of administering an amphetamine to a human having an 30 impairment in memory consolidation in an amount effective to improve memory consolidation in the human, wherein the amphetamine is at least about 80 mole percent 1-amphet amine. In still another embodiment, the invention includes a Another embodiment of the invention includes a method of 35 method of improving memory consolidation in a human, improving memory consolidation in a human, comprising the comprising the step of administering an amphetamine to a step of administering an amphetamine to a human having an human having an impairment in memory consolidation in an impairment in memory consolidation in an amount effective amount effective to improve memory consolidation in the to improve memory consolidation in the human, wherein the human, wherein the amphetamine is at least about 90 mole amphetamine is at least about 99 mole percent 1-amphetamine 40 percent 1-methamphetamine. and the l-amphetamine is administered to the human in a dose In a further embodiment, the invention includes a method of at least about a 0.01 mg dose. of improving memory consolidation in a human, comprising In yet another embodiment, the invention includes a the step of administering an amphetamine to a human having method of improving memory consolidation in a human, 45 an impairment in memory consolidation in an amount effec comprising the step of administering an amphetamine to a tive to improve memory consolidation in the human, wherein human having an impairment in memory consolidation in an the amphetamine is at least about 85 mole percent 1-metham amount effective to improve memory consolidation in the phetamine. human, wherein the amphetamine is at least about 90 mole An additional embodiment of the invention includes a percent 1-amphetamine and the 1-amphetamine is adminis 50 method of improving memory consolidation in a human, tered to the human in a dose between about a 0.01 mg dose to comprising the step of administering an amphetamine to a about a 125 mg dose. human having an impairment in memory consolidation in an In an additional embodiment, the invention includes a amount effective to improve memory consolidation in the method of improving memory consolidation in a human, human, wherein the amphetamine is at least about 80 mole comprising the step of administering an amphetamine to a 55 percent 1-methamphetamine. human having an impairment in memory consolidation in an In yet another embodiment, the invention includes a amount effective to improve memory consolidation in the method of improving memory consolidation in a human, human, wherein the amphetamine is at least about 80 mole comprising the step of administering an amphetamine to a percent 1-amphetamine and the 1-amphetamine is adminis human having an impairment in memory consolidation in an tered to the human in a dose at lease about a 0.01 mg dose. 60 amount effective to improve memory consolidation in the In a further embodiment, the invention includes a method human, wherein the amphetamine is at least about 99 mole of improving memory consolidation in a human, comprising percent 1-methamphetamine and the dose of 1-methamphet the step of administering an amphetamine to a human having amine administered to the human is at least about a 0.01 mg an impairment in memory consolidation in an amount effec dose. tive to improve memory consolidation in the human, wherein 65 Another embodiment of the invention includes a method of the amphetamine is between about 80 mole percent 1-amphet improving memory consolidation in a human, comprising the amine to about 99 mole percent 1-amphetamine. step of administering an amphetamine to a human having an US 7,619,005 B2 5 6 impairment in memory consolidation in an amount effective In still another embodiment, the invention is a pharmaceu to improve memory consolidation in the human, wherein the tical preparation comprising one or more amphetamine com amphetamine is at least about 90 mole percent 1-methamphet pounds provided in the form of a transdermal patch and amine and the 1-methamphetamine is administered to the formulated for Sustained release of the amphetamine(s) in human in a dose at least about a 0.01 mg dose. order to administer an amount Sufficient to enhance long-term In yet another embodiment, the invention includes a memory in a patient but resulting in a concentration in the method of improving memory consolidation in a human, patient lower than its ECs as a CNS stimulant. comprising the step of administering an amphetamine to a In particular embodiments, the pharmaceutical kits and human having an impairment in memory consolidation in an preparations of the invention comprise at least one of the amount effective to improve memory consolidation in the 10 amphetamine compounds represented by Formula I, or a human, wherein the amphetamine is at least about 80 mole pharmaceutically acceptable salt, Solvate, metabolite or pro percent 1-methamphetamine and the dose of 1-methamphet drug thereof: amine administered to the human is at least about a 0.01 mg dose. In a further embodiment, the invention includes a method 15 (I) of improving memory consolidation in a human, comprising the step of administering an amphetamine to a human having an impairment in memory consolidation in an amount effec tive to improve memory consolidation in the human, wherein the amphetamine is between about 80 mole percent 1-meth amphetamine to about 99 mole percent 1-methamphetamine. An additional embodiment of the invention includes a method of improving memory consolidation in a human, wherein, as Valence and stability permit, comprising the step of administering an amphetamine to a R, independently for each occurrence, represents hydro human having an impairment in memory consolidation in an 25 gen or substituted or unsubstituted lower alkyl, lower amount effective to improve memory consolidation in the alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het human, wherein the amphetamine is between about 80 mole eroaryl, cycloalkyl, or cycloalkylalkyl, percent 1-methamphetamine to about 99 mole percent 1-meth R represents hydrogen or substituted or unsubstituted amphetamine and the 1-methamphetamine is administered to lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, the human in a dose at least about a 0.01 mg dose. 30 heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla Another embodiment of the invention includes a method of lkyl: improving memory consolidation in a human, comprising R represents hydrogen or Substituted or unsubstituted assessing the degree of impairment in memory consolidation lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, in a human having an impairment in memory consolidation heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla and administering an amphetamine to the human in an 35 lkyl; amount effective to improve memory consolidation in the human, wherein the amphetamine is at least about 80 mole R represents from 1 to 3 substituents on the ring to which percent 1-methamphetamine. The improvement in memory it is attached, selected from the group consisting of consolidation after administering the amphetamine to the hydrogen, halogen, hydroxy, alkoxy, amino, alky human is determined. 40 lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, In an additional embodiment, the invention includes a formyl, amido, acylamino, acyloxy, lower alkyl, lower method of improving memory consolidation in a human, alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, comprising the step of administering an amphetamine to a Sulfamoyl, and Sulfonamido. human having an impairment in memory consolidation in an In certain embodiments, R represents hydrogen, while in amount effective to improve memory consolidation in the 45 other embodiments, R represents lower alkyl. Such as human, wherein the amphetamine is at least about 90 mole methyl, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, percent 1-methamphetamine and has the structural formula: etc., hydroxy, amino, or carbonyl. In certain embodiments, R represents hydrogen, while in other embodiments, R represents from 1 to 3 substituents on 50 the ring to which it is attached selected from halogen, hydroxy, amino, Sulfhydryl, cyano, nitro, lower alkyl, and oHCI sulfate. In certain embodiments, R represents hydrogen and at least one of R, R2, and R represents hydrogen. In certain 55 embodiments, R represents hydrogen and at least two of R, In one embodiment, the invention is a pharmaceutical kit R, and R represents hydrogen. In certain embodiments, R. comprising one or more amphetamine compound(s) in an represents hydrogen and at least three of R, R2, and R amount Sufficient to enhance long-term memory in a patient, represent hydrogen. In certain embodiments, Ra represents a pharmaceutically acceptable carrier, and instructions (writ hydrogen and all four of R, R2, and R represent hydrogen. ten and/or pictorial) describing the use of the formulation for 60 In certain embodiments, one R represents hydrogen, one enhancing memory. R represents lower alkyl. Such as methyl, ethyl, propyl, iso In another embodiment, the invention is a pharmaceutical propyl. n-butyl, isobutyl, t-butyl, etc., R represents lower preparation comprising one or more amphetamine com alkyl, such as methyl, ethyl, propyl, isopropyl. n-butyl, isobu pounds provided as a single oral dosage formulation in an tyl, t-butyl, etc., R and R represent hydrogen. amount Sufficient to enhance long-term memory in a patient 65 In certain preferred embodiments, one occurrence of R but resulting in a concentration in the patient lower than its represents hydrogen, the second occurrence of R represents ECs as a CNS stimulant. hydrogen, or lower alkyl; R represents hydrogen or lower US 7,619,005 B2 7 8 alkyl, R represents hydrogen or lower alkyl, and Ra repre R, and R represents hydrogen. In certain embodiments, R. sents hydrogen or from 1 to 3 Substituents on the ring to which represents hydrogen and at least three of R. R. and R it is attached, selected from halogen, trifluoromethyl, represent hydrogen. In certain embodiments, R represents hydroxy, amino, cyano, nitro, and lower alkyl. hydrogen and all four of R, R2, and R represent hydrogen. In certain preferred embodiments, R represents hydrogen In certain embodiments, one R represents hydrogen, one and at least one of R, R2, and R represents hydrogen. R represent lower alkyl, such as methyl, ethyl, propyl, iso In certain preferred embodiments, R represents hydrogen propyl. n-butyl, isobutyl, t-butyl, etc., R represents lower and at least two of R, R2, and R represent hydrogen. alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, In certain preferred embodiments, both occurrences of R t-butyl, etc., R and R represent hydrogen. represent independently hydrogen, R represents methyl, R 10 In certain preferred embodiments, one occurrence of R represents hydrogen and Ra represents hydrogen. represents hydrogen, the second occurrence of R represents In certain preferred embodiments, one occurrence of R hydrogen, or lower alkyl; R represents hydrogen or lower represents hydrogen, the second occurrence of R represents alkyl, R represents hydrogen or lower alkyl, and Ra repre methyl, R represents methyl, R represents hydrogen and R. sents hydrogen or from 1 to 2 substituents on the ring to which represents hydrogen. 15 it is attached, selected from halogen, trifluoromethyl, In most preferred embodiments, R, independently and for hydroxy, amino, cyano, nitro, and lower alkyl. each occurrence, represents hydrogen, R represents methyl, In certain preferred embodiments, R represents hydrogen and R and R independently and for each occurrence repre and at least one of R, R2, and R represents hydrogen. sent hydrogen. In certain preferred embodiments, R represents hydrogen In other preferred embodiments the pharmaceutical kits and at least two of R. R. and R represent hydrogen. and preparations of this invention comprise at least one of the In certain preferred embodiments, both occurrences of R amphetamine compounds as a pharmaceutically acceptable represent independently hydrogen, R represents methyl, R salt represented by Formula II: represents hydrogen and R represents hydrogen. In certain preferred embodiments, one occurrence of R 25 represents hydrogen, the second occurrence of R represents (II) methyl, R represents methyl, R represents hydrogen and R. represents hydrogen. In most preferred embodiments, R, independently and for 30 each occurrence, represents hydrogen, R represents methyl, and R and R independently and for each occurrence repre sent hydrogen. In other preferred embodiments the pharmaceutical kits and preparations of this invention comprise at least one of the wherein, as Valence and stability permit, 35 amphetamine compounds as an amphetamine metabolite rep R, independently for each occurrence, represents hydro resented by Formula III: gen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het eroaryl, cycloalkyl, or cycloalkylalkyl, (III) Rs R R R represents hydrogen or Substituted or unsubstituted 40 N NN1 lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla A4 lkyl: R4 R represents hydrogen or Substituted or unsubstituted R3 Rs lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla 45 lkyl: wherein, as Valence and stability permit, R represents from 1 to 3 substituents on the ring to which R, independently for each occurrence, represents hydro it is attached, selected from the group consisting of gen or substituted or unsubstituted lower alkyl, lower hydrogen, halogen, hydroxy, alkoxy, amino, alky 50 alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, eroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally formyl, amido, acylamino, acyloxy, lower alkyl, lower Substituted by one or more Substitutents such as halogen, alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, hydroxy, alkoxy; Sulfamoyl, and Sulfonamido; and R represents hydrogen or lower alkyl, lower alkenyl, L is a non-toxic organic or inorganic acid. 55 lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, In certain embodiments, R represents hydrogen, while in cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi other embodiments, R represents lower alkyl, Such as tuted by one or more substitutents such as halogen, methyl, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, hydroxy, alkoxy; etc., hydroxy, amino, or carbonyl. R represents hydrogen or lower alkyl, lower alkenyl, In certain embodiments, R represents hydrogen, while in 60 lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, other embodiments, R represents from 1 to 3 substituents on cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi the ring to which it is attached selected from halogen, tuted by one or more substitutents such as halogen, hydroxy, amino, Sulfhydryl, cyano, nitro, lower alkyl, and hydroxy, alkoxy; sulfate. R represents from 1 to 3 substituents on the ring to which In certain embodiments, R represents hydrogen and at 65 it is attached, e.g., selected from hydrogen, halogen, least one of R, R2, and R represents hydrogen. In certain hydroxy, alkoxy, amino, alkylamino, Sulfhydryl, alky embodiments, R represents hydrogen and at least two of R, lthio, cyano, nitro, ester, ketone, formyl, amido, acy US 7,619,005 B2 10 lamino, acyloxy, lower alkyl, lower alkenyl, Sulfonate mole percent) of one amphetamine enantiomer relative to ester, amidino, Sulfonyl, Sulfoxido, Sulfamoyl, and Sul another amphetamine enantiomer (e.g., 1-amphetamine rela fonamido; tive to d-amphetamine or 1-methamphetamine relative to Rs independently for each occurrence, represents hydro d-methamphetamine). For example, an amphetamine compo gen or hydroxy. sition employed in the methods can be about 80 percent (w/w In certain embodiments, R represents hydrogen, while in or mole percent) l-amphetamine or 1-methamphetamine rela other embodiments, R represents lower alkyl, such as tive to d-amphetamine or d-methamphetamine, where d-am methyl, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, phetamine or d-methamphetamine is about 20 percent (i.e., etc., hydroxy, amino, or carbonyl. the remainder) (w/w or mole percent) of the amphetamine. In certain embodiments, R represents hydrogen, while in 10 In another embodiment, the methods of the invention other embodiments, Ra represents from 1 to 3 substituents on employ an amphetamine that is about 100 percent (w/w or the ring to which it is attached selected from halogen, mole percent) l-amphetamine or 1-methamphetamine, hydroxy, amino, Sulfhydryl, cyano, nitro, lower alkyl, and wherein the 1-amphetamine is a composition that includes at sulfate. least about 100 mole percent 1-amphetamine relative to a total In certain embodiments, R represents hydrogen and at 15 amphetamine content of the composition or wherein the least one of R. R. and R represents hydrogen. In certain 1-methamphetamine is administered as a composition that embodiments, R represents hydrogen and at least two of R, includes at least about 100 mole percent 1-amphetamine rela R, and R represent hydrogen. In certain embodiments, R. tive to a total amphetamine content of the composition. An represents hydrogen and at least three of R, R2, and R amphetamine that is “about 100 percent' l-amphetamine or represent hydrogen. In certain embodiments, R represents 1-methamphetamine can contain insignificant trace amounts hydrogen and all four of R. R. and R represent hydrogen. of d-amphetamine or d-methamphetamine. In certain embodiments, one R represents hydrogen, one In certain preferred embodiments, particularly for those R represent lower alkyl, such as methyl, ethyl, propyl, iso which use (R)-(-)-amphetamine (1-amphetamine) or 1-meth propyl. n-butyl, isobutyl, t-butyl, etc., R represents lower amphetamine, the kits, preparations, compositions and meth alkyl, such as methyl, ethyl, propyl, isopropyl. n-butyl, isobu 25 ods preferably use compositions of (R)-(-)-amphetamine tyl, t-butyl, etc., R and R represent hydrogen. which contain less than 10 percent (w/w or mole percent) In certain preferred embodiments, one occurrence of R (S)-(+)-amphetamine, and even more preferably less than less represents hydrogen, the second occurrence of R represents than 5 percent (w/w or mole percent), 1 percent (w/w or mole hydrogen, or lower alkyl; R represents hydrogen or lower percent) or even less than 0.5 percent (w/w or mole percent) alkyl, R represents hydrogen or lower alkyl, and R repre 30 (S)-(+)-amphetamine. sents hydrogen or from 1 to 2 substituents on the ring to which In another embodiment, the amphetamine employed in the methods can be a percent of the total composition adminis it is attached, selected from halogen, trifluoromethyl, tered to the human. The amphetamine component of the com hydroxy, amino, cyano, nitro, and lower alkyl. position can be about 50 percent (w/w), about 60 percent In certain preferred embodiments, R represents hydrogen (w/w), about 75 percent (w/w), about 80 percent (w/w), about and at least one of R. R. and R represents hydrogen. 35 85 percent (w/w), about 90 percent (w/w), about 95 percent In certain preferred embodiments, R represents hydrogen (w/w) and about 100 percent (w/w) of the total composition and at least two of R, R2, and R represent hydrogen. administered to the human. For example, the human can be In certain preferred embodiments, both occurrences of R administered a composition which comprises about 80 represent independently hydrogen, R represents methyl, R weight or Volume percent amphetamine and about 20 weight represents hydrogen and R represents hydrogen. 40 or Volume percent, respectively, inert excipient. The amphet In certain preferred embodiments, one occurrence of R amine component of the composition includes at least one represents hydrogen, the second occurrence of R represents member selected from the group consisting of l-amphet methyl, R represents methyl, R represents hydrogen and R. amine, 1-methamphetamine, d-amphetamine and d-metham represents hydrogen. phetamine. In one embodiment, R, independently and for each occur 45 In still another embodiment of the kits, preparations, com rence, represents hydrogen, R represents methyl, and R and positions and methods, the invention features one or more Ra independently and for each occurrence represent hydro amphetamine compound(s) provided in an amount Sufficient gen. to enhance long-term memory in a patient by a statistically In another embodiment, a metabolite of an amphetamine significant amount when assessed by a standardized perfor compound is selected from p-hydroxyamphetamine, benzyl 50 mance teSt. methyl ketone, l-phenylpropan-2-ol, benzoic acid, glycine, In certain embodiments of the kits, preparations, compo hippuric acid, p-hydroxynorephedrine, and N-hydroxylam sitions and methods, the invention features one or more phetamine. amphetamine compound(s) comprising at least 2-fold less, or In particular embodiments of the kits, preparations, com at least 4-fold less of the distomer(s) as compared to an positions and methods, the invention features a pharmaceuti 55 equally effective long term memory enhancing dose of the cal kit or preparation comprising a mixture of at least a single distomer(s) of the amphetamine compound(s). species of amphetamine compounds or at least two different In certain embodiments of the kits, preparations, compo species of amphetamine compounds. The different species of sitions and methods, the invention features amphetamine amphetamine compounds can be present in equal or in dif comprising at least 2-fold less, or at least 4-fold less of fering amounts with respect to one another. 60 (R)-(-)-amphetamine as compared to an equally effective In another embodiment of the kits, preparations, composi long term memory enhancing dose of (S)-(+)-amphetamine. tions and methods, the invention features a composition com In certain embodiments of the kits, preparations, compo prising at least about 51 percent (w/w (weight/weight) or sition and methods, the invention features one or more mole percent), about 60 percent (w/w or mole percent), about amphetamine compound(s) provided in an amount Sufficient 75 percent (w/w or mole percent), about 80 percent (w/w or 65 to enhance long-term memory in a patient by a statistically mole percent), about 85 percent (w/w or mole percent), about significant amount when assessed by Standardized perfor 95 percent (w/w or mole percent) or about 99 percent (w/w or mance test, such as one or more of a Rey Auditory and Verbal US 7,619,005 B2 11 12 Learning Test (RAVLT): Cambridge Neuropsychological tion the preparation delivers an increasing dose of the Test Automated Battery (CANTAB); a Children's Memory amphetamine compound(s) over time. Scale (CMS); a Contextual Memory Test; a Continuous Rec In other embodiments of escalating dose formulations, the ognition Memory Test (CMRT); a Denman Neuropsychology amphetamine compound(s) are formulated in a delivery sys Memory Scale; a Fuld Object Memory Evaluation (FOME): tem including a bioerodible polymer, a dose of the amphet a Graham-Kendall Memory for Designs Test; a Guild amine compound(s) present in an initial dose and a final dose, Memory Test; a Learning and Memory Battery (LAMB); a whereby the preparation delivers an initial dose then a final Memory Assessment Clinic Self-Rating Scale (MAC-S); a dose over time. Memory Assessment Scales (MAS); a Randt Memory Test; a In still other embodiments of escalating dose formulations, Recognition Memory Test (RMT): a Rivermead Behavioral 10 the amphetamine compound(s) are formulated in a delivery Memory Test; a Russell's Version of the Wechsler Memory system including a plurality of beads, each bead including a Scale (RWMS); a Test of Memory and Learning (TOMAL); a amphetamine compound and having a dissolution profile, Vermont Memory Scale (VMS); a Wechsler Memory Scale: which plurality of beads is a variegated population with and a Wide Range Assessment of Memory and Learning respect to dose and/or dissolution profile so as to deliver, upon (WRAML); First-Last Name Association (Youngjohn J. R., 15 administration, said Sustained and increasing dose over at et al., Archives of Clinical Neuropsychology 6:287-300 least 4 hours. (1991)): Name-Face Association; Wechsler Memory Scale Revised; (Wechsler, D., Wechsler Memory Scale-Revised In certain escalating dose formulations, the amphetamine Manual, NY, N.Y., The Psychological Corp. (1987)); Califor compound(s) are formulated in a delivery system wherein the nia Verbal Learning Test-Second Edition (Delis, D.C., et al., amphetamine compound is (i) contained within a nonabsorb The Californian Verbal Learning Test, Second Edition, Adult able shell that releases the drug at a controlled rate, and (ii) Version, Manual, San Antonio, Tex.: The Psychological Cor formulated in at least two different dissolution profiles. poration (2000)); Facial Recognition (delayed non-matching In another embodiment of the kits, preparations, composi to sample); Cognitive Drug Research (CDR) Computerized tions and methods, the invention further features a neuronal Assessment Battery-Wesnes; Buschke’s Selective Reminder 25 growth factor, a neuronal Survival factor, a neuronal trophic Test (Buschke, H., et al., Neurology 24:1019-1025 (1974)); factor, a cholinergic modulator, an adrenergic modulator, a Telephone Dialing Test; and Brief Visuospatial Memory Test nonadrenergic modulator, a dopaminergic modulator, a Revised. In certain embodiments, the methods of the inven tion and pharmaceutical composition features one or more glutaminergic modulator or an agent that modulates PKC. amphetamine compounds provided in an amount Sufficient to PKA, GABA, NMDA, cannabinoid, AMPA, kainate, phos enhance long-term memory (to improve memory consolida 30 phodiesterase (PDE), CREB or nootropic pathways. In one tion in a human) when assessed by a word recall test Such as embodiment, the modulation is a stimulation of one or more RAVLT. of the above-referenced pathways. In another embodiment, In yet another embodiment of the kits, preparations, com the modulation is an antagonism of one or more of the above positions and methods, the invention features one or more referenced pathways. In yet another embodiment of the kits, amphetamine compound(s) provided in an amount Sufficient 35 preparations, compositions and methods, the invention fur to enhance long-term memory in a patient by a statistically ther features methylphenidate. significant amount when assessed by a Providence Recogni Another aspect of the invention features the use of the tion Memory Test. pharmaceutical composition of amphetamine compounds in In an additional embodiment, the invention is a method to the manufacture of a medicament for prophylaxis or treat improve a memory impairment in a human having multiple 40 ment of an animal Susceptible to or Suffering from anxiety, Sclerosis by administration of the amphetamine compounds depression, age-associated memory impairment, minimal of the invention. The memory impairment and improvement cognitive impairment, amnesia, dementia, learning disabili in memory can be assessed using established criteria (for ties, memory impairment associated with toxicant exposure, example, Thornton, A. E., et al. Neuropsychology 11:357-366 brain injury, brain aneurysm, Parkinson's disease, head (1997)). These techniques include the Brown-Peterson task 45 trauma, Huntington's disease, Pick's disease, Creutzfeldt (Brown, J., Quarterly J. of Exp. Psychology 10:12-21 Jakob disease, stroke, Schizophrenia, epilepsy, Multiple Scle (1958)); the Paced Auditory Serial Addition Test (PASAT) rosis, mental retardation, Alzheimer's disease, age, age-asso (Gronwall, D.M.A., Perceptual and Motor Skills 44:367-373 ciated memory impairment, Mild Cognitive Impairment, (1977)); and tasks described, for example, by DeLuca, J., et attention deficit disorder, attention deficit hyperactivity dis 50 order, Anterior Communicating Artery Syndrome, chronic al., J. Clinical and Exp. Neuropsychology (2004). fatigue syndrome, fibromyalgia syndrome (also referred to In another embodiment of the kits, preparations, composi herein as “fibromyalgia'), chemotherapy, and traumatic brain tions and methods, the invention features one or more injury, or AIDS-related dementia, which amphetamine com amphetamine compound(s) provided in the form of a saccha pound is represented by Formula I, or a pharmaceutically rate, a Sulfate or an aspartate. 55 acceptable salt, Solvate, metabolite or pro-drug thereof: In certain embodiments, the Subject pharmaceutical prepa rations are formulated for variable dosing, and preferably to R4 (I) deliver a Sustained and increasing dose, e.g., over at least 4 R R hours, and more preferably over at least 8 or even 16 hours. N N1 For instance, the amphetamine compound is contained within 60 a nonabsorbable shell that releases the drug at a controlled 21 rate. In certain escalating dose formulations, the amphetamine compound(s) are formulated in a delivery system including a multiplicity of layers each including the same or different 65 wherein, as Valence and stability permit, polymers, a dose of the amphetamine compound(s) in an R, independently for each occurrence, represents hydro increasing dose in the multiplicity of layers, wherein in opera gen or substituted or unsubstituted lower alkyl, lower US 7,619,005 B2 13 14 alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het wherein, as Valence and stability permit, eroaryl, cycloalkyl, or cycloalkylalkyl, R, independently for each occurrence, represents hydro R represents hydrogen or Substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, gen or substituted or unsubstituted lower alkyl, lower heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het lkyl: eroaryl, cycloalkyl, or cycloalkylalkyl, R represents hydrogen or Substituted or unsubstituted R represents hydrogen or Substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla lkyl: 10 lkyl; R represents from 1 to 3 substituents on the ring to which R represents hydrogen or substituted or unsubstituted it is attached, selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, hydrogen, halogen, hydroxy, alkoxy, amino, alky heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla lamino, Sulflhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, 15 lkyl; lower alkenyl, Sulfonate ester, amidino, Sulfonyl, Sul R represents from 1 to 3 substituents on the ring to which foxido, Sulfamoyl, and Sulfonamido. it is attached, selected from the group consisting of In certain preferred embodiments, one occurrence of R hydrogen, halogen, hydroxy, alkoxy, amino, alky represents hydrogen, the second occurrence of R represents lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, hydrogen, or lower alkyl; R represents hydrogen or lower formyl, amido, acylamino, acyloxy, lower alkyl, lower alkyl, R represents hydrogen or lower alkyl, and Ra repre alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, sents hydrogen or from 1 to 2 substituents on the ring to which Sulfamoyl, and Sulfonamido; and it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl. L is a non-toxic organic or inorganic acid. In certain preferred embodiments, R represents hydrogen 25 In certain preferred embodiments, one occurrence of R and at least one of R, R2, and R represents hydrogen. represents hydrogen, the second occurrence of R represents In certain preferred embodiments, R represents hydrogen hydrogen, or lower alkyl; R represents hydrogen or lower and at least two of R. R. and R represent hydrogen. alkyl, R represents hydrogen or lower alkyl, and R repre In certain preferred embodiments, both occurrences of R 30 sents hydrogen or from 1 to 2 substituents on the ring to which represent independently hydrogen, R represents methyl, R it is attached, selected from halogen, trifluoromethyl, represents hydrogen and R4 represents hydrogen. hydroxy, amino, cyano, nitro, and lower alkyl. In certain preferred embodiments, one occurrence of R In certain preferred embodiments, R represents hydrogen represents hydrogen, the second occurrence of R represents and at least one of R. R. and R represents hydrogen. methyl, R represents methyl, R represents hydrogen and R. 35 represents hydrogen. In certain preferred embodiments, R represents hydrogen In most preferred embodiments, R, independently and for and at least two of R, R2, and R represent hydrogen. each occurrence, represents hydrogen, R represents methyl, In certain preferred embodiments, both occurrences of R and R and Raindependently and for each occurrence repre represent independently hydrogen, R represents methyl, R sent hydrogen. 40 represents hydrogen and R represents hydrogen. Another aspect of the invention features the use of an In certain preferred embodiments, one occurrence of R amphetamine compound in the manufacture of a medicament represents hydrogen, the second occurrence of R represents for prophylaxis or treatment of an animal susceptible to or methyl, R represents methyl, R represents hydrogen and R. Suffering from anxiety, depression, age-associated memory represents hydrogen. impairment, minimal cognitive impairment, amnesia, 45 dementia, learning disabilities, memory impairment associ In most preferred embodiments, R, independently and for ated with toxicant exposure, brain injury, brain aneurysm, each occurrence, represents hydrogen, R represents methyl, Parkinson's disease, head trauma, Huntington's disease, and R and R independently and for each occurrence repre Pick's disease, Creutzfeldt-Jakob disease, stroke, schizo sent hydrogen. phrenia, epilepsy, Multiple Sclerosis, mental retardation, 50 Another aspect of the invention features the use of an Alzheimer's disease, age, attention deficit disorder, attention amphetamine compound in the manufacture of a medicament deficit hyperactivity disorder, Anterior Communicating for prophylaxis or treatment of an animal susceptible to or Artery Syndrome, age-associated memory impairment, Mild Suffering from anxiety, depression, age-associated memory Cognitive Impairment, chronic fatigue syndrome, fibromyal impairment, minimal cognitive impairment, amnesia, gia, chemotherapy, traumatic brain injury, Parkinson's dis 55 ease or AIDS-related dementia, which amphetamine com dementia, learning disabilities, memory impairment associ pound is represented by Formula II: ated with toxicant exposure, brain injury, brain aneurysm, Parkinson's disease, head trauma, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, stroke, schizo phrenia, epilepsy, mental retardation, Alzheimer's disease, (II) 60 age, age-associated memory impairment, Mild Cognitive Impairment, attention deficit disorder, attention deficit hyper activity disorder, Multiple Sclerosis, Anterior Communicat ing Artery Syndrome chronic fatigue syndrome, fibromyalgia 65 syndrome, chemotherapy, traumatic brain injury, Parkinson's disease or AIDS-related dementia, which amphetamine com pound is represented by Formula III: US 7,619,005 B2 16 (III) IV Formula IV is also referred to herein as C105, levo-am 10 phetamine sulfate or 1-amphetamine sulfate. Formula IV has wherein, as Valence and stability permit, the molecular formula CH-NOS and a molecular weight R, independently for each occurrence, represents hydro of 368.50. The UPAC chemical name of Formula IV is (-)- gen or substituted or unsubstituted lower alkyl, lower 1-methyl-2-phenylethylamine sulfate (2:1) and the CAS alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het chemical name (-)-O-methylphenethylamine Sulfate (2:1). eroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally 15 In another embodiment, the (R)-(-)-amphetamine Substituted by one or more substitutents such as halogen, employed in the methods of the invention has the structural hydroxy, alkoxy; formula: R represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi tuted by one or more substitutents such as halogen, hydroxy, alkoxy; oHCI R is absent or represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het 25 eroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally Substituted by one or more substitutents such as halogen, Formula V is also referred to herein as SN522-HCl (hydro hydroxy, alkoxy; chloride), levo-methamphetamine HC1 or 1-methamphet R represents from 1 to 3 substituents on the ring to which amine HC1. Formula V has the molecular formula it is attached, e.g., selected from hydrogen, halogen, 30 CHNC1. hydroxy, alkoxy, amino, alkylamino, Sulfhydryl, alky In still another embodiment, the (R)-(-)-amphetamine lthio, cyano, nitro, ester, ketone, formyl, amido, acy employed in the methods of the invention has the structural lamino, acyloxy, lower alkyl, lower alkenyl, Sulfonate formula: ester, amidino, Sulfonyl, Sulfoxido, Sulfamoyl, and Sul fonamido; 35 Rs independently for each occurrence, represents hydro VI gen or hydroxy. In certain preferred embodiments, one occurrence of R represents hydrogen, the second occurrence of R represents hydrogen, or lower alkyl; R represents hydrogen or lower 40 alkyl, R represents hydrogen or lower alkyl, and Ra repre sents hydrogen or from 1 to 2 substituents on the ring to which Formula VI is also referred to herein as SN522, the free base it is attached, selected from halogen, trifluoromethyl, of SN522, levo-methamphetamine, levo-desoxyephedrine, hydroxy, amino, cyano, nitro, and lower alkyl. 45 1-desoxyephedrine or levmetamfetamine. Formula VI has the In certain preferred embodiments, R represents hydrogen molecular formula CoHN and a molecular weight of and at least one of R, R2, and R represents hydrogen. 149.24. In certain preferred embodiments, R represents hydrogen In still another embodiment, the amphetamine compounds and at least two of R. R. and R represent hydrogen. employed in the methods of the invention can be a combina In certain preferred embodiments, both occurrences of R 50 tion of the amphetamine compounds described herein, e.g., represent independently hydrogen, R represents methyl, R Formulas IV, V and/or VI can be employed in any combina represents hydrogen and R represents hydrogen. tion. For example, a human having mild cognitive impair In certain preferred embodiments, one occurrence of R ment, Alzheimer's disease and an impairment in a cognitive represents hydrogen, the second occurrence of R represents function (e.g., attention, executive function, reaction time, methyl, R represents methyl, R represents hydrogen and R. 55 learning, information processing, conceptualization, prob represents hydrogen. lem solving, Verbal fluency) or memory (e.g., memory con Solidation, short-term memory, working memory, long-term In most preferred embodiments, R, independently and for memory, declarative memory or procedural memory) can be each occurrence, represents hydrogen, R represents methyl, treated, with 1-amphetamine (e.g., C105) and 1-methamphet and R and R independently and for each occurrence repre 60 amine (e.g., SN522, SN522-HCl), either in combination or sent hydrogen. sequentially. Levo-amphetamine, 1-amphetamine and (R)-(-)-amphet The amphetamine compounds employed in the methods of amine are used interchangeably herein. Levo-methamphet the invention (e.g., 1-amphetamine and/or 1-methamphet amine, 1-methamphetamine and (R)-(-)-methamphetamine amine) can be administered as a component of a composition are used interchangeably herein. 65 that includes at least about 99 mole 96, at least about 95 mole In one embodiment, the (R)-(-)-amphetamine employed in %, at least about 90 mole 96, at least about 85 mole 96, at least the methods of the invention has the structural formula: about 80 mole %, at least about 75 mole 96, at least about 70 US 7,619,005 B2 17 18 mole'6, at least about 65 mole'6, or at least about 60 mole'6, nia Verbal Learning Test—Second Edition (Delis, D.C., et ofl-amphetamine relative to the total amphetamine contentin al., The Californian Verbal Learning Test, Second Edition, the composition; or at least about 99 mole%, at least about 95 Adult Version, Manual, San Antonio, Tex.: The Psychological mole 96, at least about 90 mole %, at least about 85 mole %, Corporation (2000)); Facial Recognition (delayed non at least about 80 mole %, at least about 75 mole %, at least matching to sample); Cognitive Drug Research (CDR) Com about 70 mole %, at least about 65 mole %, or at least about puterized Assessment Battery-Wesnes; Buschke’s Selective 60 mole%, of 1-methamphetamine relative to the total amount Reminder Test (Buschke, H., et al., Neurology 24:1019-1025 of amphetamine content in the composition. (1974)); Telephone Dialing Test; and Brief Visuospatial In certain embodiments, the animal to be treated is a mam Memory Test-Revised. mal. In certain preferred embodiments the animal to be 10 In certain embodiments, the pharmaceutical composition treated is a human, dog, cat, cattle, horse, sheep, hog or goat. features one or more amphetamine compound(s) provided in In certain embodiments, the pharmaceutical composition an amount Sufficient to enhance long-term memory in a is for oral administration. patient by a statistically significant amount when assessed by In certain other embodiments the pharmaceutical compo a word recall test such as the Rey Auditory and Verbal Learn sition is a transdermal patch. In certain embodiments the 15 ing Test (RAVLT). transdermal patch includes one or more penetration enhanc In certain embodiments, the pharmaceutical composition CS. features one or more amphetamine compound(s) provided in In certain embodiments, the pharmaceutical composition the form of a saccharate, a sulfate or an aspartate. features an amphetamine compound provided as at least In other embodiments of the kits, preparations, composi about 51 percent (w/w or mole percent), about 60 percent tions and methods, the invention further features amphet (w/w or mole percent), about 75 percent (w/w or mole per amine compound(s) being provided as a single oral dosage cent), about 80 percent (w/w or mole percent), about 85 formulation in an amount Sufficient to enhance long-term percent (w/w or mole percent) about 95 percent (w/w or mole memory in a patient but resulting in a concentration in the percent), or 99 percent (w/w or mole percent) of the eutomers patient lower than its ECso as a CNS stimulant. relative to the distomers of the amphetamine compound (e.g., 25 1-amphetamine relative to d-amphetamine). In another In other embodiments of the kits, preparations, composi tions and methods, the invention further features amphet embodiment, the amphetamine employed to treat a human is amine compound(s) being provided for treating and/or pre about 100% 1-amphetamine (w/w or mole percent). venting memory impairment (impairment in memory In certain embodiments, the pharmaceutical compositions consolidation, impairment in short term memory, impairment are formulated for variable dosing, preferably to deliver a 30 Sustained dose, e.g., over at least 4 hours and more preferably in working memory), wherein the memory impairment over at least 8 or even 16 hours. For instance, the amphet results from one or more of anxiety, depression, age-associ amine compound(s) are contained within a nonabsorbable ated memory impairment, minimal cognitive impairment, shell that releases the drug at a controlled rate. amnesia, dementia, learning disabilities, memory impairment In certain embodiments, the pharmaceutical composition 35 associated with toxicant exposure, brain injury, brain aneu features an amphetamine compound (e.g., 1-amphetamine, rysm, Parkinson's disease, head trauma, Huntington's dis 1-methamphetamine) provided in an amount Sufficient to treat ease, Pick's disease, Creutzfeldt-Jakob disease, stroke, Mild Cognitive Impairment, Alzheimer's disease, enhance Schizophrenia, epilepsy, mental retardation, Alzheimer's dis long-term memory, short-term memory, working memory, ease, age, age-associated memory impairment, Mild Cogni declarative memory, procedural memory or cognitive pro 40 tive Impairment, attention deficit disorder, attention deficit cesses such as attention, executive function, reaction time or hyperactivity disorder, Multiple Sclerosis, Anterior Commu learning in a patient by a statistically significant amount when nicating Artery Syndrome or AIDS-related dementia, chronic assessed by a standardized performance test. fatigue syndrome, fibromyalgia syndrome, traumatic brain In certain embodiments, the pharmaceutical composition injury, or chemotherapy. features one or more amphetamine compound(s) provided in 45 In yet another embodiment, the invention is a method of an amount Sufficient to enhance long-term memory in a treating a perimenopausal, menopausal or postmenopausal patient by a statistically significant amount when assessed by woman having an impairment in memory (impairment in one or more of a Rey Auditory and Verbal learning Test memory consolidation, impairment in short term memory, (RAVLT), Cambridge Neuropsychological Test Automated impairment in working memory) with an amphetamine com Battery (CANTAB); a Children's Memory Scale (CMS); a 50 pound of the invention (1-amphetamine, C105, 1-metham Contextual Memory Test; a Continuous Recognition phetamine, SN522, SN522-HCl). The amphetamine com Memory Test (CMRT); a Denman Neuropsychology pound of the invention can be administered to the Memory Scale; a Fuld Object Memory Evaluation (FOME): perimenopausal, menopausal or postmenopausal woman a Graham-Kendall Memory for Designs Test; a Guild simultaneously or sequentially with other compounds, drugs Memory Test; a Learning and Memory Battery (LAMB); a 55 or agents. For example, the amphetamine compounds can be Memory Assessment Clinic Self-Rating Scale (MAC-S); a administered to a perimenopausal, menopausal or postmeno Memory Assessment Scales (MAS); a Randt Memory Test; a pausal woman undergoing Steroid hormone replacement Recognition Memory Test (RMT): a Rivermead Behavioral therapy and/or treatment for depression (e.g., selective sero Memory Test; a Russell's Version of the Wechsler Memory tonin reuptake inhibitors such as citalopram (CipramilR), Scale (RWMS); a Test of Memory and Learning (TOMAL); a 60 fluoxetine (Prozac.(R), fluvoxamine (FaverinR), paroxetine Vermont Memory Scale (VMS); a Wechsler Memory Scale: (Seroxat(R), and sertraline (Lustral(R). and a Wide Range Assessment of Memory and Learning In other embodiments of the kits, preparations, composi (WRAML); First-Last Name Association (Youngjohn J. R., tions and methods, the invention further features amphet et al., Archives of Clinical Neuropsychology 6:287-300 amine compound(s) being provided for enhancing memory in (1991)): Name-Face Association; Wechsler Memory Scale 65 normal individuals. Revised; (Wechsler, D., Wechsler Memory Scale-Revised In certain preferred embodiments of the kits, preparations, Manual, NY, N.Y., The Psychological Corp. (1987)); Califor compositions and methods, the invention features one or US 7,619,005 B2 19 20 more amphetamine compound(s), wherein the amphetamine In a further embodiment, the methods of the invention compound is (R)-(-)-amphetamine. employ multiple doses between about 0.001 mg to about 500 In certain preferred embodiments of the kits, preparations, mg of the amphetamine compound (e.g., 1-amphetamine, compositions and methods, the invention features one or C105, 1-methamphetamine, SN522, SN522-HCl), wherein more amphetamine compound(s), wherein the amphetamine 5 each of the multiple doses of the amphetamine compound is compound is (R)-(-)-methamphetamine. between about 0.001 mg to about 125 mg; or between about In one embodiment of the kits, preparations, compositions 0.001 mg to about 250 mg; or between about 0.001 mg to and methods, the invention features a single oral dosage for about 500 mg; or between about 0.01 mg to about 125 mg; or mulation of at least about 2.5 mg to about 25 mg, about 50 mg. between about 0.01 mg to about 500 mg. or between about 0.1 about 75 mg, about 100 mg or about 125 mg of an amphet 10 mg to about 125 mg; or between about 1 mg to about 125 mg: amine compound (e.g., 1-amphetamine, C105,1-methamphet or between about 1 mg and about 100 mg; or between about amine, SN522, SN522-HCl) and a pharmaceutically accept a 1 mg to about a 150 mg dose; or between about 1 mg and able carrier. about 500 mg; between about 5 mg and about 50 mg; between In another embodiment, the single dosage formulation is at about 2 mg and 60 mg between about 2.5 mg to about 25 mg. least about 0.001 mg, about 0.01 mg, about 0.1 mg, about 1 15 about 50 mg, about 75 mg, about 100 mg, about 125 mg. mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about about 250 mg, about 500 mg, about 750 mg, about 1000 mg of 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg. the eutomer(s) of amphetamine compound(s) (1-amphet about 40 mg, about 45 mg, about 50 mg, about 55 mg, about amine, C105,1-methamphetamine, SN522, SN522-HCl) and, 60 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. optionally, a pharmaceutically acceptable carrier. about 95 mg, about 100 mg, about 125 mg, about 150 mg. In a further embodiment, the methods of the invention about 200 mg, about 300 mg, about 400 mg, about 500 mg. employ a single dose of the amphetamine compound (1-am about 750 mg. or about 1000 mg of an amphetamine com phetamine, C105,1-methamphetamine, SN522, SN522-HCl) pound (e.g., 1-amphetamine, C105, 1-methamphetamine, between about 0.0015 mg/kg to about 2 mg/kg: between SN522, SN522-HCl). In a particular embodiment, the dose of about 0.015 mg/kg to about 2 mg/kg; or about 0.07 mg to an amphetamine compound (e.g., 1-amphetamine, C105. 25 about 0.7 mg or between about 0.14 mg to about 0.7 mg; or 1-methamphetamine, SN522, SN522-HCl) is between about a about 0.03 mg to about 1.0 mg per day. 5 mg dose and about a 50 mg dose; or between about a 2 mg In yet another embodiment, the methods of the invention dose and about a 60 mg dose per day; or between about 1 mg employ a single dose about 0.04 mg/kg, about 0.07 mg/kg, to between about a 100 mg dose; or between about a 1 mg to about 0.15 mg/kg, about 0.20 mg/kg, about 0.40 mg/kg, about 30 0.65 mg/kg, about 1 mg/kg, about 1.50 mg/kg, about 1.80 about a 150 mg dose. mg/kg or about 3.5 mg/kg of l-amphetamine, C105, 1-meth In still another embodiment, the methods of the invention amphetamine, SN522, SN522-HC1. employ multiple doses of an amphetamine compound. Each In an additional embodiment, the methods of the invention dose of the multiple dose is at least about 0.001 mg, about employ multiple doses of the amphetamine compound (1-am 0.01 mg, about 0.1 mg, about 1 mg, about 2.5 mg, about 5 mg. 35 phetamine, C105, 1-methamphetamine, SN522, SN522 about 10 mg, about 15 mg, about 20 mg, about 25 mg, about HCl), wherein each dose of the multiple dose is between 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg. about 0.0015 mg/kg to about 2 mg/kg; or between about 0.015 about 55 mg, about 60 mg, about 75 mg, about 80 mg, about mg/kg to about 2 mg/kg. 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 In still another embodiment, the methods of the invention mg, about 150 mg, about 200 mg, about 300 mg, about 400 40 employ multiple doses, wherein each does of the multiple mg, about 500 mg, about 750 mg or about 1000 mg of an dose is about 0.04 mg/kg, about 0.07 mg/kg, about 0.15 amphetamine compound (e.g., 1-amphetamine, C105,1-meth mg/kg, about 0.20 mg/kg, about 0.40 mg/kg, about 0.65 amphetamine, SN522, SN522-HCl). The multiple doses can mg/kg, about 1 mg/kg, about 1.50 mg/kg, about 1.80 mg/kg or be administered for a day, days, a week, weeks, a month, about 3.5 mg/kg of 1-amphetamine, C105, 1-methamphet months or years. 45 amine, SN522, SN522-HC1. The amphetamine compounds of the invention can be The cumulative dose of the amphetamine compound (1-am administered to a human acutely (briefly or short-term) or phetamine, C105,1-methamphetamine, SN522, SN522-HCl) chronically (prolonged or long-term). For example, the employed in the methods of the invention, regardless of amphetamine compounds, (e.g., 1-amphetamine, C105. whether the amphetamine is administered in a single dose or 1-methamphetamine, SN522, SN522-HCl) of the invention 50 in multiple doses is between about 0.2 mg to about 250 mg; or can be used in methods to treat a human by administering the between about 1 mg to about 1250 mg of the amphetamine amphetamine to the human once a day, multiple times (e.g., 2. compound. In a particular embodiment, the cumulative dose 3, 4) in a day, for a day, days, a week, weeks, a month, months is about 2 mg, about 10 mg, about 20 mg, about 30 mg, about or years. 50 mg, about 60 mg, about 90 mg, about 100 mg, about 150 In yet another embodiment of the kits, preparations, com 55 mg, about 200 mg, about 250 mg, about 450 mg, about 750 positions and methods, the invention features a single oral mg, about 1000 mg, about 1250 mg, about 2500 mg or about dosage formulation of between about 0.001 mg to about 125 5000 mg. mg; between about 0.001 mg to about 250 mg; between 0.001 In certain embodiments, the invention features a method mg to 500 mg. or between about 0.01 mg to about 125 mg; or for enhancing memory in an animal, a method of treating a between about 0.1 mg to about 125 mg; or between about 1 60 human with an impairment in memory consolidation or an mg to about 125 mg; or between about 1 mg to about 250 mg: impairment in short term memory oran impairment in work or between about 1 mg to about 500 mg; or between about 1 ing memory comprising administering to the animal a com mg to about 1000 mg. or between about 2.5 mg to about 25 position of an amphetamine compound in an amount Suffi mg, about 50 mg, about 75 mg, about 100 mg or about 125 mg cient to enhance long-term memory or improve memory of the eutomer(s) of amphetamine compound(s) (1-amphet 65 consolidation in the animal (human), wherein the composi amine, C105, 1-methamphetamine, SN522) and, optionally, a tion includes at least about 51 percent (w/w or mole percent), pharmaceutically acceptable carrier. about 60 percent (w/w or mole percent), about 75 percent US 7,619,005 B2 21 22 (w/w or mole percent), about 80 percent (w/w or mole per animal (human), wherein the composition includes at least cent), about 85 percent (w/w or mole percent), about 95 about 51 percent (w/w or mole percent), about 60 percent percent (w/w or mole percent), about 99 percent (w/w or mole (w/w or mole percent), about 75 percent (w/w or mole per percent) of the eutomers relative to the distomers of the cent), about 80 percent (w/w or mole percent), about 85 amphetamine or about 100% (w/w or mole percent) of com percent (w/w or mole percent, about 95 percent (w/w or mole pound represented by Formula I, orpharmaceutically accept percent), or about 99 percent (w/w or mole percent) of the able salt, solvate, metabolite or pro-drug thereof, relative to eutomers relative to the distomers of the amphetamine com the distomer of that amphetamine compound: pound, wherein the amphetamine compound is a pharmaceu tically acceptable salt represented by Formula II: 10 (I) (II) 15 wherein, as Valence and stability permit, R, independently for each occurrence, represents hydro wherein, as Valence and stability permit, gen or substituted or unsubstituted lower alkyl, lower R, independently for each occurrence, represents hydro alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het gen or substituted or unsubstituted lower alkyl, lower eroaryl, cycloalkyl, or cycloalkylalkyl, alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het R represents hydrogen or Substituted or unsubstituted eroaryl, cycloalkyl, or cycloalkylalkyl, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, 25 R represents hydrogen or substituted or unsubstituted heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lkyl: heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla R represents hydrogen or substituted or unsubstituted lkyl; lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, R represents hydrogen or Substituted or unsubstituted heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla 30 lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, lkyl: heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla R represents from 1 to 3 substituents on the ring to which lkyl; it is attached, selected from the group consisting of R represents from 1 to 3 substituents on the ring to which hydrogen, halogen, hydroxy, alkoxy, amino, alky it is attached, selected from the group consisting of lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, 35 hydrogen, halogen, hydroxy, alkoxy, amino, alky formyl, amido, acylamino, acyloxy, lower alkyl, lower lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, formyl, amido, acylamino, acyloxy, lower alkyl, lower Sulfamoyl, and Sulfonamido. alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, In certain preferred embodiments, one occurrence of R Sulfamoyl, and Sulfonamido; and represents hydrogen, the second occurrence of R represents 40 L is a non-toxic organic or inorganic acid. hydrogen, or lower alkyl; R represents hydrogen or lower In certain preferred embodiments, one occurrence of R alkyl, R represents hydrogen or lower alkyl, and R repre represents hydrogen, the second occurrence of R represents sents hydrogen or from 1 to 2 substituents on the ring to which hydrogen, or lower alkyl; R represents hydrogen or lower it is attached, selected from halogen, trifluoromethyl, 45 alkyl, R represents hydrogen or lower alkyl, and Ra repre hydroxy, amino, cyano, nitro, and lower alkyl. sents hydrogen or from 1 to 2 substituents on the ring to which In certain preferred embodiments, R represents hydrogen it is attached, selected from halogen, trifluoromethyl, and at least one of R. R. and R represents hydrogen. hydroxy, amino, cyano, nitro, and lower alkyl. In certain preferred embodiments, R represents hydrogen In certain preferred embodiments, R represents hydrogen and at least two of R, R2, and R represent hydrogen. 50 and at least one of R, R2, and R represents hydrogen. In certain preferred embodiments, both occurrences of R In certain preferred embodiments, R represents hydrogen represent independently hydrogen, R represents methyl, R and at least two of R, R2, and R represent hydrogen. represents hydrogen and R represents hydrogen. In certain preferred embodiments, both occurrences of R In certain preferred embodiments, one occurrence of R represent independently hydrogen, R represents methyl, R represents hydrogen, the second occurrence of R represents 55 represents hydrogen and Ra represents hydrogen. methyl, R represents methyl, R represents hydrogen and R. In certain preferred embodiments, one occurrence of R represents hydrogen. represents hydrogen, the second occurrence of R represents In most preferred embodiments, R, independently and for methyl, R represents methyl, R represents hydrogen and R. each occurrence, represents hydrogen, R represents methyl, represents hydrogen. and R and R independently and for each occurrence repre 60 In most preferred embodiments, R, independently and for sent hydrogen. each occurrence, represents hydrogen, R represents methyl, In certain embodiments, the invention features a method and R and R independently and for each occurrence repre for enhancing memory in an animal or a method for treating sent hydrogen. a human with an impairment in memory consolidation, com In certain embodiments, the invention features a method prising administering to the animal a composition of an 65 for enhancing memory in an animal or a method of treating a amphetamine compound in an amount Sufficient to enhance human with an impairment in memory consolidation, com long-term memory or improve memory consolidation in the prising administering to the animal a composition of an US 7,619,005 B2 23 24 amphetamine compound in an amount Sufficient to enhance In most preferred embodiments, R, independently and for long-term memory or improve memory consolidation in the each occurrence, represents hydrogen, R represents methyl, animal (human), wherein the composition includes at least and R and R independently and for each occurrence repre about 51 percent (w/w or mole percent), about 60 percent sent hydrogen. (w/w or mole percent), about 75 percent (w/w or mole per cent), about 80 percent (w/w or mole percent), about 85 In certain embodiments, the invention features a kit com percent (w/w or mole percent), about 95 percent (w/w or mole prising an amphetamine compound formulation, e.g., as percent), or about 99 percent (w/w or mole percent) of the described herein and preferably provided in single oral dos eutomers relative to the distomers of the amphetamine com age form or as a transdermal patch for enhancing memory in pound, wherein the amphetamine compound is an amphet 10 a patient (preferably a human), and in association with instructions (written and/or pictorial) describing the use of amine metabolite represented by Formula III, or pharmaceu the formulation for enhancing memory, and optionally, warn tically acceptable salt, Solvate, or pro-drug thereof: ings of possible side effects and drug-drug or drug-food inter actions. (III) 15 Another aspect of the invention relates to a method for Rs R R conducting a pharmaceutical business, which includes: (a) manufacturing the kits, preparations, and compositions of the present invention; and (b) marketing to healthcare providers A-4 R2 the benefits of using the kits, preparations, and compositions R4 of the present invention to enhance memory of treated Rs patients. Another aspect of the invention relates to a method for wherein, as Valence and stability permit, conducting a pharmaceutical business, comprising: (a) pro R, independently for each occurrence, represents hydro viding a distribution network for selling the kits, preparations, gen or substituted or unsubstituted lower alkyl, lower 25 and compositions of the present invention; and (b) providing alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het instruction material to patients or physicians for using the eroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally kits, preparations, and compositions of the present invention Substituted by one or more substitutents such as halogen, to enhance memory of treated patients. hydroxy, alkoxy; Yet another aspect of the invention relates to a method for R represents hydrogen or lower alkyl, lower alkenyl, 30 conducting a pharmaceutical business, comprising: (a) deter lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, mining an appropriate dosage of an amphetamine compound cycloalkyl, or cycloalkylalkyl, e.g., optionally substi to enhance memory function in a class of patients; (b) con tuted by one or more substitutents such as halogen, ducting therapeutic profiling of one or more formulations of hydroxy, alkoxy; the amphetamine compound identified in step (a), for efficacy R represents hydrogen or lower alkyl, lower alkenyl, 35 and toxicity in animals; and (c) providing a distribution net lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, work for selling the formulations identified in step (b) as cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi having an acceptable therapeutic profile. tuted by one or more substitutents such as halogen, For instance, the Subject business method can include an hydroxy, alkoxy; additional step of providing a sales group for marketing the R represents from 1 to 3 substituents on the ring to which 40 preparation to healthcare providers. it is attached, e.g., selected from hydrogen, halogen, Another aspect of the invention relates to a method for hydroxy, alkoxy, amino, alkylamino, Sulfhydryl, alky conducting a pharmaceutical business, comprising: (a) deter lthio, cyano, nitro, ester, ketone, formyl, amido, acy mining an appropriate dosage of an amphetamine compound lamino, acyloxy, lower alkyl, lower alkenyl, Sulfonate to enhance memory function in a class of patients; and (b) ester, amidino, Sulfonyl, Sulfoxido, Sulfamoyl, and Sul 45 licensing, to a third party, the rights for further development fonamido; and sale of the amphetamine compound for enhancing Rs independently for each occurrence, represents hydro gen or hydroxy. memory. In certain preferred embodiments, one occurrence of R In certain embodiments of the method, the class of patients 50 suffer from memory impairment. In preferred embodiments represents hydrogen, the second occurrence of R represents of the method, the memory impairment results from one or hydrogen, or lower alkyl; R represents hydrogen or lower more of anxiety, depression, age-associated memory impair alkyl, R represents hydrogen or lower alkyl, and Ra repre ment, minimal cognitive impairment, amnesia, dementia, sents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, learning disabilities, memory impairment associated with 55 toxicant exposure, brain injury, brain aneurysm, Parkinson's hydroxy, amino, cyano, nitro, and lower alkyl. disease, head trauma, Huntington's disease, Pick's disease, In certain preferred embodiments, R represents hydrogen Creutzfeldt-Jakob disease, stroke, Schizophrenia, epilepsy, and at least one of R, R2, and R represents hydrogen. mental retardation, Alzheimer's disease, age, age-associated In certain preferred embodiments, R represents hydrogen memory impairment, Mild Cognitive Impairment, attention and at least two of R. R. and R represent hydrogen. 60 deficit disorder, attention deficit hyperactivity disorder, Mul In certain preferred embodiments, both occurrences of R tiple Sclerosis, Anterior Communicating Artery Syndrome, represent independently hydrogen, R represents methyl, R AIDS-related dementia, chronic fatigue syndrome, fibromy represents hydrogen and R represents hydrogen. algia Syndrome, traumatic brain injury, chemotherapy. In In certain preferred embodiments, one occurrence of R other preferred embodiments of the method, the class of represents hydrogen, the second occurrence of R represents 65 patients are normal individuals. methyl, R represents methyl, R represents hydrogen and R. Another aspect of the invention features Solid dosage form represents hydrogen. comprising a eutomer of an amphetamine compound repre US 7,619,005 B2 25 26 sented by Formula I, or a pharmaceutically acceptable salt, formyl, amido, acylamino, acyloxy, lower alkyl, lower Solvate, metabolite or pro-drug thereof, in an amount of 25 alkenyl, ester, amidino, Sulfonyl, Sulfoxido, Sulfamoyl, mg or less: and Sulfonamido; and L is a non-toxic organic or inorganic acid. 5 Another aspect of the invention features Solid dosage form (I) comprising a eutomer of an amphetamine metabolite repre sented by Formula III, solvate or pro-drug thereof, in an amount of about 25 mg or less: 10 (III) Rs N R NN1 R wherein, as Valence and stability permit, A4 R, independently for each occurrence, represents hydro 15 R4 R gen or substituted or unsubstituted lower alkyl, lower R3 Rs alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het eroaryl, cycloalkyl, or cycloalkylalkyl, wherein, as Valence and stability permit, R represents hydrogen or Substituted or unsubstituted R, independently for each occurrence, represents hydro lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, gen or substituted or unsubstituted lower alkyl, lower heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het lkyl: eroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally R represents hydrogen or Substituted or unsubstituted Substituted by one or more Substitutents such as halogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, hydroxy, alkoxy; heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla 25 R represents hydrogen or lower alkyl, lower alkenyl, lkyl: lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, R represents from 1 to 3 substituents on the ring to which cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi it is attached, selected from the group consisting of tuted by one or more substitutents such as halogen, hydrogen, halogen, hydroxy, alkoxy, amino, alky hydroxy, alkoxy; lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, R represents hydrogen or lower alkyl, lower alkenyl, formyl, amido, acylamino, acyloxy, lower alkyl, lower lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, cycloalkyl, or cycloalkylalkyl, e.g., optionally Substi Sulfamoyl, and Sulfonamido. tuted by one or more substitutents such as halogen, Another aspect of the invention features Solid dosage form hydroxy, alkoxy; comprising a pharmaceutically acceptable salt of a eutomer R represents from 1 to 3 substituents on the ring to which of an amphetamine compound employed in the methods of it is attached, e.g., selected from hydrogen, halogen, the invention, for example, represented by Formula II, sol hydroxy, alkoxy, amino, alkylamino, Sulfhydryl, alky Vate, metabolite or pro-drug thereof, in an amount of 25 mg or less: lthio, cyano, nitro, ester, ketone, formyl, amido, acy 40 lamino, acyloxy, lower alkyl, lower alkenyl, Sulfonate ester, amidino, Sulfonyl, Sulfoxido, Sulfamoyl, Sulfona mido; (II) Rs independently for each occurrence, represents hydro gen or hydroxy. 45 In another embodiment, the invention is a method of treat ing mild cognitive impairment in a human, comprising the step of administering an effective amount of an amphetamine to the human, wherein the amphetamine is administered as a component of a composition that includes amphetamine and, 50 optionally, a methamphetamine, wherein at least about 85 wherein, as Valence and stability permit, mole percent of the total amphetamine and methamphet R, independently for each occurrence, represents hydro amine content of the composition is 1-amphetamine. gen or substituted or unsubstituted lower alkyl, lower In an additional embodiment, the invention is a method of alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, het treating mild cognitive impairment in a human, comprising eroaryl, cycloalkyl, or cycloalkylalkyl, 55 the step of administering an effective amount of a metham R represents hydrogen or substituted or unsubstituted phetamine to the human, wherein the methamphetamine is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, administered as a component of a composition that includes heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla methamphetamine and, optionally, an amphetamine, wherein lkyl: at least about 85 mole percent of the total methamphetamine R represents hydrogen or Substituted or unsubstituted 60 and amphetamine content of the composition is 1-metham lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, phetamine. heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkyla In a further embodiment, the invention is a method of lkyl: treating mild cognitive impairment in a human, comprising R represents from 1 to 3 substituents on the ring to which the step of administering an effective amount of an amphet it is attached, selected from the group consisting of 65 amine to the human, wherein the amphetamine is adminis hydrogen, halogen, hydroxy, alkoxy, amino, alky tered as a component of a composition that includes amphet lamino, Sulfhydryl, alkylthio, cyano, nitro, ester, ketone, amine and, optionally, a methamphetamine, wherein at least US 7,619,005 B2 27 28 about 85 mole percent of the total amphetamine and meth component of a composition that includes amphetamine and, amphetamine content of the composition is 1-amphetamine optionally, a methamphetamine, wherein at least about 95 and wherein the amphetamine is administered at a dose of mole percent of the total amphetamine and methamphet between about a 2 mg dose and about a 60 mg dose per day. amine content of the composition is 1-amphetamine and In still another embodiment, the invention is a method of 5 wherein the amphetamine is administered at a dose of at least treating mild cognitive impairment in a human, comprising about a 2 mg and about a 60 mg dose per day. the step of orally administering an effective amount of an In still another embodiment, the invention is a method of amphetamine to the human, wherein the amphetamine is treating Alzheimer's disease in a human, comprising the step administered as a component of a composition that includes of administering an effective amount of a methamphetamine amphetamine and, optionally, a methamphetamine, wherein 10 to the human, wherein the methamphetamine is administered at least about 95 mole percent of the total amphetamine and as a component of a composition that includes methamphet methamphetamine content of the composition is 1-amphet amine and, optionally, an amphetamine, wherein at least amine and wherein the amphetamine is administered at a dose about 85 mole percent of the total methamphetamine and of between about a 2 mg dose and about a 60 mg dose per day. amphetamine content of the composition is l-methamphet Another embodiment of the invention is a method of treat 15 amine and wherein the methamphetamine is administered at ing mild cognitive impairment in a human, comprising the a dose of at least about a 2 mg and about a 60 mg dose per day. step of administering an effective amount of a methamphet A yet another embodiment, the invention is a method of amine to the human, wherein the methamphetamine is admin treating Alzheimer's disease in a human, comprising the step istered as a component of a composition that includes meth of orally administering an effective amount of a methamphet amphetamine and, optionally, an amphetamine, wherein at amine to the human, wherein the methamphetamine is admin least about 85 mole percent of the total methamphetamine istered as a component of a composition that includes meth and amphetamine content of the composition is 1-metham amphetamine and, optionally, an amphetamine, wherein at phetamine and wherein the methamphetamine is adminis least about 95 mole percent of the total methamphetamine tered at a dose of between about a 2 mg dose and about a 60 and amphetamine content of the composition is 1-metham mg dose per day. 25 phetamine and wherein the methamphetamine is adminis An additional embodiment of the invention is a method of tered at a dose of at least about a 2 mg and about a 60 mg dose treating mild cognitive impairment in a human, comprising per day. the step of orally administering an effective amount of a Another embodiment of the invention is a method of treat methamphetamine to the human, wherein the methamphet ing mild cognitive impairment in a human, comprising the amine is administered as a component of a composition that 30 step of orally administering an effective amount of amphet includes methamphetamine and, optionally, an amphetamine, amine to the human, wherein the amphetamine is at least wherein at least about 95 mole percent of the total metham about 95 mole percent 1-amphetamine relative to the total phetamine and amphetamine content of the composition is amphetamine content of the composition. 1-methamphetamine and wherein the methamphetamine is In yet an additional embodiment, the invention is a method administered at a dose of between about a 2 mg dose and 35 of treating mild cognitive impairment in the human, compris about a 60 mg dose per day. ing the step of orally administering an effective amount of In yet another embodiment, the invention is a method of methamphetamine to the human, wherein the methamphet treating Alzheimer's disease in a human, comprising the step amine is at least about 95 mole percent 1-methamphetamine of administering an effective amount of an amphetamine to relative to the total methamphetamine content of the compo the human, wherein the amphetamine is administered as a 40 sition. component of a composition that includes amphetamine and, In a further embodiment, the invention is a method of optionally, a methamphetamine, wherein at least about 85 treating Alzheimer's disease in a human, comprising the step mole percent of the total amphetamine and methamphet of orally administering an effective amount of amphetamine amine content of the composition is 1-amphetamine. to the human, wherein the amphetamine is at least about 95 In still another embodiment, the invention is a method of 45 mole percent 1-amphetamine relative to the total amphet treating Alzheimer's disease in a human, comprising the step amine content of the composition. of administering an effective amount of a methamphetamine In an additional embodiment, the invention is a method of to the human, wherein the methamphetamine is administered treating Alzheimer's disease in the human, comprising the as a component of a composition that includes methamphet step of orally administering an effective amount of metham amine and, optionally, an amphetamine, wherein at least 50 phetamine to the human, wherein the methamphetamine is at about 85 mole percent of the total methamphetamine and least about 95 mole percent 1-methamphetamine relative to amphetamine content of the composition is l-methamphet the total methamphetamine content of the composition. amine. In yet another embodiment, the invention is a method of A further embodiment of the invention is a method of treating a human for a memory impairment, comprising the treating Alzheimer's disease in a human, comprising the step 55 step of administering an amphetamine composition selected of administering an effective amount of an amphetamine to from the group consisting of l-amphetamine, 1-methamphet the human, wherein the amphetamine is administered as a amine or a combination of both to a human having an impair component of a composition that includes amphetamine and, ment in memory associated with multiple Sclerosis. optionally, a methamphetamine, wherein at least about 85 In still another embodiment, the invention is a method of mole percent of the total amphetamine and methamphet 60 treating a human for an impairment in a cognitive function, amine content of the composition is 1-amphetamine and comprising the step of administering an amphetamine com wherein the amphetamine is administered at a dose of at least position selected from the group consisting of l-amphet about a 2 mg and about a 60 mg dose per day. amine, 1-methamphetamine or a combination of both to a Another embodiment of the invention is a method of treat human having impairment in a cognitive function associated ing Alzheimer's disease in a human, comprising the step of 65 with multiple sclerosis. orally administering an effective amount of an amphetamine In an additional embodiment, the invention is a method of to the human, wherein the amphetamine is administered as a treating a human for an impairment in a cognitive function, US 7,619,005 B2 29 30 comprising the step of administering an amphetamine com ment in a cognitive function associated with Mild Cognitive position selected from the group consisting of l-amphet Impairment, wherein the methamphetamine is administered amine, 1-methamphetamine or a combination of both to a as a component of a composition that includes methamphet human having an impairment in a cognitive function associ amine and, optionally, an amphetamine, wherein at least ated with a brain aneurysm. about 85 mole percent of the total methamphetamine and In still another embodiment, the invention is a method of amphetamine content of the composition is l-methamphet treating a human for an impairment in a cognitive function, amine and wherein the methamphetamine is administered at comprising the step of administering an amphetamine com a dose of between about a 1 mg dose and about a 150 mg dose position selected from the group consisting of l-amphet per day and wherein the human does not have an impairment amine, 1-methamphetamine or a combination of both to a 10 in memory, attention and learning. human having an impairment in a cognitive function associ In still another embodiment, the invention is a method of ated with mental retardation. treating a human for an impairment in a cognitive function, In another embodiment, the invention includes a method of comprising the step of administering an effective amount of a treating a human for an impairment in a cognitive function, methamphetamine to a human having an impairment in a comprising the step of administering an effective amount of 15 cognitive function associated with Alzheimer's disease, an amphetamine to a human having an impairment in a cog wherein the methamphetamine is administered as a compo nitive function associated with Mild Cognitive Impairment, nent of a composition that includes methamphetamine and, wherein the amphetamine is administered as a component of optionally, an amphetamine, wherein at least about 85 mole a composition that includes amphetamine and, optionally, a percent of the total methamphetamine and amphetamine con methamphetamine, wherein at least about 85 mole percent of tent of the composition is l-methamphetamine and wherein the total amphetamine and methamphetamine content of the the human does not have an impairment in memory, attention composition is 1-amphetamine and wherein the human does and learning. not have an impairment in memory, attention and learning. In another embodiment, the invention is a method of treat In yet another embodiment, the invention is a method of ing a human for an impairment in a cognitive function, com treating a human for an impairment in a cognitive function, 25 prising the step of administering an effective amount of an comprising the step of administering an effective amount of a amphetamine to a human having an impairment in a cognitive methamphetamine to a human having an impairment in a function associated with Alzheimer's disease, wherein the cognitive function associated with Mild Cognitive Impair amphetamine is administered as a component of a composi ment, wherein the methamphetamine is administered as a tion that includes amphetamine and, optionally, a metham component of a composition that includes methamphetamine 30 phetamine, wherein at least about 85 mole percent of the total and, optionally, an amphetamine, wherein at least about 85 amphetamine and methamphetamine content of the compo mole percent of the total methamphetamine and amphet sition is l-methamphetamine and wherein the human does not amine content of the composition is l-methamphetamine and have an impairment in memory, attention and learning. wherein the human does not have an impairment in memory, In another embodiment, the invention is a method of treat attention and learning. 35 ing a human for an impairment in a cognitive function, com In still another embodiment, the invention includes a prising the step of orally administering an effective amount of method of treating a human for an impairment in a cognitive an amphetamine to a human having an impairment in a cog function, comprising the step of administering an effective nitive function associated with Alzheimer's disease, wherein amount of an amphetamine to a human having an impairment the amphetamine is administered as a component of a com in a cognitive function associated with Mild Cognitive 40 position that includes amphetamine and, optionally, a meth Impairment, wherein the amphetamine is administered as a amphetamine, wherein at least about 95 mole percent of the component of a composition that includes amphetamine and, total amphetamine and methamphetamine content of the optionally, a methamphetamine, wherein at least about 85 composition is 1-amphetamine and wherein the amphetamine mole percent of the total amphetamine and methamphet is administered at a dose of at least about a 1 mg and about a amine content of the composition is 1-amphetamine and 45 150 mg dose per day and wherein the human does not have an wherein the amphetamine is administered at a dose of impairment in memory, attention and learning. between about a 1 mg dose and about a 150 mg dose per day In an additional embodiment, the invention is a method of and wherein the human does not have an impairment in treating a human for an impairment in a cognitive function, memory, attention and learning. comprising the step of orally administering an effective In an additional embodiment, the invention is a method of 50 amount of a methamphetamine to a human having an impair treating a human for an impairment in a cognitive function, ment in a cognitive function associated with Alzheimer's comprising the step of orally administering an effective disease, wherein the methamphetamine is administered as a amount of an amphetamine to a human having an impairment component of a composition that includes methamphetamine in a cognitive function associated with Mild Cognitive and, optionally, an amphetamine, wherein at least about 95 Impairment, wherein the amphetamine is administered as a 55 mole percent of the total methamphetamine and amphet component of a composition that includes amphetamine and, amine content of the composition is l-methamphetamine and optionally, a methamphetamine, wherein at least about 85 wherein the methamphetamine is administered at a dose of at mole percent of the total amphetamine and methamphet least about a 1 mg and about a 150 mg dose per day and amine content of the composition is 1-amphetamine and wherein the human does not have an impairment in memory, wherein the amphetamine is administered at a dose of 60 attention and learning. between about a 1 mg dose and about a 150 mg dose per day In yet another embodiment, the invention is a method of and wherein the human does not have an impairment in treating a human for an impairment in a cognitive function, memory, attention and learning. comprising the step of orally administering an effective In a further embodiment, the invention is a method of amount of amphetamine to a human having an impairment in treating a human for an impairment in a cognitive function, 65 a cognitive function associated with Mild Cognitive Impair comprising the step of orally administering an effective ment, wherein the amphetamine is at least about 95 mole amount of a methamphetamine to a human having an impair percent 1-amphetamine relative to the total amphetamine con US 7,619,005 B2 31 32 tent of the composition and wherein the human does not have amphetamine is administered as a component of a composi an impairment in memory, attention and learning. tion that includes amphetamine and, optionally, a metham In still another embodiment, the invention is a method of phetamine, wherein at least about 85 mole percent of the total treating a human for an impairment in a cognitive function, amphetamine and methamphetamine content of the compo comprising the step of orally administering an effective 5 sition is 1-amphetamine and wherein the human does not have amount of methamphetamine to a human having an impair an impairment in memory, attention and learning. ment in a cognitive function associated with Mild Cognitive In still another embodiment, the invention is a method of Impairment, wherein the methamphetamine is at least about treating a human for an impairment in a cognitive function, 95 mole percent 1-methamphetamine relative to the total comprising the step of administering an effective amount of a methamphetamine content of the composition and wherein 10 methamphetamine to a human having an impairment in a the human does not have an impairment in memory, attention cognitive function associated with Parkinson's disease, and learning. wherein the methamphetamine is administered as a compo In a further embodiment, the invention is a method of nent of a composition that includes methamphetamine and, treating a human for an impairment in a cognitive function, optionally, an amphetamine wherein at least about 85 mole comprising the step of orally administering an effective 15 percent of the total methamphetamine in amphetamine con amount of amphetamine to a human having an impairment in tent of the composition is l-methamphetamine and wherein a cognitive function associated with Alzheimer's disease, the human does not have an impairment in memory, attention wherein the amphetamine is at least about 95 mole percent and learning. 1-amphetamine relative to the total amphetamine content of In still another embodiment, the invention is a method of the composition and wherein the human does not have an treating a human for a memory impairment, comprising the impairment in memory, attention and learning. step of administering an amphetamine composition selected In still another embodiment, the invention is a method of from the group consisting of l-amphetamine, 1-methamphet treating a human for an impairment in a cognitive function, amine or a combination of both to a human having an impair comprising the step of orally administering an effective ment in memory associated with chronic fatigue syndrome. amount of methamphetamine to a human having an impair 25 In another embodiment, the invention is a method of treat ment in a cognitive function associated with Alzheimer's ing a human for an impairment in a cognitive function, com disease, wherein the methamphetamine is at least about 95 prising the step of administering an amphetamine composi mole percent 1-methamphetamine relative to the total meth tion selected from the group consisting of 1-amphetamine, amphetamine content of the composition and wherein the 1-methamphetamine or a combination of both to human hav human does not have an impairment in memory, attention and 30 ing an impairment in a cognitive function associated with learning. chronic fatigue syndrome. In still another embodiment, the invention is a method of In still another embodiment, the invention is a method of treating a human for a memory impairment, comprising the treating a human for a memory impairment, comprising the step of administering an amphetamine composition selected step of administering an amphetamine composition selected from the group consisting of l-amphetamine, 35 from the group consisting of 1-amphetamine, 1-methamphetamine or a combination of both to a human 1-methamphetamine or a combination of both to a human having an impairment in memory associated with multiple having an impairment in memory associated with fibromyal Sclerosis. gia Syndrome. An additional embodiment of the invention is a method of In another embodiment, the invention is a method of treat 40 ing a human for an impairment in a cognitive function, com treating a human for an impairment in a cognitive function, prising the step of administering an amphetamine composi comprising the step of administering an amphetamine com tion selected from the group consisting of l-amphetamine, position selected from the group consisting of l-amphet 1-methamphetamine or a combination of both to a human amine, 1-methamphetamine or a combination of both to having an impairment in a cognitive function associated with 45 human having impairment in a cognitive function associated multiple Sclerosis. with fibromyalgia Syndrome. In a further embodiment, the invention is a method of In still another embodiment, the invention is a method of treating a human for an impairment in a cognitive function, treating a human for a memory impairment, comprising the comprising the step of administering an amphetamine com step of administering an amphetamine composition selected from the group consisting of 1-amphetamine, position selected from the group consisting of l-amphet 50 amine, 1-methamphetamine or a combination of both to a 1-methamphetamine or a combination of both to a human human having an impairment in a cognitive function associ having an impairment in memory associated with chemo ated with a brain aneurysm and wherein the human does not therapy treatment. have an impairment in memory, attention and learning. In a further embodiment, the invention is a method of In yet another embodiment, the invention is a method of 55 treating a human for an impairment in a cognitive function, treating an impairment in a cognitive function in a human, comprising the step of administering an amphetamine com comprising the step of administering an amphetamine com position selected from the group consisting of l-amphet position selected from the group consisting of l-amphet amine, 1-methamphetamine or a combination of both to a amine, 1-methamphetamine or a combination of both to a human having an impairment in a cognitive function associ human having an impairment in a cognitive function associ 60 ated with a brain injury and wherein the human does not have ated with mental retardation and wherein the impairment is an impairment in memory, attention and learning. not an impairment in memory, attention and learning. In still another embodiment, the invention is a method of In another embodiment, the invention is a method of treat treating a human for an impairment in a cognitive function, ing a human for an impairment in a cognitive function, com comprising the step of administering an amphetamine com prising the step of administering an effective amount of an 65 position selected from the group consisting of l-amphetat amphetamine to a human having an impairment in a cognitive mine, 1-methamphetamine or a combination of both to a function associated with Parkinson's disease, wherein the human having an impairment in a cognitive function associ US 7,619,005 B2 33 34 ated with a stroke and wherein the human does not have an Scopolamine, whereby the cognitive impairment consequent impairment in memory, attention and learning. to the exposure to Scopolamine is at least partially attenuated. In another embodiment, the invention includes a method of In another embodiment, the invention includes a method of treating a human for memory impairment, comprising admin treating a human, comprising administering to the human at istering to the human at least one member selected from the least one member selected from the group consisting of 1-am group consisting of 1-amphetamine, 1-methamphetamine, phetamine, 1-methamphetamine, 1-threo-methylphenidate, 1-threo-methylphenidate, d-threo-methylphenidate, meth d-threo-methylphenidate, methylphenidate, atomoxetine and ylphenidate, atomoxetine and modafinil at one or more points modafinil at one or more points in time selected from the in time selected from the group consisting of before, con group consisting of before, concomitantly with and Subse comitantly with and Subsequent to exposure of the human to 10 quent to a memory impairment that is a consequence of expo a muscarinic cholinergic receptor antagonist, whereby the Sure of the human to a muscarinic cholinergic receptor memory impairment consequent to the exposure to the mus antagonist, whereby the memory impairment is at least par carinic cholinergic receptor antagonist is at least partially tially attenuated. attenuated. An additional embodiment of the invention includes a In yet another embodiment, the invention includes a 15 method of treating a human, comprising administering to the method of treating a human for cognitive impairment, com human at least one member selected from the group consist prising administering to the human at least one member ing of l-amphetamine, 1-methamphetamine, l-threo-meth selected from the group consisting of l-amphetamine, 1-meth ylphenidate, d-threo-methylphenidate, methylphenidate, ato amphetamine, 1-threo-methylphenidate, d-threo-meth moxetine and modafinil before, concomitantly with, or ylphenidate, methylphenidate, atomoxetine and modafinil at Subsequent to a cognitive impairment that is a consequence of one or more points in time selected from the group consisting exposure of the human to a muscarinic cholinergic receptor of before, concomitantly with and Subsequent to exposure of antagonist, whereby the cognitive impairment is at least par the human to a muscarinic cholinergic receptor antagonist, whereby the cognitive impairment consequent to the expo tially attenuated. Sure to the muscarinic cholinergic receptor antagonist is at 25 In still another embodiment, the invention includes a least partially attenuated. method of treating a human, comprising administering to the In an additional embodiment, the invention includes a human at least one member selected from the group consist method of treating a human for memory impairment, com ing of l-amphetamine, 1-methamphetamine, l-threo-meth prising administering to the human at least one member ylphenidate, d-threo-methylphenidate, methylphenidate, ato selected from the group consisting of l-amphetamine, 1-meth 30 moxetine and modafinil before, concomitantly with, or amphetamine, 1-threo-methylphenidate, d-threo-meth Subsequent to a memory impairment is a consequence of ylphenidate, methylphenidate, atomoxetine and modafinil at exposure of the human to atropine, whereby the memory one or more points in time selected from the group consisting impairment is at least partially attenuated. of before, concomitantly with and Subsequent to exposure of In yet another embodiment, the invention includes a the human to atropine, whereby the memory impairment 35 method of treating a human, comprising administering to the consequent to the exposure to atropine is at least partially human at least one member selected from the group consist attenuated. ing of l-amphetamine, 1-methamphetamine, l-threo-meth In yet another embodiment, the invention includes a ylphenidate, d-threo-methylphenidate, methylphenidate, ato method of treating a human for memory impairment, com moxetine and modafinil before, concomitantly with, or prising administering to the human at least one member 40 Subsequent to a memory impairment is a consequence of selected from the group consisting of l-amphetamine, 1-meth exposure of the human to Scopolamine, whereby the memory amphetamine, 1-threo-methylphenidate, d-threo-meth impairment is at least partially attenuated. ylphenidate, methylphenidate, atomoxetine and modafinil at The practice of the present invention will employ, unless one or more points in time selected from the group consisting otherwise indicated, conventional techniques of synthetic of before, concomitantly with and Subsequent to exposure of 45 chemistry, organic chemistry, inorganic chemistry, organo the human to Scopolamine, whereby the memory impairment metallic chemistry, pharmaceutical chemistry, and behavioral consequent to the exposure to Scopolamine is at least partially science, which are within the skill of the art. Such techniques attenuated. are described in the literature. See, for example, Advanced In still another embodiment, the invention includes a Organic Chemistry. Reactions, Mechanisms, And Structure method of treating a human for cognitive impairment, com 50 by J. March (John Wiley and Sons, N.Y., 1992); The Chem prising administering to the human at least one member ist's Companion: A Handbook Of Practical Data, Tech selected the group consisting of l-amphetamine, 1-metham niques, And References by A. J. Gordon and R. A. Ford phetamine, l-threo-methylphenidate, d-threo-methylpheni (Wiley, NY, 1972); Synthetic Methods Of Organometallic date, methylphenidate, atomoxetine and modafinil at one or And Inorganic Chemistry by W. A. Herrmann and Brauer more points in time selected from the group consisting of 55 (Georg Thieme Verlag, N.Y., 1996); Experimental Organic before, concomitantly with and Subsequent to exposure of the Chemistry by D. Todd (Prentice-Hall, N.J., 1979); Experi human to atropine, whereby the cognitive impairment conse mental Organic Chemistry: Standard And Microscale by L. quent to the exposure to atropine is at least partially attenu M. Harwood (Blackwell Science, M.A., 1999); Experimental ated. Analysis. Of Behavior by I. H. Iversen and K. A. Lattal In a further embodiment, the invention includes a method 60 (Elsevier, N.Y., 1991); A Practical Guide To Behavioral of treating a human for cognitive impairment, comprising Research: Tools And Techniques by R. Sommer and B. Som administering to the human at least one member selected the mer (Oxford University Press, N.Y., 2002); Advances. In Drug group consisting of 1-amphetamine, 1-methamphetamine, Discovery Techniques by A. L. Harvey (Chichester, N.Y., 1-threo-methylphenidate, d-threo-methylphenidate, meth 1998); Ouantitative Calculations. In Pharmaceutical Prac ylphenidate, atomoxetine and modafinil at one or more points 65 tice And Research by T. P. Hadjiioannou (VCH, N.Y., 1993); in time selected from the group consisting of before, con Drug Fate And Metabolism. Methods And Techniques by E. comitantly with and Subsequent to exposure of the human to R. Garrett and J. L. Hirtz (M. Dekker, N.Y., 1977); Behavioral US 7,619,005 B2 35 36 Science Techniques. An Annotated Bibliography For Health Optionally, methods, kits, compositions or other subject Professionals by M. K. Tichy (Praeger Publishers, N.Y., matter disclosed and/or claimed in co-pending U.S. applica 1975). tion Ser. Nos. 10/003,740 (publication no. 20020115725) The invention described herein provides methods of treat and/or 10/139,606 (publication no. 200301 19884), and/or ing a human having an impairments in a cognitive function Patent Co-operation Treaty (PCT) Application No.: PCT/ (e.g., attention, executive function, reaction time, learning US01/45793 (publication no.: WO02/39998) and/or any information processing, conceptualization, problem solving, national or regional patent filing derived therefrom are Verbal fluency) and memory (e.g., memory consolidation, excluded from the scope of the claims of the present inven short term memory, working memory, long term memory, tion. For example, methods of treating memory consolida declarative memory or procedural memory). Advantages of 10 tion, short-term memory, long-term memory, attention, learn the claimed invention include, for example, the treatment of ing and anxiety for conditions or diseases as disclosed and humans suffering an impairment in a cognitive function or claimed in U.S. application Ser. Nos. 10/003,740, and/or memory in a cost effective manner and without significant 10/139,606, and/or PCT/US01/45793, are optionally side affects, especially in individuals who have had a condi excluded from the scope of method claims in the present tion or disease for an extended period of time and where 15 invention. Methods, kits, compositions or other subject mat clinical management strategies are difficult to implement. Of ter not disclosed and/or not claimed in U.S. application Ser. particular importance, are conditions which require long Nos. 10/003,740 and/or 10/139,606, and/or PCT/US01/ term treatment where addictive and potent side effects would 45793 and/or any national or regional patent filing derived be considerably undesirable. The claimed methods provide therefrom are not excluded from the scope of the claims of the an efficient way to treat and reduce the severity of an impair present invention. ment in a cognitive function (also referred to herein as “cog nition') and memory in humans. BRIEF DESCRIPTION OF THE DRAWINGS The invention described herein also provides a method for treating an individual, in particular a human individual, hav FIG. 1 presents the effectiveness of various doses of S-(+)- ing an impairmentina cognitive function (e.g., an impairment 25 amphetamine on Performance in the Inhibitory Avoidance in attention, an impairment in alertness, an impairment in Task. wakefulness, and impairment in arousal, an impairment in FIG.2 demonstrates the effect of 2 mg/kg of S-(+)-amphet executive function, an impairment in reaction time, an impair amine on Performance in the Inhibitory Avoidance Task. ment in vigilance, an impairment in information processing, FIG. 3 shows the varying effect of S-(+)-amphetamine an impairment in conceptualization, an impairment in prob 30 depending on the time between administration and inception lem solving, an impairment in Verbal fluency) and/or a of training. memory process (e.g., impairment in memory consolidation, FIG. 4 illustrates the effect of S-(+)-amphetamine on impairment in short-term memory, an impairment in working memory retention one week after the initial training. memory, an impairment in declarative memory, an impair FIG.5 depicts the effects of S-(+)-amphetamine on normal ment in procedural memory). The individual can have an 35 impairment in a cognitive or memory processes as a conse and fornix-lesioned animals. quence of exposure to a muscarinic cholinergic receptor FIG. 6 shows the effect of S-(+)-amphetamine (2.0 mg/kg) antagonist. The claimed methods provide an efficient way to on Performance in Inhibitory Avoidance. treat a human by preventing, reducing, diminishing, attenu FIGS. 7A, 7B, 7C, 7D, 7E and 7F show the effect of ating, minimizing or reversing the onset or severity of impair 40 S-(+)-amphetamine on Activity Levels. ments in cognitive and memory processes in humansas, for FIG. 8 shows the effectiveness of various doses of R-(-)- example, a consequence of exposure to muscarinic cholin amphetamine on memory retention. ergic receptor antagonists or as associated with mild cogni FIG. 9 shows the effectiveness of R-(-)-amphetamine on tive impairment, Alzheimer's disease, multiple Sclerosis, memory retention. mental retardation, brain aneurysm, chronic fatigue syn 45 FIG. 10 shows the effect of R-(-)-amphetamine (0.5 drome, fibromyalgia syndrome, chemotherapy, traumatic mg/kg) on Performance in the Inhibitory Avoidance Task. brain injury, stroke or Parkinson's disease. FIG.11 shows the effect of Post Training Administration of In addition, the invention described herein provides meth R-(-)-amphetamine (0.5 mg/kg) on Performance in the ods for improving memory and cognition in Subjects who do Inhibitory Avoidance Task. not have an impairment in memory or a cognitive function 50 FIG. 12 shows the effect of R-(-)-amphetamine (1.0 (also referred to herein as “normal subjects). mg/kg) on Inhibitory Avoidance Performance in Fornix Thus, treatment with 1-amphetamine (e.g., C105) or Lesion Rats. 1-methamphetamine (e.g., SN522, SN522-HCl) can halt, FIGS. 13A, 13B, 13C and 13D show the effect of R-(-)- reverse or diminish the progression of the impairment in amphetamine on Performance in the Object RecognitionTask cognition and memory, thereby increasing the quality of life 55 in Normal and Fornix Lesion Rats. without adverse side affects, such as addiction, alterations in FIGS. 14A, 14B, 14C, 14D, 14E and 14F show the effect of blood pressure and heart rate. In addition, treatment with at R-(-)-amphetamine (0.5 mg/kg) on Activity Levels. least one member selected from the group consisting of 1-am FIGS. 15A, 15B, 15C, 15D, 15E and 15F shows the effect phetamine, 1-methamphetamine, l-threo-methylphenidate, of S-(+)-amphetamine (2 mg/kg) on Activity Levels. d-threo-methylphenidate, methylphenidate, atomoxetine and 60 modafinil can potentially prevent, halt, reverse, diminish, FIG. 16 shows the effect of R-(-)-amphetamine on Tail attenuate or minimize the initiation or progression of an Flick Analgesia. impairment in cognitive and memory processes as a conse FIG. 17 shows an exemplary sustained release device. quence of exposure to muscarinic cholinergic receptor FIG. 18 depicts the pharmacokinetics of R-(-)-amphet antagonists, thereby increasing the ability to execute, form or 65 amine and Memory Assessments and PK. maintain cognitive and memory processes, which can FIG. 19 shows that administration of R-(-)-amphetamine improve the quality of life. to human patients can improve verbal memory. US 7,619,005 B2 37 38 FIG. 20 depicts the Step-Through Latency (sec) for rats FIG. 41A-41C depict keys for visuo-motor speed tests. treated with control/vehicle (veh), d-amphetamine (d-amph), FIG. 42 depicts the study design for treatment of humans 1-amphetamine (C105) or 1-methamphetamine (SN522). with multiple sclerosis. FIG. 21 depicts the Step-Through Latency (sec) for rats treated with control (O) or varying doses of 1-methamphet DETAILED DESCRIPTION OF THE INVENTION amine (SN522). The asterisk indicates a significant difference from the control (p<0.05). The features and other details of the invention, either as FIG. 22 depicts the Escape Latency (sec) for rats treated steps of the invention or as combinations of parts of the with saline control or 1-methamphetamine (SN522). invention, will now be more particularly described and FIG. 23 depicts the Activity Measure (% increase from 10 pointed out in the claims. It will be understood that the par control) for rats treated with 1-methamphetamine (SN522). ticular embodiments of the invention are shown by way of FIG. 24 depicts the Activity Measure (% increase from illustration and not as limitations of the invention. The prin control) for rats treated with D-amphetamine (d-amph). cipal features of this invention can be employed in various FIG. 25 depicts the Memory Score, as assessed by the Rey embodiments without departing from the scope of the inven Auditory and Verbal Learning Test, following a 30 minute 15 tion. (min) and a 24 hour (hr) recall time for humans treated with The present invention relates to the discovery that the 1-amphetamine (C105). The asterisk depicts significant dif amphetamine class of compounds (collectively referred to ferences. hereinas'amphetamine compounds’) can be used to enhance FIG. 26 compares individual Subject's memory scores, as and/or restore cognitive or memory function and perfor assessed by the Rey Auditory and Verbal Learning Test mance, e.g., to improve attention, executive function, reactive (RAVLT Score (0-15)), following placebo treatment to their time, learning, short-term memory, working memory, long best score following treating with 1-amphetamine (C105). term memory, declarative memory, or procedural memory in FIG. 27 illustrates the keyboard proficiency for subjects animal subjects. More particularly, the invention relates to the diagnosed with mild cognitive impairment treated with 1-am discovery that particular stereoisomers of amphetamine com phetamine (5 mg, 15 mg, 30 mg) and Subjects diagnosed with 25 pounds are the most effective for therapeutic use. The mild cognitive impairment receiving placebo. amphetamine compounds of the invention (e.g., R-(-)-am FIG. 28 illustrates improvements in learning in subjects phetamine and R-(-)-methamphetamine) improve cognitive diagnosed with mild cognitive impairment following treat processes and memory (e.g., memory consolidation or the ment with 1-amphetamine compared to placebo controls. process of storing new information in long-term memory) in FIG. 29 illustrates improvements in memory in subjects 30 a human. diagnosed with mild cognitive impairments following treat Furthermore, the present invention relates to the discovery ment with 1-amphetamine compared to placebo controls. that the amphetamine compounds can be used to enhance FIG. 30 illustrates improvements in executive function in and/or restore cognitive processes Such as attention span, Subjects diagnosed with mild cognitive impairment following focus, executive function, reaction time or learning in animal treatment with 1-amphetamine compared to placebo controls. 35 Subjects. The compounds can be useful in improving the FIG. 31 illustrates improvement in memory and learning, attention span of normal individuals, as well as improving the as depicted by Z Scores, in Subjects diagnosed with mild attention span of individuals characterized by a deficit in cognitive impairment following treatment with 1-amphet attention span and/or focus (e.g., individuals diagnosed with amine (30 mg) compared to placebo controls. an attention deficit disorder). Lack of attentiveness may lead FIG. 32 depicts the Step-Through Latency (sec) for rats 40 to a failure to process new information and accordingly com treated with Saline control (Sal); and Scopolamine rats treated mit Such new information to memory. Lack of focus may also with varying doses of 1-methamphetamine (SN522) or no lead to difficulties in later recalling previously processed 1-methamphetamine (O). information. Thus, deficits in attentiveness and/or focus may FIG. 33 depicts the Step-Through Latency (sec) for rats affect learning and memory. In addition to memory and learn treated with Saline alone (sal-Sal); and Scopolamine rats 45 ing difficulties, lack of attentiveness has many other negative treated with varying doses of 1-amphetamine (C105) or saline Social and behavioral consequences. Accordingly, the Subject (sal). The asterisk indicates a significant difference between amphetamine compounds may be used to enhance and/or group means (p<0.05). restore at least one of memory, learning, attentiveness, or FIG. 34 depicts an improvement in memory in humans focus. following the administration of 1-methamphetamine 50 In a particular embodiment, compositions of 1-amphet (SN522). amine or 1-methamphetamine are employed to treat impair FIG. 35 depicts an improvement in total speed score from ments in cognitive and memory processes in a human having baseline following the administration of 1-methamphetamine Alzheimer's disease or mild cognitive impairment. to humans. Amphetamine is a nervous system stimulant that may FIG. 36 depicts improvements in Picture Recognition/Sen 55 mildly increase blood pressure and decreases appetite. Abuse sitivity Index following the administration of 1-methamphet of amphetamine has been shown to cause severe side effects amine to humans. including dependence and possibly induced psychosis. FIG. 37 depicts an improvement of 1-methamphetamine in Amphetamine is synonymous with actedron; actemin; adder Information Processing-Targets Detected following the all; adipan; akedron; allodene; alpha-methyl-(-)-benze administration of 1-methamphetamine to humans. 60 neethanamine; alpha-methylbenzeneethanamine; alpha-me FIG. 38 depicts an improvement in Information Process thylphenethylamine; amfetamine; amphate; anorexine; ing-False Alarms following the administration of 1-metham benzebar; benzedrine; benzyl methyl carbinamine; ben phetamine to humans. Zolone; beta-amino propylbenzene, beta-phenylisopropy FIG. 39 depicts the memory cabinet employed in learning lamine; biphetamine; desoxynorephedrine; dietamine; DL and memory tests. 65 amphetamine; elastonon; fenopromin; finam, isoamyne; FIG. 40 depicts a key for simple attention (response direc isomyn, mecodrin; monophos; mydrial; norephedrane; novy tion 1) and response reversal (response direction 2) tests. drine; obesin: obesine; obetrol; octedrine; oktedrin; phe US 7,619,005 B2 39 40 namine; phenedrine; phenethylamine, alpha-methyl-, per mulated in an amount Sufficient to improve memory consoli comon; profamina; profetamine; propisamine; racephen; dation in an animal. The preparations and methods can be raphetamine; rhinalator, sympamine; simpatedrin; simpa treatments using amphetamine compounds effective for tina; sympatedrine; and weckamine. human and/or animal Subjects. In addition to humans, other The present invention contemplates, in part, the use of an animal to which the invention is applicable extend to both amphetamine composition which is enriched for eutomers of domestic animals and livestock, raised either as pets or for amphetamine compounds. In particular, the use of pharma commercial purposes. Examples are dogs, cats, cattle, horses, ceutical preparations for improving memory consolidation in sheep, hogs, and goats. humans, include (R)-(-)-amphetamine or a derivative thereof. (R)-(-)-amphetamine (1-amphetamine, levo-amphet 10 Still another aspect of the invention relates to the use of amine, C105) is effective at a dose one-fourth (4) the dose of enantiomerically enriched preparations of amphetamine the (S)-(+) enantiomer (d-amphetamine, dexo-amphetamine) compounds for lessening the severity or prophylactically pre of amphetamine. In addition, unlike (S)-(+)-amphetamine, venting the occurrence of learning and/or memory defects in the (R)-(-) enantiomer has not been shown to be addictive and an animal, and thus, altering the learning ability and/or does not produce undesirable side effects such as increased 15 memory capacity of the animal. As a result, the compounds of activity, increased blood pressure or increased heart rate. the present invention may be useful for treating and/or pre In certain embodiments, a mixture of enantiomers of the venting memory impairment, e.g., due to toxicant exposure, Subject compounds may be employed, e.g., a racemic mixture brain injury, brain aneurysm, age-associated memory impair containing both enantiomers of a chosen compound, e.g., ment, mild cognitive impairment, epilepsy, mental retarda with each enantiomer being present in equal amounts, or in tion in children, and dementia resulting from a disease. Such differing amounts. In certain embodiments, the therapeutic as Parkinson's disease, Alzheimer's disease, AIDS, head preparation may be enriched to provide predominantly one trauma, Huntington's disease, Pick's disease, Creutzfeldt enantiomer of a Subject compound. In one embodiment, an Jakob disease, age-associated memory impairment, Mild enantiomerically enriched mixture can comprise an amphet Cognitive Impairment, Multiple Sclerosis, Anterior Commu amine compound that is at least about 51 W/w or mole per 25 nicating Artery Syndrome, chronic fatigue syndrome, fibro cent, about 60 w/w or mole percent, about 75 w/w or mole myalgia syndrome, chemotherapy, traumatic brain injury, percent, about 80 w/w or mole percent, about 85 w/w or mole stroke or Parkinson's disease. In addition, the compounds of percent, about 90 w/w or mole percent, about 95 w/w or mole the invention may be useful in enhancing memory in normal percent or about 99 w/w or mole percent 1-amphetamine individuals. relative to d-amphetamine. In another embodiment, the 30 amphetamine compound employed in the methods is about The invention also relates to the conjoint use of an amphet 100 w/w or mole percent 1-amphetamine. In preferred amine compound with agents that mimic or stimulate PKC embodiments, the amphetamine compound provided in the and/or PKA pathways. In another embodiment, the invention is a method of treat formulation is at least about 60 percent (w/w or mole percent) ing an impairment in cognitive processes. Cognition is also of the eutomer relative to the distomer of the amphetamine 35 compound, and more preferably at least about 75 w/w or mole referred to herein as a cognitive process or a cognitive func percent, about 80 w/w or mole percent, about 85 w/w or mole tion. Using standard cognition testing criteria, one of skill in percent, about 90 w/w or mole percent, about 95 w/w or mole the art would be capable of determining whetheraperson has percent or about 99 w/w or mole percent. Furthermore, the an impairment in a cognitive process, the degree of cognitive present invention is based on using the Subject compounds for 40 impairment and an improvement in cognition following treat enhancing or restoring attention span and/or focus. The ments by the methods described herein. effects of the Subject compounds on attention span may have The impairment in a cognitive process can be in a human secondary consequences on the ability to process and/or having mild cognitive impairment, Alzheimer's disease, mul recall information, and therefore may also enhance memory tiple Sclerosis, chronic fatigue syndrome, fibromyalgia Syn and/or learning. 45 drome, chemotherapy, traumatic brain injury, stroke or Par The amphetamine compounds can also be provided in the kinson's disease. In another embodiment, methods of the form of pharmaceutical salts and as prodrugs. invention are employed to improve a cognitive function in a In certain embodiments, the method includes administer human having an impairment in a cognitive function associ ing, conjointly with the pharmaceutical preparation, one or ated with a brain aneurysm (e.g., anterior communicating more of a neuronal growth factor, a neuronal Survival factor, 50 artery brain aneurysm) or a human having an impairment in a and a neuronal trophic factor. Additionally or alternatively, a cognitive function associated with mental retardation. Subject compound may be administered in conjunction with a Impairment in a cognitive function treated by the methods cholinergic, adrenergic, nonadrenergic, dopaminergic, or described herein can be an impairment in attention, which is glutaminergic modulator. Other agents directed at modulat the capacity or process of selecting out of the totality of ing GABA, NMDA, cannabinoid, AMPA, kainate, phos 55 available sensory or affective stimuli, those stimuli that are phodiesterase (PDE), PKA, PKC, CREB or nootropic sys most appropriate or desirable for focus at a given time tems may be important to the improvement of cognitive (Kinchla, R. A., et al., Annu. Rev. Psychol. 43:711-742 function and may be administered in conjunction with a Sub (1992)). The impairment in a cognitive process can be an ject compound. An agent to be administered conjointly with a impairment in executive function, which are neuropsycho Subject compound may be formulated together with a subject 60 logical functions such as decision making, planning, initia compound as a single pharmaceutical preparation, e.g., as a tive, assigning priority, sequencing, motor control, emotional pill or other medicament including both agents, or may be regulation, inhibition, problem solving, planning, impulse administered as a separate pharmaceutical preparation. control, establishing goals, monitoring results of action and In another aspect, the present invention provides pharma self-correcting (Elliott, R., Br: Med. Bull. 65:49-59 (2003)). ceutical preparations comprising, as an active ingredient, an 65 The cognitive impairment can be an impairment in alertness, enantiomerically enriched preparation of R-(-) amphetamine wakefulness, arousal, vigilance, and reaction time informa or a derivative thereof. The amphetamine compound is for tion processing, conceptualization, problem solving and/or US 7,619,005 B2 41 42 verbal fluency. One of skill in the art would be capable of identifying and evaluating the impairmentina cognitive func tion in the individual. VIII In a particular embodiment, impairments in cognitive pro CH cesses are treated by the methods described herein in humans having a mild cognitive impairment or Alzheimer's disease. CH DEFINITIONS The dextro enantiomer of amphetamine is referred to in the 10 art as the d, (+), D or S isomer and is represented by the For convenience, certain terms employed in the specifica general formula: tion, examples, and appended claims are collected here. As used herein, the term "amphetamine compounds” is meant to include amphetamine, analogs of amphetamine, 15 enantiomerically or isomerically enriched amphetamine, and enantiomerically or isomerically enriched analogs of amphet amine, as well as pharmaceutically acceptable salts of Such compounds and prodrugs. In particular, amphetamine com pounds of the invention, or analogs thereof which are admin The levo enantiomer of amphetamine is referred to in the istered to the human having an impairment in memory (im art as the 1, (-), L or R isomer and is represented by the pairment in memory consolidation, impairment in short-term general formula: memory, an impairment in working memory), include com pounds having the structure as given in Formulas I, II, III, IV, 25 V and VI above. H. NH2 The term "amphetamine.” such as is used when referring to “l-amphetamine' and “d-amphetamine” means a compound CH3 having Formula VII, including its salts, acids, esters, amides, carbamates, Schiffbases, prodrugs and other structural and 30 The racemic mixtures may be referred to as dl or (+,-) or functional derivatives thereof. “An amphetamine” can be in (+) or DL or (R)(S). the form of the free base, salt, acid, ester, amide, carbamate, The term "EDs” means the dose of a drug which produces Schiff base, prodrug and other structural and functional 50% of its maximum response or effect. derivatives of amphetamine or any combination thereof. In a 35 An "effective amount of e.g., an amphetamine com preferred embodiment, the amphetamine is the compound pound, with respect to the subject method of treatment, refers represented by Formula VII including salts, acids, esters, to an amount of the activator in a pharmaceutical preparation which, when applied as part of a desired dosage regimen amides, carbamates and Schiff bases. In another preferred brings about enhanced memory (memory consolidation, embodiment, the amphetamine is the compound represented short term memory, working memory, declarative memory, or by Formula VII, including its salts and acids. In still another 40 procedural memory) according to clinically acceptable stan preferred embodiment, the amphetamine is the compound of dards. Formula VII: The term “LDs, means the dose of a drug which is lethal in 50% of test subjects. VII 45 A“patient' or “subject’ to be treated by the subject method CH3 can mean either a human or non-human animal. The term “prodrug” represents compounds which are rap idly transformed in vivo, for example, by hydrolysis in blood into the therapeutically active agents of the present invention. 50 A common method for making a prodrug is to include selected moieties which are converted under physiologic con The term “methamphetamine such as is used when refer ditions (enzymatic or nonenzymatic) to reveal the desired ring to “l-methamphetamine” and “d-methamphetamine.” molecule. A thorough discussion is provided in T. Higuchi means a compound having Formula VIII, including its salts, and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of acids, esters, amides, carbamates, Schiffbases, prodrugs and 55 the A.C.S. Symposium Series, and in Edward B. Roche, ed., other structural and functional derivatives thereof. “A meth Bioreversible Carriers in Drug Design, American Pharma amphetamine' can be in the form of the free base, salt, acid, ceutical Association and Pergamon Press, 1987, both of ester, amide, carbamate, Schiffbase, prodrug and other struc which are incorporated herein by reference. tural and functional derivatives of methamphetamine or any The term “therapeutic index' refers to the therapeutic combination thereof. In a preferred embodiment, the meth 60 index of a drug defined as LDso/EDso. amphetamine is the compound represented by Formula VIII By “transdermal patch’ is meanta system capable of deliv including salts, acids, esters, amides, carbamates and Schiff ery of a drug to a patient via the skin, or any Suitable external bases. In another preferred embodiment, the methamphet Surface, including mucosal membranes, such as those found amine is the compound represented by Formula VIII, includ inside the mouth. Such delivery systems generally comprise a ing its salts and acids. In still another preferred embodiment, 65 flexible backing, an adhesive and a drug retaining matrix, the the methamphetamine is the compound represented by For backing protecting the adhesive and matrix and the adhesive mula VIII: holding the whole on the skin of the patient. On contact with US 7,619,005 B2 43 44 the skin, the drug-retaining matrix delivers drug to the skin, clyl, an aralkyl, or an aromatic or heteroaromatic moiety. It the drug then passing through the skin into the patients will be understood by those skilled in the art that the moieties system. substituted on the hydrocarbon chain can themselves be sub The term “adrenergic” refers to neurotransmitters or neu stituted, if appropriate. For instance, the Substituents of a romodulators chemically related to adrenaline (epinephrine) substituted alkyl may include substituted and unsubstituted or to neurons which release Such adrenergic mediators. forms of amino, azido, imino, amido, phosphoryl (including Examples are dopamine, norepinephrine, epinephrine. Such phosphonate and phosphinate), Sulfonyl (including Sulfate, agents are also referred to as catecholamines, which are Sulfonamido, Sulfamoyl and Sulfonate), and silyl groups, as derived from the amino acid tyrosine. well as ethers, alkylthios, carbonyls (including ketones, alde The term “biogenic amines’ refers to a class of neurotrans 10 hydes, carboxylates, and esters), —CF, —CN and the like. mitters which include catecholamines (e.g., dopamine, nore Exemplary substituted alkyls are described below. pinephrine, and epinephrine) and serotonin. Cycloalkyls can be further substituted with alkyls, alkenyls, The term “catecholamines' refers to neurotransmitters that alkoxys, alkylthios, aminoalkyls, carbonyl-substituted have a catechol ring (e.g., a 3,4-dihydroxylated benzene alkyls, —CF, —CN, and the like. ring). Examples are dopamine, norepinephrine, and epineph 15 Unless the number of carbons is otherwise specified, 1. “lower alkyl as used herein means an alkyl group, as defined The term “cholinergic” refers to neurotransmitters or neu above, but having from one to eight carbons, more preferably romodulators chemically related to choline or to neurons from one to five carbon atoms in its backbone structure. which release such cholinergic mediators. Likewise, “lower alkenyl and “lower alkynyl have similar The term "dopaminergic' refers to neurotransmitters or chain lengths. Throughout the application, preferred alkyl neuromodulators chemically related to dopamine or to neu groups are lower alkyls. In preferred embodiments, a Sub rons which release Such dopaminergic mediators. stituent designated herein as alkyl is a lower alkyl. The term "dopamine refers to an adrenergic neurotrans The term “alkylthio’ refers to an alkyl group, as defined mitter, as is known in the art. above, having a sulfur radical attached thereto. In preferred Herein, the term “aliphatic group' refers to a straight 25 embodiments, the “alkylthio’ moiety is represented by one of chain, branched-chain, or cyclic aliphatic hydrocarbon group —S-alkyl, —S-alkenyl. —S-alkynyl, and —S—(CH2) - and includes Saturated and unsaturated aliphatic groups. Such Rs, wherein Rs represents an aryl, a cycloalkyl, a cycloalk as an alkyl group, an alkenyl group, and an alkynyl group. enyl, a heterocycle or a polycycle; and m is Zero or an integer The terms “alkenyl and “alkynyl refer to unsaturated in the range of 1 to 8. Representative alkylthio groups include aliphatic groups analogous in length and possible Substitution 30 methylthio, ethylthio, and the like. to the alkyls described above, but that contain at least one The terms “amine' and “amino” are art-recognized and double or triple bond respectively. refer to both unsubstituted and substituted amines, e.g., a The terms “alkoxyl or “alkoxy” as used herein refers to an moiety that can be represented by the general formula: alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include meth 35 oxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether is two hydrocarbons covalently linked by an oxygen. Accord ingly, the Substituent of an alkyl that renders that alkyl an ether is or resembles analkoxyl. Such as can be represented by one of—O-alkyl, —O-alkenyl, -O-alkynyl. —O—(CH), 40 —Rs, where Rs represents an aryl, a cycloalkyl, a cycloalk wherein Ro and Ro eachindependently representahydrogen, enyl, a heterocycle or a polycycle; and m is Zero or an integer an alkyl, an alkenyl, -(CH), Rs, or Ro and Rio taken in the range of 1 to 8 together with the Natom to which they are attached complete The term “alkyl refers to the radical of saturated aliphatic a heterocycle having from 4 to 8 atoms in the ring structure; groups, including straight-chain alkyl groups, branched 45 Rs represents an aryl, a cycloalkyl, a cycloalkenyl, a hetero chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-sub cycle or a polycycle; and m is Zero or an integer in the range stituted cycloalkyl groups, and cycloalkyl-substituted alkyl of 1 to 8. In preferred embodiments, R., and Ro each inde groups. In preferred embodiments, a straight chain or pendently represent a hydrogen, an alkyl, an alkenyl, or branched chain alkyl has 8 or fewer carbon atoms in its —(CH) Rs, wherein Rs represents an aryl, a cycloalkyl, a backbone (e.g., C-Cs for straight chains, C-Cs for branched 50 cycloalkenyl, a heterocycle or a polycycle; and m is Zero oran chains), and more preferably 5 or fewer. Likewise, preferred integer in the range of 1 to 8. Thus, the term “alkylamine' as cycloalkyls have from 3-10 carbon atoms in their ring struc used herein means an amine group, as defined above, having ture, and more preferably have 5, 6 or 7 carbons in the ring a substituted or unsubstituted alkyl attached thereto, i.e., at Structure. least one of Ro and Rio is an alkyl group. Moreover, the term “alkyl (or “lower alkyl) as used 55 The term "amido' is art-recognized as an amino-Substi throughout the specification, examples, and claims is tuted carbonyl and includes a moiety that can be represented intended to include both “unsubstituted alkyls' and “substi tuted alkyls', the latter of which refers to alkyl moieties by the general formula: having Substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can 60 include, for example, a halogen, a hydroxyl, a carbonyl (Such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thiofor mate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a 65 cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a Sulfate, a wherein R. Ro areas defined above. Preferred embodiments Sulfonate, a Sulfamoyl, a Sulfonamido, a Sulfonyl, a heterocy of the amide will not include imides which may be unstable. US 7,619,005 B2 45 46 The term “aralkyl, as used herein, refers to an alkyl group clyl groups include, for example, thiophene, thianthrene, Substituted with an aryl group (e.g., an aromatic or heteroaro furan, pyran, isobenzofuran, chromene, Xanthene, phenox matic group). athiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, The term “aryl as used herein includes 5-, and 6-mem pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoin bered single-ring aromatic groups that may include from Zero dole, indole, indazole, purine, quinolizine, isoquinoline, to four heteroatoms, for example, benzene, pyrrole, furan, quinoline, phthalazine, naphthyridine, quinoxaline, quinaZo thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, line, cinnoline, pteridine, carbazole, carboline, phenanthri pyridine, pyrazine, pyridazine and pyrimidine, and the like. dine, acridine, pyrimidine, phenanthroline, phenazine, phe Those aryl groups having heteroatoms in the ring structure narsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, may also be referred to as “arylheterocycles”, “heteroaryls', 10 oxolane, thiolane, oxazole, piperidine, piperazine, morpho or "heteroaromatics.” The aromatic ring can be substituted at line, lactones, lactams such as aZetidinones and pyrrolidino one or more ring positions with Such substituents as described nes, Sultams, Sultones, and the like. The heterocyclic ring can above, for example, halogen, azide, alkyl, aralkyl, alkenyl, be substituted at one or more positions with such substituents alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, Sulfhy as described above, as for example, halogen, alkyl, aralkyl, dryl, imino, amido, phosphate, phosphonate, phosphinate, 15 alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, Sulfhy carbonyl, carboxyl, silyl ether, alkylthio, Sulfonyl, Sulfona dryl, imino, amido, phosphate, phosphonate, phosphinate, mido, ketone, aldehyde, ester, heterocyclyl, aromatic or het carbonyl, carboxyl, silyl ether, alkylthio. Sulfonyl, ketone, eroaromatic moieties, —CF, —CN, or the like. The term aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic “aryl also includes polycyclic ring systems having two or moiety, —CF, —CN, or the like. more cyclic rings in which two or more carbons are common The term “metabolites’ refers to active derivatives pro to two adjoining rings (the rings are “fused rings’) wherein at duced upon introduction of a compound into a biological least one of the rings is aromatic, e.g., the other cyclic rings milieu, Such as a patient. L-amphetamine and 1-methamphet can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or amine employed in the methods of the invention are not heterocyclyls. metabolites resulting from the administration of 1-deprenyl. The term “carbocycle' or “cyclic alkyl, as used herein, 25 The oral administration of l-amphetamine or 1-methamphet refers to an aromatic or non-aromatic ring in which each atom amine means ingestion of l-amphetamine and/or 1-metham of the ring is carbon. phetamine by the Subject (e.g., human) not a metabolite of The term "carbonyl is art-recognized and includes such anotheringested compound Such as 1-deprenyl. Humans with moieties as can be represented by the general formula: impairments in a cognitive function or memory are treated 30 with amphetamine and/or methamphetamine, wherein the amphetamine and/or methamphetamine is enantiomerically enriched for 1-amphetamine of 1-methamphetamine relative to the total content of amphetamine and/or methamphetamine in the composition, wherein the 1-amphetamine and/or 35 1-methamphetamine is not administered as 1-deprenyl or a result of the metabolism of 1-deprenyl in the human. As used herein, the term "nitro” means —NO; the term wherein X is a bond or represents an oxygen or a Sulfur, and “halogen designates —F. —Cl, Br or —I; the term “sulf R, represents a hydrogen, an alkyl, an alkenyl, -(CH) - hydryl' means —SH; the term “hydroxyl means —OH; and Rs or a pharmaceutically acceptable metal oraminergic coun 40 the term "sulfonyl” means - SO . terion, R' represents a hydrogen, an alkyl, an alkenyl or The terms “polycyclyl or “polycyclic group' refer to two —(CH) Rs, wherein Rs represents an aryl, a cycloalkyl, a or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalky cycloalkenyl, a heterocycle or a polycycle; and m is Zero oran nyls, aryls and/or heterocyclyls) in which two or more car integer in the range of 1 to 8. Where X is an oxygen and R. bons are common to two adjoining rings, e.g., the rings are or R' is not hydrogen, the formula represents an “ester. 45 “fused rings'. Rings that are joined through non-adjacent Where X is an oxygen, and R is as defined above, the moiety atoms are termed “bridged rings. Each of the rings of the is referred to herein as a carboxyl group, and particularly polycycle can be substituted with such substituents as when R is a hydrogen, the formula represents a "carboxylic described above, as for example, halogen, alkyl, aralkyl, alk acid. Where X is an oxygen, and R' is hydrogen, the for enyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, Sulfhydryl, mula represents a “formate'. In general, where the oxygen 50 imino, amido, phosphate, phosphonate, phosphinate, carbo atom of the above formula is replaced by sulfur, the formula nyl, carboxyl, silyl ether, alkylthio. Sulfonyl, ketone, alde represents a “thiocarbonyl group. Where X is a sulfur and hyde, ester, a heterocyclyl, an aromatic or heteroaromatic R or R' is not hydrogen, the formula represents a moiety, —CF, —CN, or the like. “thioester.” Where X is a sulfur and R is hydrogen, the The phrase “protecting group’ as used herein means tem formula represents a “thiocarboxylic acid.” Where X is a 55 porary Substituents which protect a potentially reactive func Sulfur and R' is hydrogen, the formula represents a “thio tional group from undesired chemical transformations. formate.” On the other hand, where X is a bond, and R is not Examples of Such protecting groups include esters of car hydrogen, the above formula represents a “ketone' group. boxylic acids, silyl ethers of alcohols, and acetals and ketals Where X is a bond, and R is hydrogen, the above formula of aldehydes and ketones, respectively. The field of protecting represents an 'aldehyde' group. 60 group chemistry has been reviewed (Greene, T. W.; Wuts, P. The term "heteroatom' as used herein means an atom of G. M. Protective Groups in Organic Synthesis, 2" ed., Wiley: any element other than carbon or hydrogen. Preferred het New York, 1991). eroatoms are nitrogen, oxygen and Sulfur. As used herein, the term “substituted” is contemplated to The terms "heterocyclyl or "heterocyclic group' refer to include all permissible Substituents of organic compounds. In 3- to 10-membered ring structures, more preferably 3- to 65 a broad aspect, the permissible Substituents include acyclic 7-membered rings, whose ring structures include one to four and cyclic, branched and unbranched, carbocyclic and het heteroatoms. Heterocycles can also be polycycles. Heterocy erocyclic, aromatic and nonaromatic Substituents of organic US 7,619,005 B2 47 48 compounds. Illustrative Substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate O. O organic compounds. For purposes of this invention, the het \/ eroatoms such as nitrogen may have hydrogen Substituents 1. YOR and/or any permissible Substituents of organic compounds described herein which satisfy the valences of the heteroat in which R is an electron pair or represents a metal or oms. This invention is not intended to be limited in any aminergic counterion, hydrogen, alkyl, cycloalkyl, or aryl. manner by the permissible Substituents of organic com 10 The terms “sulfoxido’ or “sulfinyl', as used herein, refers pounds. to a moiety that can be represented by the general formula: It will be understood that “substitution' or 'substituted with includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom O 15 and the substituent, and that the substitution results in a stable S compound, e.g., which does not spontaneously undergo 1. y transformation Such as by rearrangement, cyclization, elimi nation, etc. in which R is selected from the group consisting of hydro The term "statistically significant as used herein means gen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, that the obtained results are not likely to be due to chance or aryl. fluctuations at the specified level of probability. The two most The term "sulfonyl', as used herein, refers to a moiety that commonly specified levels of significance are 0.05 (p=0.05) can be represented by the general formula: and 0.01 (p=0.01). The level of significance equal to 0.05 and 25 0.01 means that the probability of error is 5 out of 100 and 1 out of 100, respectively. O O The term “sulfamoyl is art-recognized and includes a 1. S y moiety that can be represented by the general formula: 30 in which R is selected from the group consisting of hydro O. O gen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or \/ heteroaryl. 1N1 35 Analogous Substitutions can be made to alkenyl and alky nyl groups to produce, for example, aminoalkenyls, ami R10 noalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substi tuted alkenyls or alkynyls. in which Ro and Ro are as defined above. 40 As used herein, the definition of each expression, e.g., The term "sulfate' is art recognized and includes a moiety alkyl, m, n, etc., when it occurs more than once in any struc that can be represented by the general formula: ture, is intended to be independent of its definition elsewhere in the same structure. 45 Contemplated equivalents of the compounds described above include compounds which otherwise correspond V / thereto, and which have the same general properties thereof No1 S YOR (e.g., the ability to effect long-term memory), wherein one or more simple variations of Substituents are made which do not 50 adversely affect the efficacy of the compound. In general, the compounds of the present invention may be prepared by the in which R is an electron pair or represents a metal or methods described below, or by modifications thereof, using aminergic counterion, hydrogen, alkyl, cycloalkyl, or aryl. readily available starting materials, reagents and conven The term "sulfonamido' is art recognized and includes a tional synthesis procedures. In these reactions, it is also pos moiety that can be represented by the general formula: 55 sible to make use of variants which are in themselves known, but are not mentioned here. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Ele ments, CAS version, Handbook of Chemistry and Physics, 60 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term “hydrocarbon is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydro carbons include acyclic and cyclic, branched and in which R and R' are as defined above. 65 unbranched, carbocyclic and heterocyclic, aromatic and non The term "sulfonate' is art-recognized and includes a moi aromatic organic compounds which can be substituted or ety that can be represented by the general formula: unsubstituted. US 7,619,005 B2 49 50 Exemplary Compounds of the Invention The pharmaceutically acceptable salts of the Subject com In preferred embodiments of the invention, a compound pounds represented by Formula IX include the conventional useful in the compositions and methods described herein has non-toxic salts of the compounds, e.g., from non-toxic a structure of Formula IX: organic or inorganic acids. For example, Such conventional non-toxic salts include those derived from inorganic acids Such as hydrochloric, hydrobromic, Sulfuric, Sulfamic, phos IX phoric, nitric, and the like; and the salts prepared from organic acids such as acetic, 2-acetoxybenzoic, ascorbic, benzene Sulfonic, benzoic, chloroacetic, citric, ethane disulfonic, 10 ethane Sulfonic, formic, fumaric, gluconic, glutamic, gly colic, hydroxymaleic, isothionic, lactic, maleic, malic, meth anesulfonic, oxalic, palmitic, phenylacetic, propionic, salicy clic, Stearic, succinic, Sulfanilic, tartaric, toluenesulfonic, and the like. 15 In particular, the Sulfate salt of l-amphetamine represented wherein, as Valence and stability permit, by Formula IV (C105) and the hydrochloride salt of 1-meth R, independently for each occurrence, represents H or amphetamine represented by Formula V (SN522) are substituted or unsubstituted lower alkyl, lower alkenyl, lower employed in the methods described herein. alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or In certain embodiments. Such salts have a structure repre cycloalkylalkyl, e.g., optionally Substituted by one or more sented by the general Formula X: Substitutents such as halogen, hydroxy, alkoxy, etc.; R represents H or lower alkyl, lower alkenyl, lower alky nyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or (X) cycloalkylalkyl, e.g., optionally Substituted by one or more Substitutents such as halogen, hydroxy, alkoxy, etc.; 25 R represents H or lower alkyl, lower alkenyl, lower alky nyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally Substituted by one or more Substitutents such as halogen, hydroxy, alkoxy, etc.; R is absent, or represents from 1 to 3 substituents on the 30 ring to which it is attached, e.g., selected from halogen, hydroxy, alkoxy, amino, alkylamino, Sulfhydryl, alkylthio. wherein, as Valence and stability permit, cyano, nitro, ester, ketone, formyl, amido, acylamino, acy loxy, lower alkyl, lower alkenyl, Sulfonate ester, amidino, R. R. R. and R are defined as above; Sulfonyl, Sulfoxido, Sulfamoyl, Sulfonamido, and phospho 35 L is a non-toxic organic or inorganic acid. nate, etc. In certain embodiments, L is selected from the following In certain embodiments, at least one occurrence of R inorganic acids: hydrochloric, hydrobromic, nitric, phospho represents hydrogen. In certain embodiments, both occur ric, Sulfamic, and Sulfuric, or from the following organic rences of R represent hydrogen. In other embodiments, one acids: 2-acetoxybenzoic, ascorbic, benzene Sulfonic, ben occurrence of R represents lower alkyl, Such as methyl, 40 Zoic, chloroacetic, citric, ethane disulfonic, ethane Sulfonic, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, etc. formic, fumaric, gluconic, glutamic, glycolic, hydroxyma leic, isothionic, lactic, maleic, malic, methanesulfonic, In certain embodiments, R represents hydrogen, while in oxalic, palmitic, phenylacetic, propionic, Salicyclic, Stearic, other embodiments, R represents lower alkyl, Such as Succinic, Sulfanilic, tartaric, and toluenesulfonic. methyl, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, 45 etc. The compounds of the present invention further include In certain embodiments, R represents hydrogen, while in metabolites of the Subject amphetamine compounds, other embodiments, R represents lower alkyl, such as included but not limited to the following: p-hydroxyamphet methyl, ethyl, propyl, isopropyl. n-butyl, isobutyl, t-butyl, amine, benzyl methyl ketone, l-phenylpropan-2-ol, benzoic acid, glycine, hippuric acid, p-hydroxynorephedrine, and etc., hydroxy, amino, or carbonyl. 50 N-hydroxylamphetamine. In certain embodiments, Ra represents hydrogen, while in other embodiments, Ra represents from 1 to 3 substituents on In certain embodiments, these metabolites have a structure the ring to which it is attached selected from halogen, represented by the general Formula XI: hydroxy, amino, Sulfhydryl, cyano, nitro, and lower alkyl. In certain embodiments, R represents hydrogen and at 55 (XI) least one of R. R. and R represents hydrogen. In certain Rs R R embodiments, R is absent and at least two of R, R2, and R N NN1 represent hydrogen. In certain embodiments, Ra represents hydrogen and at least three of R, R2, and R represent hydro A4 R gen. In certain embodiments, R represents hydrogen and all 60 R4 four of R, R2, and R represent hydrogen. R3 Rs As set out above, certain embodiments of compounds of Formula IX may contain a basic functional group, Such as amino or alkylamino, and thus, can be utilized in a free base wherein, as Valence and stability permit, form or as pharmaceutically acceptable salt forms derived 65 R, independently for each occurrence, represents hydro from pharmaceutically acceptable organic and inorganic gen or substituted or unsubstituted lower alkyl, lower alkenyl, acids. lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, US 7,619,005 B2 51 52 cycloalkyl, or cycloalkylalkyl, e.g., optionally Substituted by ergic receptor antagonists. In addition, the compounds of the one or more Substitutents such as halogen, hydroxy, alkoxy, invention may be useful in enhancing cognition or memory in etc., normal individuals. R represents hydrogen or lower alkyl, lower alkenyl, The present invention also relates to treatment with at least lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, one member selected from the group consisting of l-amphet cycloalkyl, or cycloalkylalkyl, e.g., optionally Substituted by amine, 1-methamphetamine, 1-threo-methylphenidate, one or more Substitutents such as halogen, hydroxy, alkoxy, d-threo-methylphenidate, methylphenidate, atomoxetine etc., (also referred to as STRATTERAR or tomoxetine) and R represents hydrogen or lower alkyl, lower alkenyl, modafinil (also referred to as PROVIGIL(R) to improve cog lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, 10 nitive and memory processes in individuals exposed to a cycloalkyl, or cycloalkylalkyl, e.g., optionally Substituted by muscarinic cholinergic receptor antagonist. one or more Substitutents such as halogen, hydroxy, alkoxy, As described herein, levo-amphetamine and levo-metham etc., phetamine have been demonstrated to reduced impairment in R represents from 1 to 3 substituents on the ring to which memory that is a consequence of exposure to a muscarinic it is attached, e.g., selected from hydrogen, halogen, hydroxy, 15 cholinergic receptor antagonist. Specifically, levo-amphet alkoxy, amino, alkylamino, Sulfhydryl, alkylthio, cyano, amine or levo-methamphetamine improves memory in rats nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower that have an impairment in the ability to form new long term alkyl, lower alkenyl, Sulfonate ester, amidino, Sulfonyl, Sul memory as a consequence of exposure to a muscarinic cho foxido, Sulfamoyl, Sulfonamido, and phosphonate, etc.; linergic receptor antagonist. The ability to form new long Rs independently for each occurrence, represents hydro term memory is the process of memory consolidation (“Neu gen or hydroxy. roscience: Exploring The Brain. Bear, M. F. et al., Williams & Wilkins, Baltimore, Md., Ch. 19, pp. 517-545 (1996): In certain embodiments, the method includes administer McGaugh, J. L. Science 287: 248-251 (2000)). ing, conjointly with the pharmaceutical preparation, one or A human individual can have an impairment in cognitive more of a neuronal growth factor, a neuronal Survival factor, 25 and memory processes as a consequence of exposure to a and a neuronal trophic factor. Additionally or alternatively, a muscarinic cholinergic receptor antagonist (agents or drugs). Subject compound may be administered in conjunction with a An embodiment of the invention includes a method of reduc cholinergic, adrenergic, noradrenergic, dopaminergic, ingapotential impairment in memory or cognition in a human glutaminergic or other modulators. Other agents directed at who will be exposed to a muscarinic cholinergic receptor modulating GABA, NMDA, cannabinoid, AMPA, kainate, 30 antagonist. A "potential impairment in memory or cogni phosphodiesterase (PDE), PKA, PKC, CREB or nootropic tion, as used herein, refers to a possible effect of the musca systems may be important to the improvement of cognitive rinic cholinergic receptor antagonist in the human which function and may be administered in conjunction with a Sub results in a diminished capacity in memory or cognition in the ject compound. human as a consequence of exposure to the muscarinic cho An agent to be administered conjointly with a Subject com 35 linergic receptor. pound may be formulated together with a subject compound In one embodiment, the invention includes a method of as a single pharmaceutical preparation, e.g., as a pill or other treating a human, comprising administering to the human at medicament including both agents, or may be administered as least one member selected from the group consisting of 1-am a separate pharmaceutical preparation. phetamine, 1-methamphetamine, 1-threo-methylphenidate, In another aspect, the present invention provides pharma 40 d-threo-methylphenidate, methylphenidate, atomoxetine and ceutical preparations comprising, as an active ingredient modafinil at one or more points in time selected from the amphetamine or a derivative thereof. The subject amphet group consisting of before, concomitantly with and Subse amine compound is formulated in an amount Sufficient to quent to a memory and/or cognitive impairment that is a improve LTP in an animal. The Subject preparations and consequence of exposure of the human to a muscarinic cho methods can be treatments using amphetamine compounds 45 linergic receptor antagonist, whereby the memory and/or effective for human and/or animal subjects. In addition to cognitive impairment is at least partially attenuated. humans, other animal Subjects to which the invention is appli The amphetamine (e.g., 1-amphetamine, d-amphetamine, cable extend to both domestic animals and livestock, raised 1-methamphetamine, d-methamphetamine or any combina eitheras pets or for commercial purposes. Examples are dogs, tion thereof), threo-methylphenidate (e.g., d-threo-meth cats, cattle, horses, sheep, hogs, and goats. 50 ylphenidate, l-threo-methylphenidate, or any combination Still another aspect of the invention relates to the use of therof), methylphenidate, atomoxetine and modofinil are amphetamine compounds for lessening the severity or pro referred to herein, with respect to the methods of treating as a phylactically preventing the occurrence of cognitive, learning consequence of exposure of a human to a muscarinic cholin and/or memory defects in an animal, and thus, altering the ergic receptor antagonist, as "compounds.” “compounds of cognitive, learning ability and/or memory capacity of the 55 the invention,” or “compounds employed in the methods.” animal. As a result, the compounds of the present invention “Before exposure to the muscarinic cholinergic receptor may be useful for treating and/or preventing cognitive or antagonist, as used herein, refers to the administration of at memory impairment, e.g., due to toxicant exposure, brain least one member selected from the group consisting of 1-am injury, brain aneurysm, age-associated memory impairment, phetamine, 1-methamphetamine, 1-threo-methylphenidate, mild cognitive impairment, epilepsy, Multiple Sclerosis, age 60 d-threo-methylphenidate, methylphenidate, atomoxetine and associated memory impairment, Mild Cognitive Impairment, modafinil at a time (e.g., minutes, hours, days, weeks, mental retardation in children, and dementia resulting from a months) preceding exposure of the individual to the muscar disease, such as Parkinson's disease, Alzheimer's disease, inic cholinergic receptor antagonist. “Prior to is used inter AIDS, head trauma, Huntington's disease, Pick's disease, changeably with “before.” For example, at least one member Creutzfeldt-Jakob disease, Anterior Communicating Artery 65 selected from the group consisting of l-amphetamine, 1-meth Syndrome, hypoxia, postcardiac Surgery, Downs Syndrome, amphetamine, 1-threo-methylphenidate, d-threo-meth stroke, as a consequence of exposure to muscarinic cholin ylphenidate, methylphenidate, atomoxetine and modafinil US 7,619,005 B2 53 54 can be administered hours (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9. Subsequent to a memory and/or cognitive impairment that is 10 or 12 hours), days (e.g., about 1, 2, 3, 4, 5, 6, 7 days) or a consequence of exposure of the human to a muscarinic weeks (e.g., 1, 2, 3, 4, 5, 6, 7, 8 weeks) before the individual cholinergic receptor antagonist. "Subsequent to as used being exposed to the muscarinic cholinergic receptor antago herein, refers to the administration of at least one member nist. selected from the group consisting of l-amphetamine, 1-meth In another embodiment, at least one member selected from amphetamine, 1-threo-methylphenidate, d-threo-meth the group consisting of l-amphetamine, 1-methamphetamine, ylphenidate, methylphenidate, atomoxetine and modafinil to 1-threo-methylphenidate, d-threo-methylphenidate, meth the human after the human is exposed to the muscarinic ylphenidate, atomoxetine and modafinil can be administered cholinergic receptor antagonist. For example, at least one concomitantly (also referred to herein as “at about the same 10 member selected from the group consisting of l-amphet point in time' or “during) with exposure of the human to a amine, 1-methamphetamine, 1-threo-methylphenidate, muscarinic cholinergic receptor antagonist. d-threo-methylphenidate, methylphenidate, atomoxetine and “Concomitantly, as used herein, refers to the simultaneous modafinil can be administered hours (e.g., about 1, 2, 3, 4, 5, or sequential administration of at least one member selected 6, 7, 8, 9, 10 or 12 hours), days (e.g., about 1, 2, 3, 4, 5, 6, 7 from the group consisting of l-amphetamine, 1-methamphet 15 days), weeks (e.g., about 1, 2, 3, 4, 5, 6, 7, 8 weeks), months amine, l-threo-methylphenidate, d-threo-methylphenidate, (e.g., about 1,2,3,4,5,6,7,8,9, 10, 11 months) or years (e.g., methylphenidate, atomoxetine and modafinil to the human about 1, 2, 3, 4, 5 years) Subsequent to exposure of the indi and exposure of the human to the muscarinic cholinergic vidual to the muscarinic cholinergic receptor antagonist. receptor antagonist. Concomitant administration of at least The amphetamine of the invention can be administered to a one member selected from the group consisting of l-amphet individual acutely (briefly or short-term) or chronically (pro amine, 1-methamphetamine, l-threo-methylphenidate, longed or long-term) before, concomitantly with or Subse d-threo-methylphenidate, methylphenidate, atomoxetine and quent to exposure of the individual to a muscarinic cholin modafinil and exposure to the muscarinic cholinergic recep ergic receptor antagonist. tor antagonist can occur by administering a single formula The compounds employed in the methods of the invention tion, which contains both at least one member selected from 25 can be administered before, concomitantly with, Subsequent the group consisting of l-amphetamine, 1-methamphetamine, to or any combination thereof (e.g., before; before and con 1-threo-methylphenidate, d-threo-methylphenidate, meth comitantly with; concomitantly with; concomitantly with and ylphenidate, atomoxetine and modafinil; and the muscarinic Subsequent to; before and Subsequent to; Subsequent to) of the cholinergic receptor antagonist, to the human. The single human to exposure of the muscarinic cholinergic receptor formulation results in simultaneous administration of at least 30 antagonist. one member selected from the group consisting of l-amphet amine, 1-methamphetamine, l-threo-methylphenidate, Administration of at least one member selected from the d-threo-methylphenidate, methylphenidate, atomoxetine and group consisting of 1-amphetamine, 1-methamphetamine, modafinil; and exposure to the muscarinic cholinergic recep 1-threo-methylphenidate, d-threo-methylphenidate, meth tor antagonist. 35 ylphenidate, atomoxetine and modafinil to the human before, Additionally, or alternatively, at least one member selected concomitantly with and/or Subsequent to a memory and/or from the group consisting of l-amphetamine, 1-methamphet cognition impairment that is a consequence of exposure to the amine, l-threo-methylphenidate, d-threo-methylphenidate, muscarinic cholinergic receptor antagonist can prevent, methylphenidate, atomoxetine and modafinil can be admin reduce or at least partially attenuate the impairment that can istered concomitantly to the human by sequential administra 40 occur as a consequence of Subsequent exposure to a muscar tion of a formulation of at least one member selected from the inic cholinergic receptor antagonist. At least partially attenu group consisting of 1-amphetamine, 1-methamphetamine, ated as used herein, refers to any decrease or diminution in 1-threo-methylphenidate, d-threo-methylphenidate, meth the severity, amount or intensity of the memory and/or cog nitive impairment in the human exposed to a muscarinic ylphenidate, atomoxetine and modafinil and a separate for cholinergic receptor antagonist, as a consequence of admin mulation of the muscarinic cholinergic receptor antagonist. 45 Both the formulation of at least one member selected from istration of the compounds. the group consisting of l-amphetamine, 1-methamphetamine, Exposure to the muscarinic cholinergic receptorantagonist 1-threo-methylphenidate, d-threo-methylphenidate, meth can be intentional exposure or unintentional exposure. Inten ylphenidate, atomoxetine and modafinil and the separate tional exposure can be by administration (e.g., self adminis muscarinic cholinergic receptor antagonist formulation are 50 tration) of a muscarinic cholinergic receptor antagonist to an concomitantly administered to the human by sequential individual. For example, intentional exposure of an indi administration. The sequential administration can be the vidual can be administered through the application (e.g., administration of at least one member selected from the group transdermal), injection (e.g., intramuscular, intravenous) or consisting of 1-amphetamine, 1-methamphetamine, l-threo ingestion (e.g., oral) of a muscarinic cholinergic receptor methylphenidate, d-threo-methylphenidate, methylpheni 55 antagonist (e.g., Scopolamine, atropine) to the individual. date, atomoxetine and modafinil followed by exposure to the Unintentional exposure of the individual to a muscarinic cho muscarinic cholinergic receptor antagonist at about the same linergic receptor antagonist can be by any route of exposure time; or exposure to the muscarinic cholinergic receptor other than intentional exposure. For example, unintentional antagonist followed by the administration of at least one exposure of an individual can result from environmental or member selected from the group consisting of l-amphet 60 airborne exposure to a muscarinic cholinergic receptor amine, 1-methamphetamine, l-threo-methylphenidate, antagonist. d-threo-methylphenidate, methylphenidate, atomoxetine and In one embodiment, the muscarinic cholinergic receptor modafinil to the human at about the same time. antagonist is an exogenous (originating or produced outside In yet another embodiment, at least one member selected of the individual) muscarinic cholinergic receptor antagonist. from the group consisting of l-amphetamine, 1-methamphet 65 In another embodiment, the muscarinic cholinergic receptor amine, l-threo-methylphenidate, d-threo-methylphenidate, antagonist is an endogenous (originating or produced inside methylphenidate, atomoxetine and modafinil is administered the individual) muscarinic cholinergic receptor antagonist. US 7,619,005 B2 55 56 In another embodiment, the invention includes a method of ylphenidate, methylphenidate, atomoxetine and modafinil is treating a human for memory impairment, comprising admin assessed or determined by a word recall test such as RAVLT. istering to the human at least one member selected from the A muscarinic cholinergic receptor antagonist includes any group consisting of 1-amphetamine, 1-methamphetamine, Substance which blocks, diminishes, attenuates, inhibits, hin 1-threo-methylphenidate, d-threo-methylphenidate, meth ders, limits, decreases, reduces, restricts or interferes with the ylphenidate, atomoxetine and modafinil at one or more points action of acetylcholine (ACh) thereby disrupting ACh-medi in time selected from the group consisting of before, con ated cell signaling between presynaptic and postsynaptic neu comitantly with and Subsequent to exposure of the human to rons. The antagonist can, for example, oppose the action of a muscarinic cholinergic receptor antagonist, whereby the ACh by acting in a manner which prevents ACh from binding memory impairment consequent to the exposure to the mus 10 to a muscarinic receptorona postsynaptic neuron, from medi carinic cholinergic receptor antagonist is at least partially ating post-synaptic, events following binding of ACh to a attenuated. muscarinic receptor, interfere with ACh degradation by In yet another embodiment, the invention includes a acetycholinesterase in the synaptic cleft or interfere with method of treating a human for cognitive impairment, com release of ACh from presynaptic neurons. For example, inter prising administering to the human at least one member 15 action of the muscarinic cholinergic receptor with an ACh selected from the group consisting of l-amphetamine, 1-meth receptor can prevent ACh from activating a G protein on amphetamine, 1-threo-methylphenidate, d-threo-meth post-synaptic neurons which in turn can prevent activation of ylphenidate, methylphenidate, atomoxetine and modafinil at phospholipase C (PLC) and the subsequent generation of the one or more points in time selected from the group consisting second messengers diacylglycerol (DAG) and inositol 1,4,5- of before, concomitantly with and Subsequent to exposure of triphosphate (IP). Failure to generate intracellular DAG can the human to a muscarinic cholinergic receptor antagonist, prevent activation of protein kinase C (PKC) which can dis whereby the cognitive impairment consequent to the expo rupt Subsequent cellular events such as phosphorylation of Sure to the muscarinic cholinergic receptor antagonist is at Substrates implicated in the formation of memory. Likewise, least partially attenuated. failure to generate IP can prevent a mobilization of calcium The cognitive and/or memory processes and impairments 25 from internal stores which can disrupt Subsequent cellular in cognitive and/or memory processes can be assessed or events such as long-term potentiation (LTP), which may be a determined by established techniques. For example, memory cellular mechanism of memory (Malenka, R. C., Science can be assessed before, concomitantly with or after treatment 285:1870-1874 (1999)). of the individual with at least one member selected from the Additionally, or alternatively, a muscarinic cholinergic group consisting of 1-amphetamine, 1-methamphetamine, 30 receptor antagonist can prevent ACh from activating GC, 1-threo-methylphenidate, d-threo-methylphenidate, meth protein on presynaptic neurons which in turn can lead to ylphenidate, atomoxetine and modafinil by one or more well increased levels of cAMP by preventing inhibition of adenyl established tests known to one of skill in the art. Such tests cyclase. Increased cAMP levels can lead to activation of include the Rey Auditory Verbal Learning Test (RAVLT): cyclic-AMP-dependent protein kinase A (PKA) which can Cambridge Neuropsychological Test Automated Battery 35 modulate Subsequent cellular events such as phosphorylation (CANTAB); a Children's Memory Scale (CMS); a Contex of alpha-amino-3-hydroxy-5-methylisoxazoleproprionic tual Memory Test; a Continuous Recognition Memory Test acid (AMPA) receptors and the regulation of LTP. Phospho (CMRT); a Denman Neuropsychology Memory Scale; a Fuld rylation of AMPA receptors can increase the inflow of sodium Object Memory Evaluation (FOME); a Graham-Kendall (Na) ions thereby increasing the cell depolarization and/or Memory for Designs Test; a Guild Memory Test; a Learning 40 increasing the number of AMPA receptors at the synapse. and Memory Battery (LAMB); a Memory Assessment Clinic It is envisioned that the muscarinic cholinergic receptor Self-Rating Scale (MAC-S); a Memory Assessment Scales antagonists can oppose the action of ACh in any one or more (MAS); a Randt Memory Test; a Recognition Memory Test of the above-referenced manners. A muscarinic cholinergic (RMT): a Rivermead Behavioral Memory Test; a Russell's receptor antagonist is also referred to as a muscarinic cholin Version of the Wechsler Memory Scale (RWMS); a Test of 45 ergic antagonist. Memory and Learning (TOMAL); a Vermont Memory Scale As a consequence of exposure to a muscarinic cholinergic (VMS); a Wechsler Memory Scale; a Wide Range Assess receptor antagonist, the individual can have deficiencies or ment of Memory and Learning (WRAML); First-LastName disruptions in signaling pathways which can lead to impair Association (Youngjohn J. R., et al., Archives of Clinical ments in cognitive and memory processes. As a consequence Neuropsychology 6:287-300 (1991)): Name-Face Associa 50 of muscarinic cholinergic receptorantagonist’ as used herein, tion: Wechsler Memory Scale-Revised (Wechsler, D., Wech refers to an impairment in cognition and/or memory pro sler Memory Scale-Revised Manual, NY, N.Y., The Psycho cesses that follows exposure of an individual to a muscarinic logical Corp. (1987)); California Verbal Learning Test cholinergic receptor antagonist. Second Edition (Delis, D.C., et al., The Californian Verbal In one embodiment, the individual (also referred to herein Learning Test, Second Edition, Adult Version, Manual, San 55 as a “subject) can have an impairment in memory. The Antonio, Tex.: The Psychological Corporation (2000)); impairment in memory can be an impairment in memory Facial Recognition (delayed non-matching to sample); Cog consolidation, the process of storing new information in long nitive Drug Research (CDR) Computerized Assessment Bat term memory (“Neuroscience: Exploring The Brain. Bear, tery-Wesnes; Buschke’s Selective Reminder Test (Buschke, M. F. et al., Williams & Wilkins, Baltimore, Md., Ch. 19, pp. H., et al., Neurology 24: 1019-1025 (1974)); Telephone Dial 60 517-545 (1996): McGaugh, J. L. Science 287: 248-251 ing Test; Brief Visuospatial Memory Test-Revised; and Test (2000)). Alternatively, or additionally, the impairment in of Everyday Attention (Perry, R. J., et al., Neuropsychologia memory can be an impairment in short-term memory or an 38: 252-271 (2000)). impairment in working memory. Short-term memory and In a particular embodiment, the memory of the human working memory are processes whereby newly acquired before, during or after administration of at least one member 65 information is maintained for short periods of time and the selected from the group consisting of l-amphetamine, 1-meth newly acquired information is made available for further amphetamine, 1-threo-methylphenidate, d-threo-meth information processing (“Neuroscience: Exploring The US 7,619,005 B2 57 58 Brain. Bear, M. F. et al., Williams & Wilkins, Baltimore, attenuated, reversed, prevented or reduced by treatment with Md., Ch. 19, pp. 517-545 (1996): McGaugh, J. L. Science at least one member selected from the group consisting of 287: 248-251 (2000); Becker, J.T., et al., Brain and Cognition 1-amphetamine, 1-methamphetamine, l-threo-methylpheni 41:1-8 (1999)). date, d-threo-methylphenidate, methylphenidate, atomoxet The impairment in memory can also be an impairment in 5 ine and modafinil. declarative memory, which is the memory of facts and events The term “threo-methylphenidate, such as is used when (“Neuroscience: Exploring The Brain. Bear, M. F. et al., referring to “l-threo-methylphenidate' and “d-threo-meth Williams & Wilkins, Baltimore, Md., Ch. 19, pp. 517-545 ylphenidate means a compound represented by Formula (1996): McGaugh, J. L. Science 287: 248-251 (2000); Tulv XII, including its salts, acids, esters, amides, carbamates, ing, E., et al., Science 247: 301-306 (1990); Squire, L. R., et 10 Schiff bases, prodrugs and other structural and functional al., Proc. Natl. Acad. Sci. 93: 13515-13522 (1996)). The derivatives thereof. In a preferred embodiment, the threo impairment in memory can also be an impairment in proce methylphenidate is the compound represented by Formula dural memory (also referred to as “tacit knowledge” or XII including salts, acids, esters, amides, carbamates and “implicit knowledge'), which is the memory for skills or Schiff bases. In another preferred embodiment, the threo behavior (“Neuroscience: Exploring The Brain. Bear, M. F. 15 methylphenidate is the compound represented by Formula et al., Williams & Wilkins, Baltimore, Md., Ch. 19, pp. 517 XII, including its salts and acids. In still another preferred 545 (1996): McGaugh, J. L. Science 287: 248-251 (2000)). embodiment, the threo-methylphenidate is the compound The impairment can also be an impairment in attention, represented by Formula XII: acquisition, retrieval or retention. One of skill in the art would be capable of identifying and evaluating the impairment in XII memory in the individual. In a particular embodiment, at least one member selected from the group consisting of l-amphetamine, 1-methamphet amine, l-threo-methylphenidate, d-threo-methylphenidate, OMe methylphenidate, atomoxetine and modafinil is administered 25 to a human having an impairment in memory consolidation as a consequence of exposure to a muscarinic cholinergic recep tor antagonist. In another embodiment, the individual can have an impair ment in a cognitive process (Carlson, N. R., Physiology of 30 The dextro enantiomer of threo-methylphenidate is Behavior, Allyn and Bacon, Boston, Mass. (1986); Cognition referred to as the d, (+), or D enantiomer and is represented by on Cognition, eds., Mehler, J. et al., Bradford Books (1995)). the following structural formula: The impairment in a cognitive process can be an impairment in attention, which is the capacity or process of selecting out XIII of the totality of available sensory or affective stimuli, those 35 stimuli that are most appropriate or desirable for focus at a given time (Kinchla, R. A., et al., Annu. Rev. Psychol. 43: 711-742 (1992)). The impairment in a cognitive process can OMe be an impairment in executive function, which are neuropsy chological functions such as decision making, planning, ini 40 tiative, assigning priority, sequencing, motor control, emo tional regulation, inhibition, problem solving, planning, impulse control, establishing goals, monitoring results of action and self-correcting (Elliott, R., Br: Med. Bull. 65:49-59 The levo enantiomer of threo-methylphenidate is referred (2003)). The cognitive impairment can be an impairment in 45 to as the 1, (-), or Lenantiomer and is represented by the alertness, wakefulness, arousal, vigilance, reaction time, following structural formula: attention, information processing, conceptualization, and verbal fluency. One of skill in the art would be capable of XIV identifying and evaluating the impairment in cognition in the individual. 50 In an embodiment of the invention, the impairment in memory or cognition in an individual is a consequence of exposure to scopolamine (also referred to hereinas hyoscine). In another embodiment, the impairment in memory or cog nition can be a consequence of exposure to atropine. In yet 55 another embodiment, the impairment in memory or cognition in an individual is a consequence of exposure to homatropine. In still another embodiment, the muscarinic cholinergic Racemic mixtures of d-threo-methylphenidate and 1-threo receptor antagonist is trihexyphenidyl. Muscarinic cholin methylphenidate are referred to as d.l. (+,-), (t), or DL. ergic receptor antagonism by, for example, Scopolamine, 60 The term “methylphenidate.” as used herein, means a com atropine, homatropine and trihexyphenidyl can result in an pound represented by Formula XV, including its salts, acids, impairment in memory (impairment in memory consolida esters, amides, carbamates, Schiffbases, prodrugs and other tion, impairment in short term memory, impairment in work structural and functional derivatives thereof. In a preferred ing memory) and/or cognition (e.g., alertness, executive func embodiment, methylphenidate is the compound represented tion, arousal, wakefulness, attention, Vigilance, reaction time, 65 by Formula XV including salts, acids, esters, amides, car information processing, conceptualization, problem solving bamates and Schiff bases. In another preferred embodiment, and verbal fluency) that can be ameliorated, diminished, methylphenidate is the compound represented by Formula US 7,619,005 B2 59 60 XV, including its salts and acids. In still another preferred a consequence of exposure to a muscarinic cholinergic recep embodiment, methylphenidate is the compound represented tor antagonist can comprise at least about 51 percent (w/w by Formula XV: (weight/weight) or mole percent), about 60 percent (w/w or mole percent), about 70 percent (w/w or mole percent), about 75 percent (w/w or mole percent), about 80 percent (w/w or mole percent), about 85 percent (w/w or mole percent), about 90 percent (w/w or mole percent), about 95 percent (w/w or mole percent), or about 99 percent (w/w or mole percent) of one enantiomer relative to another enantiomer (e.g., 1-am 10 phetamine relative to d-amphetamine; or 1-threo-meth OCH ylphenidate to d-threo-methylphenidate). For example, an amphetamine compound employed in the methods of the invention can be 1-amphetamine, wherein the 1-amphetamine is administered as a component of a composition that includes 15 at least about 80 percent (w/w or mole percent) 1-amphet amine or 1-methamphetamine relative to a total amphetamine The term "atomoxetine, as used herein, means a com or methamphetamine, respectively, content of the composi pound represented by Formula XVI, including its salts, acids, tion. Likewise, a threo-methylphenidate compound esters, amides, carbamates, Schiffbases, prodrugs and other employed in the methods of the invention can be 1-threo structural and functional derivatives thereof. In a preferred methylphenidate, wherein the 1-threo-methylphenidate is embodiment, atomoxetine is the compound represented by administered as a component of a composition that includes Formula XVI including salts, acids, esters, amides, carbam at least about 80 percent (w/w or mole percent) l-threo-me ates and Schiffbases. In another preferred embodiment, ato thylphenidate relative to a total threo-methylphenidate con moxetine is the compound represented by Formula XVI, tent of the composition. including its salts and acids. In still another preferred embodi 25 In another embodiment, the amphetamine, threo-meth ment, atomoxetine is the compound represented by Formula ylphenidate and methylphenidate compounds employed are XVI: about 100 percent (w/w or mole percent) 1-amphetamine rela tive to d-amphetamine; or 1-threo-methylphenidate relative to XVI d-threo-methylphenidate is about 100 percent (w/w or mole 30 percent). An amphetamine or threo-methylphenidate com pound that is “about 100 percent 1-amphetamine, 1-metham phetamine or 1-threo-methylphenidate is a composition that includes about 100 percent (w/w or mole percent) 1-amphet amine, 1-methamphetamine or 1-threo-methylphenidate rela 35 tive to a total content of the composition. An amphetamine or threo-methylphenidate compound that is “about 100 percent can have insignificant traces of other components, such as d-amphetamine, d-threo-methylphenidate. Atomoxetine and modafinil can beat least about 51 percent 40 (w/w (weight/weight) or mole percent), about 60 percent (w/w or mole percent), about 70 percent (w/w or mole per The term “modafinil, as used herein, means a compound cent), about 75 percent (w/w or mole percent), about 80 represented by Formula XVII, including its salts, acids, percent (w/w or mole percent), about 85 percent (w/w or mole esters, amides, carbamates, Schiffbases, prodrugs and other percent), about 90 percent (w/w or mole percent), about 95 structural and functional derivatives thereof. In a preferred 45 percent (w/w or mole percent), or about 99 percent (w/w or embodiment, modafinil is the compound represented by For mole percent) of the total composition administered to the mula XVII including salts, acids, esters, amides, carbamates individual. and Schiffbases. In another preferred embodiment, modafinil In yet another embodiment, the atomoxetine and modafinil is the compound represented by Formula XVII, including its employed in the methods of the invention are about 100 50 percent (w/w or mole percent) atomoxetine or about 100 salts and acids. In still another preferred embodiment, percent (w/w or more percent) modafinil. Anatomoxetine or modafinil is the compound represented by Formula XVII: modafinil that is “about 100 percent atomoxetine or modafi nil can contain insignificant trace amounts of other com XVII pounds. 55 The compounds employed in the methods of the invention O O can be the free base or can exist as salts with pharmaceutically S acceptable acids. Examples of Such salts include hydrochlo NH2 rides, hydrobromides, Sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tar 60 trates, (-)-tartrates or mixtures thereof including racemic mixtures). Succinates, benzoates and salts with amino acids Such as glutamic acid. In another embodiment, the compounds employed in the methods can be a percent of the total composition adminis The amphetamine, threo-methylphenidate and meth 65 tered to the human. The amphetamine, threo-methylpheni ylphenidate, compounds employed in methods of treating a date, methylphenidate, atomoxetine and/or modafinil compo human having an impairment in memory and/or cognition as nent of the composition can be about 50 percent (w/w), about US 7,619,005 B2 61 62 60 percent (w/w), about 75 percent (w/w), about 80 percent quent to the memory and/or cognitive impairment that is a (w/w), about 85 percent (w/w), about 90 percent (w/w), about consequence of exposure to the muscarinic cholinergic recep 95 percent (w/w) and about 100 percent (w/w) of the total tor antagonist. For example, a human undergoing treatment composition administered to the human. For example, the with atropine in anticipation of a nerve gas attack or to coun human can be administered a composition which comprises teract the effects of nerve gas exposure can be treated with at about 80 weight or volume percent amphetamine and/or least one member selected from the group consisting of 1-am threo-methylphenidate and about 20 weight or volume per phetamine, 1-methamphetamine, 1-threo-methylphenidate, cent, respectively, of an inert excipient. Likewise, the human d-threo-methylphenidate, methylphenidate, atomoxetine and can be administered a composition which comprises about 80 modafinil, concomitantly with or Subsequent to exposure of weight or Volume percent modafinil and/or atomoxetine and 10 the human to the atropine to prevent, minimize, alleviate or about 20 weight or volume percent, respectively, of an inert improve an impairment in memory or cognition as a conse excipient. Similarly, the human can be administered a com quence of exposure to the atropine. position which comprises about 80 weight or volume percent The compounds employed in the methods of the invention of an amphetamine, a threo-methylphenidate, a methylpheni can be administered as a single dose or as multiple doses. date, atomoxetine and/or modafinil and about 20 weight or 15 Additional doses of the compounds of the invention can be Volume percent, respectively, of an inert excipient. administered to the human, as needed, to improve cognition Another embodiment of the invention relates to assessing and/or memory or to Sustain an improvement in cognition the degree of impairment in cognitive and/or memory pro and/or memory. Cognition and/or memory can be assessed cesses in a human having an impairment in a cognitive and/or and determined before, concomitantly with or after treatment memory process as a consequence of exposure to a muscar with the compounds to determine the progress of improve inic cholinergic receptor antagonist. The improvement in ment in memory and the need for further doses. cognitive or memory processes after administering at least In one embodiment of the methods of the invention, the one member selected from the group consisting of l-amphet compound(s) employed in the methods of the invention (e.g., amine, 1-methamphetamine, l-threo-methylphenidate, 1-amphetamine, 1-methamphetamine, l-threo-methylpheni d-threo-methylphenidate, methylphenidate, atomoxetine and 25 date, d-threo-methylphenidate, methylphenidate, atomoxet modafinil to the human can be determined at one or more time ine and modafinil) is administered as a single oral dosage points following administration of at least one member formulation of at least about 2.5 mg to about 25 mg, about 50 selected from the group consisting of l-amphetamine, 1-meth mg, about 75 mg, about 100 mg or about 125 mg of the amphetamine, 1-threo-methylphenidate, d-threo-meth compound (e.g., 1-amphetamine, C105, 1-methamphetamine, ylphenidate, methylphenidate, atomoxetine and modafinil. 30 SN522, SN522-HCl, 1-threo-methylphenidate, d-threo-meth The method can further include comparing the impairment ylphenidate, methylphenidate, atomoxetine and modafinil) in memory or cognition in the human before administering at and a pharmaceutically acceptable carrier. least one member selected from the group consisting of 1-am In another embodiment, the single dosage formulation is at phetamine, 1-methamphetamine, l-threo-methylphenidate, least about 0.001 mg, about 0.01 mg, about 0.1 mg, about 1 d-threo-methylphenidate, methylphenidate, atomoxetine and 35 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg. modafinil to the improvement in memory in the human after about 20 mg, about 25 mg, about 30 mg, about 35 mg, about administering the compound. 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg. In a particular embodiment, memory is assessed prior to about 75 mg, about 80 mg, about 85 mg, about 90 mg, about administration of the at least one member selected from the 95 mg, about 100 mg, about 125 mg, about 150 mg, about 200 group consisting of 1-amphetamine, 1-methamphetamine, 40 mg, about 300 mg, about 400 mg, about 500 mg, about 750 1-threo-methylphenidate, d-threo-methylphenidate, meth mg, or about 1000 mg of the compound (e.g., 1-amphetamine, ylphenidate, atomoxetine and modafinil and determined after C105,1-methamphetamine, SN522, SN522-HCl, 1-threo-me administration of at least one member selected from the group thylphenidate, d-threo-methylphenidate, methylphenidate, consisting of 1-amphetamine, 1-methamphetamine, l-threo atomoxetine and modafinil). methylphenidate, d-threo-methylphenidate, methylpheni 45 In still another embodiment, the methods of the invention date, atomoxetine and modafinil by a word recall test Such as employ multiple doses of the compound (e.g., 1-amphet RAVLT (Rey, A. (1941). Lexamen psychologique dans les amine, C105, 1-methamphetamine, SN522, SN522-HCl, cas d’encephalopathie traumatique. Archives de Psychologie, 1-threo-methylphenidate, d-threo-methylphenidate, meth 28, 21, Lezak, M.D. (1995). Neuropsychological Assessment ylphenidate, atomoxetine and modafinil). Each dose of the (3rd ed.). New York: Oxford University Press). 50 multiple dose is at least about 0.001 mg, about 0.01 mg, about In yet another embodiment, the invention is a method of 0.1 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg. improving an impaired memory and/or cognition in a human. about 15 mg, about 20 mg, about 25 mg, about 30 mg, about A human is exposed to a muscarinic cholinergic receptor 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg. antagonist and, as a consequence of exposure to the muscar about 60 mg, about 75 mg, about 80 mg, about 85 mg, about inic cholinergic receptorantagonist, the human has an impair 55 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 ment in memory or cognition. The human with an impaired mg, about 200 mg, about 300 mg, about 400 mg, about 500 memory or impaired cognition is administered at least one mg, about 750 mg or about 1000 mg of the compound (e.g., member selected from the group consisting of l-amphet 1-amphetamine, C105, 1-methamphetamine, SN522, SN522 amine, 1-methamphetamine, l-threo-methylphenidate, HCl, 1-threo-methylphenidate, d-threo-methylphenidate, d-threo-methylphenidate, methylphenidate, atomoxetine and 60 methylphenidate, atomoxetine and modafinil). The multiple modafinil to improve the impairment in memory and/or cog doses can be administered for a day, days, a week, weeks, a nition. month, months or years. In the methods of the invention, the human can be admin The compounds employed in the methods of the invention istered at least one member selected from the group consist can be administered to a human acutely (briefly or short-term) ing of l-amphetamine, 1-methamphetamine, l-threo-meth 65 or chronically (prolonged or long-term). For example, the ylphenidate, d-threo-methylphenidate, methylphenidate, compounds, (e.g., 1-amphetamine, C105, 1-methamphet atomoxetine and modafinil concomitantly with and/or Subse amine, SN522, SN522-HCl, 1-threo-methylphenidate, US 7,619,005 B2 63 64 d-threo-methylphenidate, methylphenidate, atomoxetine and The cumulative dose of the compounds (e.g., 1-amphet modafinil) of the invention can be used in methods to treat a amine, C105, 1-methamphetamine, SN522, SN522-HCl, human by administering the compound to the human once a 1-threo-methylphenidate, d-threo-methylphenidate, meth day, multiple times (e.g., 2, 3, 4) in a day, for a day, days, a ylphenidate, atomoxetine and modafinil) employed in the week, weeks, a month, months or years. methods of the invention, regardless of whether the com In yet another embodiment of the invention, the methods pound is administered in a single dose or in multiple doses is employ a single oral dosage formulation of between about between about 0.2 mg to about 250 mg. or between about 1 0.001 mg to about 125 mg; between about 0.001 mg to about mg to about 1250 mg of the compound(s). In a particular 250 mg; between 0.001 mg to 500 mg; between about 0.01 mg embodiment, the cumulative dose is about 2 mg, about 10 mg. to about 125 mg; between about 0.1 mg to about 125 mg: 10 about 20 mg, about 30 mg, about 50 mg, about 60 mg, about between about 1 mg to about 125 mg; between about 1 mg to 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 about 250 mg; between about 1 mg to about 500 mg; or mg, about 450 mg, about 750 mg, about 1000 mg, about 1250 between about 1 mg to about 1000 mg of the compound mg, about 2500 mg. or about 5000 mg. employed in the methods (e.g., 1-amphetamine, C105. The multiple doses or cumulative dose of the compound 1-methamphetamine, SN522, SN522-HCl, 1-threo-meth 15 can be any combination of a compound of the invention (e.g., ylphenidate, d-threo-methylphenidate, methylphenidate, ato 1-amphetamine, C105, 1-methamphetamine, SN522, SN522 moxetine and modafinil) and, optionally, a pharmaceutically HCl, 1-threo-methylphenidate, d-threo-methylphenidate, acceptable carrier. methylphenidate, atomoxetine and modafinil) in any combi In a further embodiment, the methods of the invention employ multiple doses of the compound (e.g., 1-amphet nation of dose or doses. amine, C105, 1-methamphetamine, SN522, SN522-HCl, An “effective amount’ or “amount effective,” when refer 1-threo-methylphenidate, d-threo-methylphenidate, meth ring to the amount of the compound (e.g., 1-amphetamine, ylphenidate, atomoxetine and modafinil), wherein each of the C105,1-methamphetamine, SN522, SN522-HCl, 1-threo-me multiple doses of the compound is between about 0.001 mg to thylphenidate, d-threo-methylphenidate, methylphenidate, about 125 mg; or between about 0.001 mg to about 250 mg; or 25 atomoxetine and modafinil) administered to the individual, is between about 0.001 mg to about 500 mg; or between about defined as that amount, or dose, of the compound that, when 0.01 mg to about 125 mg; or between about 0.1 mg to about administered to an individual having an impairment in 125 mg; or between about 0.01 mg; to about 500 mg; or memory as a consequence of exposure to a muscarinic cho between about 1 mg to about 125 mg; or between about 1 mg linergic receptor antagonist, is sufficient for therapeutic effi to about 500 mg; or between about 2.5 mg to about 25 mg. 30 cacy (e.g., an amount Sufficient to improve memory in an about 50 mg, about 75 mg, about 100 mg, about 125 mg. individual having an impairment in memory; an amount Suf about 250 mg, about 500 mg or about 1000 mg of the com ficient to improve cognition in an individual having an pound(s) (e.g., 1-amphetamine, C105, 1-methamphetamine, impairment in cognition). SN522, SN522-HCl, 1-threo-methylphenidate, d-threo-meth The methods of the present invention can be accomplished ylphenidate, methylphenidate, atomoxetine and modafinil) 35 by the administration of the compounds (e.g., 1-amphetamine, and, optionally, a pharmaceutically acceptable carrier. C105,1-methamphetamine, SN522, SN522-HCl, 1-threo-me In a further embodiment, the methods of the invention thylphenidate, d-threo-methylphenidate, methylphenidate, employ a single dose of the compound (e.g., 1-amphetamine, atomoxetine and modafinil) of the invention by enteral or C105,1-methamphetamine, SN522, SN522-HCl, 1-threo-me parenteral means. Specifically, the route of administration thylphenidate, d-threo-methylphenidate, methylphenidate, 40 can be by oral ingestion (e.g., tablet, capsule form) or injec atomoxetine and modafinil) between about 0.0015 mg/kg to tion (e.g., intramuscular) of the compound. Other routes of about 2 mg/kg; or between about 0.015 mg/kg to about 2 administration are also encompassed by the present invention mg/kg. including intravenous, intraarterial, intraperitoneal, Subcuta In yet another embodiment, the methods of the invention neous routes or nasal administration. Suppositories or trans employ a single dose about 0.04 mg/kg, about 0.07 mg/kg, 45 dermal patches can also be employed. about 0.15 mg/kg, about 0.20 mg/kg, about 0.40 mg/kg, about The compounds employed in the methods of the invention 0.65 mg/kg, about 1 mg/kg, about 1.50 mg/kg, about 1.80 can be administered alone or can be coadministered to the mg/kg or about 3.5 mg/kg of the compound (e.g., 1-amphet human. Coadministration is meant to include simultaneous or amine, C105, 1-methamphetamine, SN522, SN522-HCl, sequential administration of one or more of the compounds 1-threo-methylphenidate, d-threo-methylphenidate, meth 50 (1-amphetamine, C105,1-methamphetamine, SN522, SN522 ylphenidate, atomoxetine and modafinil). HCl, 1-threo-methylphenidate, d-threo-methylphenidate, In an additional embodiment, the methods of the invention methylphenidate, atomoxetine and modafinil) individually or employ multiple doses of the compound (e.g., 1-amphet in combination. The simultaneous or sequential administra amine, C105, 1-methamphetamine, SN522, SN522-HCl, tion of compounds of the invention is conducted so that the 1-threo-methylphenidate, d-threo-methylphenidate, meth 55 mode of administration and the timing of administration ylphenidate, atomoxetine and modafinil), wherein each dose results in a maximal improvement in memory (memory con of the multiple dose is between about 0.0015 mg/kg to about Solidation, short term memory, working memory) or cogni 2 mg/kg, or between about 0.015 mg/kg to about 2 mg/kg. tion (e.g., attention, executive function, alertness, wakeful In still another embodiment, the methods of the invention ness, arousal, conceptualization, information processing, employ multiple doses, wherein each does of the multiple 60 problem solving, verbal fluency) with minimal side effects dose is about 0.04 mg/kg, about 0.07 mg/kg, about 0.15 (e.g., addiction, increases in heart rate, increases in blood mg/kg, about 0.20 mg/kg, about 0.40 mg/kg, about 0.65 pressure). It is also envisioned that multiple routes of admin mg/kg, about 1 mg/kg, about 1.50 mg/kg, about 1.80 mg/kg or istration (e.g., oral, transdermal, Suppository, intramuscular) about 3.5 mg/kg of the compound (e.g., 1-amphetamine, can be used to administer 1-amphetamine, C105, 1-metham C105,1-methamphetamine, SN522, SN522-HCl, 1-threo-me 65 phetamine, SN522, SN522-HCl, 1-threo-methylphenidate, thylphenidate, d-threo-methylphenidate, methylphenidate, d-threo-methylphenidate, methylphenidate, atomoxetine and atomoxetine and modafinil). modafinil or any combination thereof. US 7,619,005 B2 65 66 The dosage and frequency (single or multiple doses) can be prepared by reacting a ketone of the formula: administered to an individual can vary depending upon a variety of factors, including the duration of exposure to the muscarinic cholinergic receptor antagonistand severity of the O impairment in memory (e.g., impairment in memory consoli dation, impairment in short-term memory, an impairment in R working memory) or cognition (e.g., attention, alertness, executive function, wakefulness, arousal, Vigilance, execu with an amine of the formula: R"NH and reducing the tive function, reaction time); size, age, sex, health, body ketimine intermediate formed without or after isolation. The weight, body mass index and diet of the human; nature and 10 reduction can be carried out by methods known perse, e.g., by extent of symptoms of the impairment in memory or cogni catalytic hydrogenation (preferably in the presence of a pal tion, kind of concurrent treatment (e.g., atropine, Scopola ladium or Raney-nickel catalyst) or by using a complex metal mine), complications from exposure to the muscarinic cho hydride (e.g. sodium borohydride) or with the aid of a con linergic receptor antagonist, or other health-related problems ventional reducing agent (e.g. sodium dithionite or amalgam 15 ated aluminum). of the human being treated. R-(-)-amphetamine and S-(+)-amphetamine may be Other therapeutic regimens or agents can be used in con obtained by optical resolution of racemic mixtures of R- and junction with the methods and compounds employed in the S-enantiomers of amphetamine. Such a resolution can be methods of the invention. Adjustment and manipulation of accomplished by any conventional resolution methods well established dosages (e.g., frequency and duration) are well known to a person skilled in the art, such as those described in within the ability of those skilled in the art. J. Jacques, A. Collet and S. Wilen, “Enantiomers, Racemates The invention also relates to the conjoint use of a amphet and Resolutions. Wiley, N.Y. (1981). For example, the reso amine compound with agents that mimic or stimulate PKC lution may be carried out by preparative chromatography on and/or PKA pathways. a chiral column. Another example of a Suitable resolution A. Synthesis of Amphetamine Compounds 25 method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl deriva As described in further detail below, it is contemplated that tives of amino acids, such as N-acetyl leucine, followed by the Subject methods can be carried out using a stereomerically recrystallization to isolate the diastereomeric salt of the enriched preparation in a eutomer of amphetamine desired Renantiomer. compound(s), particularly R-(-)-amphetamine, or a variety 30 of different derivatives thereof. The suitability of use of a In one embodiment, a Subject R-(-)-amphetamine may be particular amphetamine compound can be readily deter resolved according to the methods set forth in J. Med. Chem, mined, for example, by Such drug screening assays as 1988, 31:1558: 1570. Briefly, racemic amphetamine is com described herein. bined with a hot ethanol solution of D-(-)-tartaric acid. The The Subject amphetamine compounds, and derivatives 35 solution is allowed to cool to room temperature and the white thereof, can be prepared readily by employing known syn crystals are collected and recrystallized twice more from thetic methodology. As is well known in the art, these cou ethanol to give D-tartaric acid salt of R-(-)-amphetamine. To pling reactions are carried out under relatively mild condi recover R-(-)-amphetamine, the D-tartaric acid salt of R-(-)- tions and tolerate a wide range of “spectator functionality. amphetamine is treated with sodium hydroxide in water and Additional compounds may be synthesized and tested in a 40 extracted with diethyl ether. combinatorial fashion, to facilitate the identification of addi The compounds of the present invention may also be pro tional amphetamine compounds which may be employed in vided in the form of prodrugs, e.g., to protect a drug from the subject method. being altered while passing through a hostile environment, Numerous methods for synthesizing amphetamine and for Such as the digestive tract. Prodrugs can be prepared by form resolving the enantiomers of amphetamine have been 45 ing covalent linkages between the drug and a modifier. See, described in the art, see for example: U.S. Pat. No. 5,075,338 for example, Balant at al., Eur. J. Drug Metab. Pharmacoki to Knoll et al.; U.S. Pat. No. 2,828,343 to Tindall; U.S. Pat. netics, 1990, 15(2), 143-153. The linkage is usually designed No. 3,458,576 to Bryan; UK Patent No. GB 2,122,617; U.S. to be broken under defined circumstances, e.g., pH changes or Pat. No. 3,996,381 to Florvallet al.: Croceet al., 1996, GazZ. exposure to specific enzymes. The covalent linkage of the Chim. Ital. 126:107-109; Mastagliet. al., 1950, Bull. Soc. 50 drug to a modifier essentially creates a new molecule with Chim. Fr. 1045-1047; Smith et al., 1988, J. Med. Chem. new properties such as an altered log Pvalue and/or as well as 31:1558-1566; Bobranski et al., 1941, J. Applied Chem. a new spatial configuration. The new molecule can have dif (U.S.S.R.) 14:410-414; Magidson, 1941, J. Gen. Chem. ferent solubility properties and be less susceptible to enzy (U.S.S.R.) 11:339-343. The contents of these publications are matic digestion. For general references on prodrug designand 55 preparation, see: Bundraard, Design of Prodrugs, Elsevier incorporated herein by reference. Science Pub.Co., N.Y. (1985), and Prodrugs as Novel Drug In one embodiment, a subject amphetamine compound can Delivery Systems Symposium, 168.sup.th Annual Meeting, be synthesized according to the methods set forth in U.S. Pat. American Chemical Society, Atlantic City, N.J., Eds. T. Higu No. 5,075,338. Briefly, amphetamine compounds of the gen chi and V. Stella, ACS Symposium Series 14, 1975, which are eral formula: 60 herein incorporated by reference. Prodrugs of amine-containing compounds are well known in the art and have been prepared, e.g., by reacting the amine moiety of a drug with a carboxylic acid, acid chloride, chlo roformate, or sulfonyl chloride modifiers, and the like, result 65 ing in the formation of amides, Sulfonamides, carboxya R mides, carbamates, Schiffbases and similar compounds. See, for example, Abuchowski et al., J. Biol. Chem. 1977, 252, US 7,619,005 B2 67 68 3578-358: Senter et al., J. Org. Chem., 1990, 55,2975-2978: tion (e.g., perirhinal cortex, amygdala, medial septal nucleus, Amsberry et al., J. Org. Chem., 1990, 55, 5867-5877; Klotz, locus coeruleus, hippocampus, mammalary bodies). Lesions Clin. Pharmacokinetics, 1985, 10, 285-302, which are herein in the mammal can be produced by mechanical or chemical incorporated by reference. Similar and other protocols may disruption. For example, the fornix lesion can be caused by be followed for the formation of prodrugs of the compounds Surgical ablation, electrolytic, neurotoxic and other chemical of the present invention. ablation techniques, or reversible inactivation Such as by The compounds of the present invention, particularly injection of an anesthetic, e.g., tetrodotoxin or lidocaine, to libraries of amphetamine analogs having various representa temporarily arrest activity in the fornix. tive classes of Substituents, are amenable to combinatorial chemistry and other parallel synthesis schemes (see, for 10 To further illustrate, fimbrio-fornix (rodents) and fornix example, PCT WO94/08051). The resultis that large libraries (primates) lesions can be created by Stereotactic ablation. In of related compounds, e.g., a variegated library of compounds particular, neurons of the fornix structure are axotomized, represented above, can be screened rapidly in high through e.g., by transection or aspiration (suction) ablation. A com put assays in order to identify potential amphetamine analogs, plete transection of the fornix disrupts adrenergic, cholinergic as well as to refine the specificity, toxicity, and/or cytotoxic 15 and GABAergic function and electrical activity, and induces kinetic profile of a lead compound. morphological reorganization in the hippocampal formation. Simply for illustration, a combinatorial library for the pur In general, the fornix transection utilized in the Subject poses of the present invention is a mixture of chemically method will not disconnect the parahippocampal region from related compounds which may be screened together for a the neocortex. In those embodiments, the fornix transection desired property. The preparation of many related compounds will not disrupt functions that can be carried out by the para in a single reaction greatly reduces and simplifies the number hippocampal region independent of processing by the hip of screening processes which need to be carried out. Screen pocampal formation, and hence would not be expected to ing for the appropriate physical properties can be done by produce the full-blown amnesia seen following more com conventional methods. plete hippocampal system damage. Diversity in the library can be created at a variety of dif 25 In one embodiment, the animal can be a rat. Briefly, the ferent levels. For instance, the Substrate aryl groups used in animals are anesthetized, e.g., with intraperitoneal injections the combinatorial reactions can be diverse interms of the core of a ketamine-Xylazine mixture and positioned in a Kopf R aryl moiety, e.g., a variegation in terms of the ring structure, Stereotaxic instrument. A Sagittal incision is made in the scalp and/or can be varied with respect to the other substituents. and a craniotomy is performed extending 2.0 mm posterior A variety of techniques are available in the art for generat 30 and 3.0 mm lateral from Bregma. An aspirative device, e.g., ing combinatorial libraries of small organic molecules such as with a 20 gauge tip, is mounted to a stereotaxic frame (Kopf R the subject amphetamine compounds. See, for example, Instruments) and fimbria-fornix is aspirated by placing the Blondelle et al. (1995) Trends Anal. Chem. 14:83; the Affy Suction tip at the correct sterotaxic location in the animals max U.S. Pat. Nos. 5,359,115 and 5,362,899: the Ellman U.S. brain. Unilateral aspirative lesions are made by Suction Pat. No. 5,288,514: the Still et al. PCT publication WO 35 through the cingulate cortex, completely transecting the fim 94/08051; the ArQule U.S. Pat. Nos. 5,736,412 and 5,712, bria fornix unilaterally, and (optionally) removing the dorsal 171; Chen et al. (1994) JACS 116:2661: Kerr et al. (1993) tip of the hippocampus as well as the overlying cingulate JACS 115:252: PCT publications WO92/10092, WO93/ cortex to inflict a partial denervation on the hippocampus 09668 and WO91/07087; and the Lerner et al. PCT publica target. See also, Gage et al., (1983) Brain Res. 268:27 and tion WO93/20242). Accordingly, a variety of libraries on the 40 order of about 100 to 1,000,000 or more diversomers of the Gage et al. (1986) Neuroscience 19:241. Subject amphetamine compounds can be synthesized and In another exemplary embodiment, the animal can be a screened for particular activity or property. monkey. The animal can be anesthetized, e.g., with isoflurane In an exemplary embodiment, a library of candidate (1.5-2.0%). Following pretreatment with mannitol (0.25 amphetamine compound diverSomers can be synthesized uti 45 g/kg, iv), unilateral transections of the left fornix can be lizing a scheme adapted to the techniques described in the performed, such as described by Kordower et al. (1990) J. Still et al. PCT publication WO94/08051, e.g., being linked Comp. Neurol., 298:443. Briefly, a surgical drill is used to to a polymer bead by a hydrolyzable or photolyzable group, create a parasagittal bone flap which exposes the frontal Supe optionally located at one of the positions of the candidate rior Sagittal sinus. The dura is retracted and a self-retaining regulators or a substituent of a synthetic intermediate. 50 retractor is used to expose the interhemispheric fissure. The According to the Still et al. technique, the library is synthe corpus callosum is longitudinally incised. At the level of the sized on a set of beads, each bead including a set of tags foramen of Monro, the fornix is easily visualized as a discrete identifying the particular diversomer on that bead. The bead 2-3 mm wide white fiber bundle. The fornix can be initially library can then be “plated with cells for which an amphet transected using a ball dissector. The cut ends of the fornix amine compound is sought. The diverSomers can be released 55 can then be Suctioned to ensure completeness of the lesion. from the bead, e.g., by hydrolysis. In still other illustrative embodiments, the fornix lesion can Many variations on the above and related pathways permit be created by excitotoxicity, or by other chemical means, the synthesis of widely diverse libraries of compounds which inhibiting or ablating fornix neurons, or the cells of the hip may be tested as amphetamine compounds. pocampus which are innervated by fornix neurons. In certain B. Generation of Animal Models to Test Agents 60 preferred embodiments, the fornix lesion is generated by Applicants have previously described an animal model for selective disruption of particular neuronal types, such as studying fornix-mediated memory consolidation. See, for fornix cholinergic and adrenergic neurons. example, Taubenfield et al., Supra. The fornix-lesioned ani For instance, the afferantfornix Signals to the hippocampus mals can be used for drug screening, e.g., to identify dosages due to cholinergic neurons can be ablated by atropine block of the Subject compositions which enhance memory consoli 65 ade. Another means for ablation of the cholinergic neurons is dation. The lesioned mammal can have a lesion of the fornix the use of 192IgG-Saporin (192IgG-Sap), e.g., intraventricu or a related brain structure that disrupts memory consolida larly injection into the fornix and hippocampus. The agents US 7,619,005 B2 69 70 such as 6-OHDA and ibotenic acid can be used to selectively that it may be rotated easily to eliminate reliance on proximal destroy fornix dopamine neurons as part of the ablative regi (e.g., olfactory) cues. A start tube is placed in the center of the C. apparatus. The subject is released from the tube and allowed In one embodiment, the animal is a non-human mammal, to explore for the baited ("correct”) hole. Such as a dog, cat, horse, cow, pig, sheep, goat, chicken, As set out above, one use for the fornix-lesioned animals is monkey, ape, rat, rabbit, etc. In another embodiment, the for testing amphetamine compounds for ability to modulate animal is a non-human primate. In still another embodiment, memory consolidation, as well as for side effects and toxicity. the Subject is a human. In general, the Subject method utilizes an animal which has There are a variety of tests for cognitive function, espe been manipulated to create at least partial disruption of cially learning and memory testing, which can be carried our 10 fornix-mediated signalling to the hippocampus, the disrup using the lesioned and normal animals. Learning and/or tion affecting memory consolidation and learned behavior in memory tests include, for example, Inhibitory Avoidance Test the animal. The animal is conditioned with a learning or (also referred to herein as “Passive Avoidance Test), contex memory regimen which results in learned behavior in the tual fear conditioning, visual delay non-match to sample, mammal in the absence of the fornix lesion. Amphetamine spatial delay non-match to sample, visual discrimination, 15 compounds are administered to the animal in order to assess Barnes circular maze, Morris water maze, radial arm maZe their effects on memory consolidation. An increase in learned tests, Ray Auditory-Visual Learning Test, the Wechsler Logi behavior, relative to the absence of the test agents, indicates cal Memory Test, and the Providence Recognition Memory that the administered combination enhances memory con Test. Solidation. An exemplary Inhibitory Avoidance Test utilizes an appa Another memory test especially developed for use in phar ratus that consists of a lit chamber that can be separated from maceutical studies is the Providence Recognition Memory a dark chamber by a sliding door. At training, the animal is Test. This test consists of one pictorial and one verbal assess placed in the lit chamber for some period of time, and the door ment of long-term declarative memory. In each of the two is opened. The animal moves to the dark chamber after a short modes, the patient views stimuli on a computer screen and is delay—the step-through latency—which is recorded. Upon 25 later asked to recognize those stimuli in a two-alternative entry into the dark chamber, the door is shut closed and a foot forced-choice format. The pictorial assessment mode con shock is delivered. Retention of the experience is determined sists of two parts: a study phase and a recognition phase. In the after various time intervals, e.g., 24 or 48 hours, by repeating study phase, patients view a series of 120 pictures, for 3 the testand recording the latency. The protocol is one of many seconds each. They are told to look at the pictures and remem variants of the passive avoidance procedures (for review, see 30 ber them, so that they can recognize them later. In the recog Rush (1988) Behav. Neural. Biol. 50:255). nition phase, patients view pictures two at a time and are An exemplary maze testing embodiment is the water maze asked to indicate by button press which of the two pictures working memory test. In general, the method utilizes an appa they saw in a study phase. Recognition memory testing ratus which consists of a circular water tank. The water in the occurs atten minutes, one hour, and 24 hours after the end of tank is made cloudy by the addition of milk powder. A clear 35 the study phase. The Verbal assessment mode consists of two plexiglass platform, Supported by a movable stand rest on the parts: a study phase and a recognition phase. In the study bottom of the tank, is submerged just below the water surface. phase, patients view a series of 60 sentences one at a time. Normally, a Swimming rat cannot perceive the location of the They are asked to read the sentences aloud and remember platform but it may recall it from a previous experience and them, so that they can recognize them later. Each sentence training, unless it suffers from Some memory impairment. 40 remains on the computer screen until the patient has finished The time taken to locate the platform is measured and referred reading it aloud. If patients read words incorrectly, the exam to as the latency. During the experiment, all orientational cues iner Supplies the correct word or words. In the recognition Such as ceiling lights, etc., remain unchanged. Longer laten phase, patients view sentences two at a time and are asked to cies are generally observed with rats with some impairment to indicate by button press which of the two sentences they saw their memory. 45 in the study phase. Recognition memory testing occurs atten Another memory test includes the eyeblink conditioning minutes, one hour, and 24 hours after the end of the study test, which involves the administration of white noise or phase. steady tone that precedes a mild air puff which stimulates the In the methods of the present invention, retention of the subject’s eyeblink. learned behavior can be determined, for example, after at Still another memory test which can be used is fear condi 50 least about 12-24 hours, 14-22 hours, 16-20 hours and or tioning, e.g., either “cued and “contextual fear condition 18-19 hours after completion of the learning phase to deter ing. In one embodiment, a freeze monitor administers a mine whether the agents promote memory consolidation. In a sequence of stimuli (sounds, shock) and then records a series particular embodiment, retention of the learned behavior can of latencies measuring the recovery from shock induced be determined 24 hours after completion of the learning freezing of the animal. 55 phase. Another memory test for the lesioned animals is a hole In addition to models for studying memory consolidation, board test, which utilizes a rotating holeboard apparatus con models to assess side effects of amphetamine compounds on taining (four) open holes arranged in a 4-corner configuration behavior have been utilized including locomotor activity in the floor of the test enclosure. A mouse is trained to poke its models. An exemplary locomotor activity test utilizes an head into a hole and retrieve a food reward from a “baited' 60 apparatus that consists of photocell activity cages with a grid hole which contains a reward on every trial. There is a food of photocell beams placed around the cage. The animals are reward (e.g., a Fruit Loop) in every exposed hole which is placed in individual activity cages some period of time prior made inaccessible by being placed under a screen. The Screen to administration of agents. Locomotor activity is measured allows the odor of the reward to emanate from the hole, but by the number of interruptions of the photoelectric beam does not allow access to the reinforcer. When an individual 65 during a given period of time. hole is baited, a reward is placed on top of the screen, where As used herein, a “control mammal can be an untreated it is accessible. The entire apparatus rests on a turntable so lesion mammal (i.e., a lesion animal receiving no agents or US 7,619,005 B2 71 72 not the same combinations to be assessed), a trained control ance, e.g., acute tolerance, in the patient, it may desirable to mammal (i.e., a mammal that undergoes training to demon formulate the compound for variable dosing, and preferably strate a learned behavior without any lesion) and/or an for use in a dose-escalation regimen. In preferred embodi untrained control mammal (i.e., a mammal with or without a ments, the Subject amphetamine compounds are formulated lesion, that receives no training to demonstrate a learned 5 to deliver a sustained and increasing dose, e.g., over at least 4 behavior). hours, and more preferably over at least 8 or even 16 hours. C. Pharmaceutical Preparations of Amphetamine Com pounds In certain embodiments, representative dosage forms In another aspect, the present invention provides pharma include hydrogel matrix containing a plurality of tiny pills. ceutical preparations comprising the Subject amphetamine 10 The hydrogel matrix comprises a hydrophilic polymer, Such compounds. The amphetamine compounds for use in the as selected from the group consisting of a polysaccharide, subject method may be conveniently formulated for admin agar, agarose, natural gum, alkali alginate including sodium istration with a biologically acceptable, non-pyrogenic, and/ alginate, carrageenan, fucoidan, furcellaran, laminaran, hyp or sterile medium, such as water, buffered saline, polyol (for nea, gum arabic, gum ghatti, gum karaya, gum tragacanth, example, glycerol, propylene glycol, liquid polyethylene gly- 15 locust bean gum, pectin, amylopectin, gelatin and a hydro col and the like) or suitable mixtures thereof. The optimum philic colloid. The hydrogel matrix comprises a plurality of concentration of the active ingredient(s) in the chosen tiny pills (such as 4 to 50), each tiny pill comprising an medium can be determined empirically, according to proce increasing dose population of from 100 ng ascending in dose dures well known to behavioral scientists. As used herein, Such as 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, etc. The “biologically acceptable medium' includes any and all sol- 20 tiny pills comprise a release rate controlling wall of 0.0 mm to vents, dispersion media, and the like which may be appropri 10 mm thickness to provide for the timed ascending release of ate for the desired route of administration of the pharmaceu drug. Representative of wall-forming materials include a trig tical preparation. The use of such media for pharmaceutically lyceryl ester selected from the group consisting of glyceryl active Substances is known in the art. Except insofar as any tristearate, glyceryl monostearate, glyceryl dipalmitate, glyc conventional media or agent is incompatible with the activity 25 eryl laureate, glyceryl didecenoate and glyceryl tridecenoate. of the amphetamine compounds, its use in the pharmaceutical Other wall forming materials comprise polyvinyl acetate preparation of the invention is contemplated. Suitable phthalate, methylcellulose phthalate, and microporous vinyl vehicles and their formulation inclusive of other proteins are olefins. Procedures for manufacturing tiny pills are disclosed described, for example, in the book Remington's Pharmaceu in U.S. Pat. Nos. 4434,153; 4,721,613; 4,853,229; 2,996, tical Sciences (Remington's Pharmaceutical Sciences. Mack 30 431; 3,139,383 and 4,752,470, which are incorporated by Publishing Company, Easton, Pa., USA 1985). These reference herein. vehicles include injectable “deposit formulations”. In certain embodiments, the drug releasing beads are char Pharmaceutical formulations of the present invention can acterized by a dissolution profile wherein 0 to 20% of the also include Veterinary compositions, e.g., pharmaceutical beads undergo dissolution and release the drug in 0 to 2 hours, preparations of the amphetamine compounds Suitable for vet- 35 20 to 40% undergo dissolution and release the drug in 2 to 4 erinary uses, e.g., for the treatment of livestock or domestic hours, 40 to 60% exhibit dissolution and release in 4 to 6 animals, e.g., dogs. hours, 60 to 80% in 6 to 8 hours, and 80 to 100% in 8 to 10 Methods of introduction may also be provided by recharge hours. The drug releasing beads can include a central com able or biodegradable devices. Various slow release poly position or core comprising a drug and pharmaceutically meric devices have been developed and tested in vivo in 40 acceptable composition forming ingredients including a recent years for the controlled delivery of drugs. A variety of lubricant, antioxidant, and buffer. The beads comprise biocompatible polymers (including hydrogels), including increasing doses of drug, for example, 1 mg, 2 mg, 5 mg, and both biodegradable and non-degradable polymers, can be So forth to a high dose, in certain preferred embodiments, of used to form an implant for the Sustained release of a amphet 15 to 100 mg. The beads are coated with a release rate con amine compound at a particular target site. In accordance 45 trolling polymer that can be selected utilizing the dissolution with the practice of this invention, it has been found that a profile disclosed above. The manufacture of the beads can be dosage form and a method can be provided that administers a adapted from, for example, Liu et al. (1994) Inter. J. of amphetamine compound in a program that Substantially less Pharm., 112:105-116; Liu et al. (1994) Inter. J. of Pharm., ens or completely compensates for tolerance in a patient. 112:117-124; Pharm. Sci., by Remington, 14th Ed. pp. 1626 Tolerance, as defined in Pharmacology in Medicine, by Brill, 50 1628 (1970); Fincher et al. (1968) J. Pharm. Sci., 57:1825 p. 227 (1965) McGraw-Hill, is characterized as a decrease in 1835; and U.S. Pat. No. 4,083,949. effect followed by administering a drug. When tolerance Another exemplary dosage form provided by the invention develops following a single dose or a few doses over a very comprises a concentration gradient of amphetamine com short time, it is referred to as acute tolerance. When the drug pound from 1 mg to 15-600 mg coated from the former low is administered over a more protracted period of time to show 55 dose to the latter high dose on a polymer substrate. The a demonstrable degree of tolerance, it is referred to as chronic polymer can be erodible or a nonerodible polymer. The tolerance. The medical literature, as exemplified in, The Phar coated substrate is rolled about itself from the latter high dose macological Bases of Therapeutics, by Goodman and Gil at the center of the dosage form, to the former low dose at the man, 8th Ed., p. 72 (1990) Pergamon Press, reported toler exposed outer end of the substrate. The coated substrate is ance may be acquired to the effects of many drugs and this 60 rolled from the high dose to the low dose to provide for the literature classifies tolerance as acute or chronic based on release of from low to high dose as the substrate unrolls or when it is acquired. That is, acute tolerance develops during a erodes. For example, 1 mg to 600 mg of amphetamine is dosing phase of one dose or on one day, and chronic tolerance coated onto an erodible polymer Such as an polypeptide, is acquired due to chronic administration typically weeks, collagen, gelatin, or polyvinyl alcohol, and the Substrate months, and years. 65 rolled concentrically from the high dose rolled over and In certain embodiments, particularly where the selected inward to adapt a center position, and then outward towards amphetamine compound is one which may produce toler the low dose to form an outer position. In operation, the US 7,619,005 B2 73 74 dosage form erodes dispensing an ascending dose of amphet (ethylene), poly(propylene), poly(vinyl acetate), poly(methyl amine that is released over time. acrylate), poly(isobutyl methacrylate), poly(alginate), poly Another dosage form provided by the invention comprises (amide), and poly(silicone). The polymers and manufactur a multiplicity of layers, wherein each layer is characterized by ing procedures are known in Polymers, by Coleman et al., an increasing dose of drug. The phrase “multiplicity of lay Vol. 31, pp. 1187-1230 (1990); Drug Carrier Systems, by ers' denotes 2 to 6 layers in contacting lamination. The mul Roerdinket al., Vol. 9, pp. 57-109 (1989); Adv. Drug Delivery tiplicity of layers are positioned consecutively, that is, one Rev., by Leong et al., Vol. 1, pp. 199-233 (1987); Handbook layer after another in order, with a first exposed layer, the sixth of Common Polymers, Compiled by Roffet al., (1971) pub layer in contact with the fifth layer and its exposed surface lished by CRC Press; and U.S. Pat. No. 3,992,518. coated with a drug impermeable polymer. The sixth layer is 10 In still other embodiments, the subject formulations can be coated with a drug impermeable polymer to insure release of a mixture of different prodrug forms of one or more different the amphetamine compound from the first layer to the sixth amphetamine compounds, each prodrug form having a dif layer. The first layer comprises, for example, 1 to 50 mg of ferent hydrolysis rate, and therefore activation rate, to provide drug and each Successive layer comprises an additional 1 to an increasing serum concentration of the active amphetamine 50 mg of drug. The biodegradable polymers undergo chemi 15 compounds. cal decomposition to form soluble monomers or soluble poly mer units. The biodegradation of polymers usually involves In other embodiments, the subject formulations can be a chemically or enzymatically catalyzed hydrolysis. Represen mixture different amphetamine compounds, each compound tative of biodegradable polymers acceptable for an increase having a different rate of adsorption (such as across the gut or drug loading in each layer of from 5 to 50 wt % over the first epithelia) and/or serum half-life. and successive layers wherein the first layer comprises 100 The dose-escalation regimen of the present invention can ng. Representative biodegradable polymers comprise a mem be used to compensate for the loss of a therapeutic effect of a ber selected from the group consisting of biodegradable poly amphetamine compound, if any, by providing a method of (amides), poly(amino acids), poly(esters), poly(lactic acid), delivery that continually compensates for the development of poly(glycolic acid), poly(orthoesters), poly(anhydrides), bio 25 acute tolerance, by considering the clinical effect (E) of a drug degradable poly(dehydropyrans), and poly(dioxinones). The at time (t) as a function of the drug concentration (C) accord polymers are known to the art in Controlled Release of Drugs, ing to Equation 1: by Rosoff, Ch. 2, pp. 53-95 (1989); and in U.S. Pat. Nos. Effect fit,C) 3,811,444; 3,962,414; 4,066,747; 4,070,347; 4,079,038; and 4,093,709. 30 In addition, the rate of drug delivered (A), in mg per hour is In still other embodiments, the invention employs a dosage inversely proportional to the concentration times the clear form comprising a polymer that releases a drug by diffusion, ance of the drug. As the effect varies with time and the flux through pores, or by rupture of a polymer matrix. The functionality is expressed, then according to this invention drug delivery polymeric system comprises a concentration (A) can be governed to ensure the therapeutic effect is main gradient, wherein the gradient is an ascent in concentration 35 tained at a clinical value. If the effect from a drug is found from a beginning or initial concentration to a final, or higher clinically to decrease with time, this decline could be linear as concentration. The dosage form comprises an exposed Sur expressed by Equation 2: face at the beginning dose and a distant nonexposed surface at the final dose. The nonexposed surface is coated with a phar Effecte-Effect-k,'t maceutically acceptable material impermeable to the passage 40 wherein. Effect is the clinical effect observed initially at of drug. The dosage form structure provides for a flux the start of drug administration and Effect (t) is the effect increase delivery of drug ascending from the beginning to the observed at time (t) hours, keffect is a proportionality con final delivered dose. stant ascertained by measuring the clinical effect (E1) at time FIG.17 illustrates such an embodiment, where the amphet (t1) hours and (E2) at time (t2) hours while maintaining a amine compound is contained within a nonabsorbable shell 45 constant plasma concentration followed by dividing (E1) that releases the drug at a controlled rate. minus (E2) by (t1) minus (t2). In order to maintain a constant The dosage form matrix can be made by procedures known effect, (A) must be adjusted with the same functionality to the polymer art. In one manufacture, 3 to 5 or more casting according to Equation 3: compositions are independently prepared wherein each cast ing composition comprises an increasing dose of drug with 50 A(t) Acini)+kefect each composition overlayered from a low to the high dose. This provides a series of layers that come together to provide wherein A is the initial drug input in mg per hour at the a unit polymer matrix with a concentration gradient. In start of the therapy and A is the drug input at time (t) hours, another manufacture, the higher does is cast first followed by and keffect is the proportionality constant presented above. If laminating with layers of decreasing dose to provide a poly 55 the therapeutic effect is found to decline exponentially with mer matrix with a drug concentration gradient. An example of time, this relationship is expressed by Equation 4: providing a dosage form comprises blending a pharmaceuti cally acceptable carrier, like polyethylene glycol, with a Effect-Effect expkie" known dose of a amphetamine compound and adding it to a wherein Effect and Effect are as defined before, keffect Silastic medical grade elastomer with a cross-linking agent, 60 (or keffect) is a rate constant (h-1), a unit of reciprocal hours, like Stannous octanoate, followed by casting in a mold. The ascertained by measuring the clinical effect (E1) at time (t1) step is repeated for each Successive layer. The system is hours and (E2) at time (t2) hours while maintaining a constant allowed to set, for 1 hour, to provide the dosage form. Rep plasma concentration followed by dividing natural log of (E1) resentative polymers for manufacturing the dosage form minus natural log of (E2) by (t1) minus (t2). To maintain a comprise a member selected from the group consisting of 65 olefin and vinyl polymers, condensation polymers, carbohy constant effect, (A) must be adjusted according to Equation 5: drate polymers, and silicon polymers as represented by poly 4() Af exp(keffect")