sign in sign up
<<
Home , Lazabemide, Mofegiline, Nitecapone

US 2013 OO17274A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0017274 A1 ANDERSEN et al. (43) Pub. Date: Jan. 17, 2013

(54) LOW DOSE LITHIUM IN THE TREATMENT Publication Classification OR PROPHYLAXIS OF PARKINSONS DISEASE (51) Int. Cl. A633/14 (2006.01) (75) Inventors: JULIE K. ANDERSEN, Novato, CA A6IP 25/6 (2006.01) (US); HWAN KIM, San Francisco, CA (52) U.S. Cl...... 424/677 (US) (73) Assignee: BUCKINSTITUTE FOR (57) ABSTRACT RESEARCH ON AGING, Novato, CA (US) In various embodiments methods of delaying the onset of (21) Appl. No.: 13/422,960 and/or mitigating the severity of one or more symptoms of Parkinson's disease in a mammal are provided. In certain (22) Filed: Mar 16, 2012 embodiments the methods involve administering to a mam mal diagnosed as having or as at risk for Parkinson's disease Related U.S. Application Data a chronic low dose of lithium (e.g., a Subtherapeutic dose). In (60) Provisional application No. 61/453,477, filed on Mar. certain embodiments the low dose lithium is administered in 16, 2011. conjunction with another agent (e.g., L-DOPA). No Lithium + Pavis Lithium + Paib No Liti Patent Application Publication Jan. 17, 2013 Sheet 1 of 13 US 2013/0017274 A1

No Lithium + Polis Lithium + Paris No Lithium - Points A. E

Patent Application Publication Jan. 17, 2013 Sheet 2 of 13 US 2013/0017274 A1

8 : : : : x S. & : 3. : ... x: : & {f} : i. : & - asw x: X.K: 3 &3. : & 3 sis.8. ;a s: 8::

k 8 Patent Application Publication Jan. 17, 2013 Sheet 3 of 13 US 2013/0017274 A1

O3. CX

x ------

Fig. 2, cont'd. Patent Application Publication Jan. 17, 2013 Sheet 4 of 13 US 2013/0017274 A1

Patent Application Publication Jan. 17, 2013 Sheet 5 of 13 US 2013/0017274 A1

Fig. 4 Patent Application Publication Jan. 17, 2013 Sheet 6 of 13 US 2013/0017274 A1

Fig. 4, cont'd. Patent Application Publication Jan. 17, 2013 Sheet 7 of 13 US 2013/0017274 A1

& &

&S

& &S &

&SSSSSSS & 88.88: 8x8 8:::::::::::x:28:8:

&

Fig. Patent Application Publication Jan. 17, 2013 Sheet 8 of 13 US 2013/0017274 A1

Hindlimb clasping 3 days of tests were combined

88: :

| Patent Application Publication Jan. 17, 2013 Sheet 9 of 13 US 2013/0017274 A1

Patent Application Publication Jan. 17, 2013 Sheet 10 of 13 US 2013/0017274 A1

TH-HC: random examples in ST

-- - c. 2: iR-- cott 3 : 3 & : 4.e P+ Siemet 5: PTP+ i +Sir Fig. 8A Patent Application Publication Jan. 17, 2013 Sheet 11 of 13 US 2013/0017274 A1

TH+ stain in Str.

:texificatist- satsika. 8x338gies is 8 Fig. 8B Patent Application Publication Jan. 17, 2013 Sheet 12 of 13 US 2013/0017274 A1

r:

|?%|* *H|||||||||||||||||||||||#!!ººº, ºz. **…* (*>. Fig. 9

:

***** odNsuisileo+HL 000 2.

%

Fig. 10 Patent Application Publication Jan. 17, 2013 Sheet 13 of 13 US 2013/0017274 A1

t3 8 US 2013/001 7274 A1 Jan. 17, 2013

LOW DOSE LITHIUM IN THE TREATMENT cells. Most idiopathic Parkinson's disease patients also have OR PROPHYLAXIS OF PARKINSONS Lewy bodies in their brain tissue, but the distribution is denser DISEASE and more widespread in DLB. Even so, the relationship between Parkinson's disease, Parkinson's disease with CROSS-REFERENCE TO RELATED , and dementia with Lewy bodies (DLB) might be APPLICATIONS most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders. 0001. This application claims benefit of and priority to 0007. The Parkinson-plus diseases may progress more U.S. Ser. No. 61/453,477, filed on Mar. 16, 2011, which is quickly than typical idiopathic Parkinson disease. If cognitive incorporated herein by reference in its entirety for all pur dysfunction occurs before or very early in the course of the poses. movement disorder then DLB may be suspected. Early pos tural instability with minimal tremor especially in the context STATEMENT OF GOVERNMENTAL SUPPORT of ophthalmoparesis should suggest PSP. Early autonomic 0002. Not Applicable dysfunction including erectile dysfunction and syncope may Suggest MSA. The presence of extreme asymmetry with BACKGROUND OF THE INVENTION patchy cortical cognitive defects such as dysphasia and aprax 0003 Aside from Alzheimer's disease, Parkinson's dis ias especially with “alien limb' phenomena should suggest ease is the most well-known disease in the neurodegenerative CBD. disease group. Parkinson's disease (PD) is a chronic and progressive degenerative disease of the brain that impairs SUMMARY motor control, speech, and other functions. In particular, it is 0008. In various embodiments methods of slowing the characterized by (1) a slowing down of all movements onset and/or inhibiting the onset and/or severity of one or (bradykinesia), quiet and monotonous speech (akinesia or more symptoms of Parkinson's Disease and/or a “Parkin hypokinesia), absence of the physiological associated move sons-plus disease are provided. In certain embodiments the ments, a stooped posture, a small-step, partially shuffling gait, methods involve the administration of low dose lithium alone, handwriting which becomes Smaller as the writing continues, or in combination with one or more pharmacological agents uncontrollable disturbances in movement, with a tendency to (e.g., L-DOPA). fall forward to the side or backward, (2) rigidity of the mus 0009. In various embodiments lithium and/or L-DOPA is culature (rigor), and (3) coarse resting tremor (trembling). provided in a form that is not a naturally occurring form, Parkinson's disease is a disease that occurs relatively fre and/or a nutritional or dietary Supplement. In various embodi quently and develops in approx. 1% of individuals aged over ments lithium is provided in a form that is not lithium orotate. 60, in particular in men. The disease is caused by loss of 0010. In various embodiments methods of slowing the in the striatum, resulting in the degeneration of onset and/or inhibiting the onset and/or severity of one or neurons in the Substantia nigra. The primary reason for loss of more symptoms of Parkinson's Disease and/or a “Parkin dopamine is not known (Dunnett and Bjorklund (1999) sons-plus disease are provided. In certain embodiments the Nature 399: A32-A39; Olanow and Tatton (1999) Annu Rev. methods involve the administration of low dose lithium alone, Neurosci. 22: 123-144). or in combination with one or more pharmacological agents 0004. The motor symptoms of PD are caused by loss of (e.g., L-DOPA). nerve cells that secrete dopamine in a tiny midbrain area 0011. In various embodiments lithium and/or L-DOPA is called the Substantia nigra. For reasons that are not fully provided in a form that is not a naturally occurring form, understood, these nerve cells are especially vulnerable to and/or a nutritional or dietary Supplement. In various embodi damage of various sorts, including , disease, and head ments lithium is provided in a form that is not lithium orotate. trauma. The term Parkinsonism is used for any process that 0012. In various embodiments a method of delaying the destroys large numbers of these cells and thereby causes the onset of and/or mitigating the severity of one or more symp same characteristic symptoms. Parkinson's disease, or more toms of Parkinson's disease in a mammal is provided. The fully, idiopathic Parkinson's disease, is typically diagnosed method typically involves administering to a mammal diag when no specific physical cause for the loss of dopamine cells nosed as having or as at risk for Parkinson's disease a chronic can be identified. low dose of lithium. In certain embodiments the low dose is a 0005. The term Parkinsonism is used for symptoms of subtherapeutic dose. In certain embodiments the low dose is tremor, stiffness, and slowing of movement caused by loss of a low therapeutic dosage. In certain embodiments the low dopamine cells in the Substantia nigra. “Parkinson's disease' dose is a dosage that results in an average serum concentra is the synonym of “primary Parkinsonism', i.e. isolated Par tion below about 0.5 mM or 0.4 mM, or below about 0.3, mM, kinsonism due to a neurodegenerative process without any or below about 0.2 mM, or below about 0.1 mM. In certain secondary systemic cause. In some cases, it would be inac embodiments the dosage ranges from about 0.05 mM, or 0.1 curate to say that the cause is “unknown” because a small mM to about 0.2 mM, or 0.3 mM, or 0.4 mM, or 0.5 mM. In proportion is caused by identifiable genetic mutations. T is certain embodiments the mammal is a human. In various possible for a patient to be initially diagnosed with Parkin embodiments human is not under treatment for a neuropsy son's disease but then to develop additional features requiring chiatric disorder. In various embodiments the human is not revision of the diagnosis. under treatment for one or more disorders selected from the 0006. There are other disorders called Parkinson-plus dis group consisting of mania, Schizophrenia, bipolar disorder, eases. These include: multiple system atrophy (MSA), pro and psychosis. In certain embodiments the mammal is a gressive Supranuclear palsy (PSP), corticobasal degeneration human diagnosed as having Parkinson's disease. In certain (CBD), and dementia with Lewy bodies (DLB). Lewy bodies embodiments the mammal is a human diagnosed as at risk for are abnormal aggregates of protein that develop inside nerve Parkinson's disease. In certain embodiments the human is a US 2013/001 7274 A1 Jan. 17, 2013

human 40 years of age or older, or 45 years of age or older, or certain embodiments the dosage ranges from about 0.05 mM, 50 years of age or older, or 55 years of age or older, or 60 years or 0.1 mM to about 0.2 mM, or 0.3 mM, or 0.4 mM, or 0.5 of age or older, or 65 years of age or older, or 70 years of age mM. In various embodiments the mammal is a human. In or older, or 75 years of age or older. In certain embodiments certain embodiments the human is not under treatment for a the administration is before the onset of cardinal motor Symp neuropsychiatric disorder. In certain embodiments the human toms of Parkinson's disease. In certain embodiments the is not under treatment for one or more disorders selected from administration is to a subject diagnosed as having olfactory the group consisting of mania, Schizophrenia, bipolar disor dysfunction. In certain embodiments the human is diagnosed der, and psychosis. In certain embodiments the mammal is a with one or more conditions selected from the group consist human diagnosed as having Parkinson's disease. In certain ing of tremor, bradykinesia, and muscle rigidity. embodiments the mammal is a human diagnosed as at risk for Parkinson's disease. In certain embodiments the human is a 0013 Methods are also provided for delaying the onset of human 40 years of age or older, or 45 years of age or older, or and/or mitigating the severity of one or more symptoms of 50 years of age or older, or 55 years of age or older, or 60 years Parkinson's disease in a mammal, where the methods typi of age or older, or 65 years of age or older, or 70 years of age cally involve administering to a mammal determined to have or older, or 75 years of age or older. In certain embodiments or to be at risk for Parkinson's disease a chronic low dose of the administration is before the onset of cardinal motor Symp lithium in conjunction with one or more pharmaceutically toms of Parkinson's disease. In certain embodiments the active agents selected from the group consisting of L-3,4- administration is to a subject diagnosed as having olfactory dihydroxyphenylalanine (L-DOPA) and/or a derivative dysfunction. In certain embodiments the human is diagnosed thereof, a MAOB inhibitor, and a . In certain with one or more conditions selected from the group consist embodiments the second agent comprises L-DOPA or a ing of tremor, bradykinesia, and muscle rigidity. derivative thereof. In certain embodiments the second agent comprises a L-DOPA/ combination. In certain 0014. In certain embodiments a formulation for delaying embodiments the lithium is administered prior to second the onset of and/or mitigating the severity of one or more agent or after the second agent, or simultaneously with the symptoms of Parkinson's disease is provided. The formula second agent. In certain embodiments the lithium and the tion typically comprises lithium; L-DOPA and/or a derivative second agent(s) are administered in a combined formulation. thereof, and one or more pharmaceutically acceptable excipi In certain embodiments the method further comprises admin ents. In certain embodiments the formulation further com istering the lithium, and L-DOPA in conjunction with a prises a DOPA decarboxylase inhibitor and/or a COMT DOPA decarboxylase inhibitor and/or a COMT inhibitor and/ inhibitor, and/or pyridoxal phosphate. In certain embodi orpyridoxal phosphate. In certain embodiments the lithium is ments the lithium a lithium salt. In certain embodiments the administered as a lithium salt. In certain embodiments the L-DOPA is provided as an L-DOPA ethyl ester. In certain L-DOPA is provided as an L-DOPA ethyl ester. In certain embodiments the formulation further comprises a peripheral embodiments the L-DOPA is provided as a combined DOPA decarboxylase inhibitor (DDCI). In certain embodi L-DOPA/carbidopa (e.g., SINEMETR) formulation. In cer ments the DDCI is selected from the group consisting of tain embodiments the L-DOPA is administered in a sub , carbidopa, and . In certain embodi therapeutic dose for Parkinson's disease. In certain embodi ments the formulation comprises carbidopa. In certain ments the method comprises administering a peripheral embodiments the formulation comprises a catechol-O-me DOPA decarboxylase inhibitor (DDCI). In certain embodi thyl transferase (COMT) inhibitor. In certain embodiments ments the DDCI is selected from the group consisting of the COMT inhibitor is selected from the group consisting of benserazide, (25)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2- , , and . In certain embodi methylpropanoic acid (carbidopa), and methyldopa. In cer ments the COMT inhibitor is entacapone. tain embodiments the L-DOPA and DDCI (e.g., carbidopa) are provided as a combined formulation. In certain embodi DEFINITIONS ments the method comprises administering a catechol-O- methyl transferase (COMT) inhibitor (e.g., entacapone, tol 0015. As used herein, “administering refers to local and/ capone, nitecapone, and the like). In certain embodiments the or systemic administration, e.g., including enteral and second agent comprises a MAOB inhibitor (e.g., , parenteral administration. Routes of administration for the desmethylselegiline, , , AGN-1135, MDL active agent(s) described herein include, but are not limited to 72195, J 508, , millacemide, , D-depre oral administration, administration as a Suppository, topical nyl, , and the like). In certain embodiments the contact, intravenous administration, intraperitoneal adminis MAOB inhibitor is administered in a sub-therapeutic dose for tration, intramuscular administration, intralesional adminis Parkinson's disease. In certain embodiments the secondagent tration, nasal administration, Subcutaneous administration, comprises a dopamine agonist (e.g., , caber the implantation of a slow-release and/or regulated release goline, , , , , apomor device e.g., a mini-osmotic pump, a depot formulation, etc., phine, rigotine, quinagolide, fenoldopam, , and the to a subject. Administration can be by any route including like). In certain embodiments the dopamine agonist is admin parenteral and transmucosal (e.g., oral, nasal, vaginal, rectal, istered in a sub-therapeutic dose for Parkinson's disease. In or transdermal). Parenteral administration includes, e.g., certain embodiments the lithium is administered at a chronic intravenous, intramuscular, intra-arteriole, intradermal, Sub low dose. In certain embodiments the low dose is a subthera cutaneous, intraperitoneal, intraventricular, ionophoretic and peutic dose. In certain embodiments the low dose is a low intracranial. Other modes of delivery include, but are not therapeutic dosage. In certain embodiments the low dose is a limited to, the use of liposomal formulations, intravenous dosage that results in an average serum concentration below infusion, transdermal patches, etc. about 0.5 mM, or below about 0.4 mM, or below about 0.3, 0016. In certain embodiments administering can include mM, or below about 0.2 mM, or below about 0.1 mM. In causing to be administered for example by prescribing for a US 2013/001 7274 A1 Jan. 17, 2013

Subject, annotating a patient's medical record, instructing an 0024. A “subtherapeutic dosage” refers to a dosage that is agent or other person to administer, and the like. below that typically used for the Subject agent in typical 0017. The terms “systemic administration' and “systemi therapeutic or prophylactic use. Thus, for example, lithium cally administered’ refer to a method of administering one or dosages typically range from a serum concentration of 0.4 more compound(s) or composition(s) to a mammalso that the mM to about 1.6 mM. A subtherapeutic dosage in this context compound(s) or composition(s) are delivered to sites in the typically results in serum concentrations below 0.4 mM. In body, including the targeted site of pharmaceutical action, certain embodiments the low-therapeutic or subtherapeutic via, for example, the circulatory system. Systemic adminis dose is defined with respect to the condition being treated. tration includes, but is not limited to, oral, intranasal, rectal Thus, for example, a Subtherapeutic dose of an agent (e.g., and parenteral (e.g., other than through the alimentary tract, lithium, MAOB inhibitors, dopamine agonists, etc.) for Par Such as intramuscular, intravenous, intra-arterial, transdermal kinson's disease is a dose lower than that typically prescribed and Subcutaneous) administration. for Parkinson's disease relying, e.g., on an additive or syner 0018. The phrase “effective amount’ means a dosage or gistic effect with another agent to facilitate the desired effect. dosage regimen Sufficient to produce a desired result. 0025. When a Markush Group or a list of particular com 0019. The term “coadministering or “concurrent admin pounds is described in the specification and/or claims it is istration', when used, for example with respect to the active intended that in various additional or alternative embodi agent(s) described herein (e.g., lithium and L-DOPA, lithium ments any Subset of that Markush group or list is contem and L-DOPA/carbidopa, etc.) refers to administration of the plated. Thus, for example, a Markush group or list consisting active agents such that both can simultaneously achieve a of elements A, B, and C also comprises a disclosure of a physiological effect. The two agents, however, need not be Markush Group or list consisting of A, and B, a Markush administered together. In certain embodiments, administra Group or list consisting of B, and C, and a Markush Group or tion of one agent can precede administration of the other. list consisting of A and C as well as elements A, B, and C Simultaneous physiological effect need not necessarily individually. Similarly, when elements in one list or Markush require presence of both agents in the circulation at the same group are described as being in combination with elements in time. However, in certain embodiments, coadministering another list or Markush group the combination of any one typically results in both agents being simultaneously present element of one group with any one element of another group in the body (e.g. in the plasma) at a significant fraction (e.g. is contemplated. Thus where a list or Markush Group con 20% or greater, preferably 30% or 40% or greater, more sisting of A, B and C is disclosed in combination with another preferably 50% or 60% or greater, most preferably 70% or list or Markush Group consisting of D, E, and F, the descrip 80% or 90% or greater) of their maximum serum concentra tion is to be recognized as contemplating the combinations tion for any given dose. A/D, A/E, A/F, B/D, B/E, B/F, C/D, C/E, C/F and/or any 0020. As used herein, the terms “treating and “treatment' combination of A, B, or C with any subgroup or member of D. refer to delaying the onset of retarding or reversing the E. and F, and/or any combination of D, E, or F, with any progress of reducing the severity of oralleviating or prevent Subgroup or member of A, B, and C. ing either the disease or condition to which the term applies, or one or more symptoms of Such disease or condition. BRIEF DESCRIPTION OF THE DRAWINGS 0021. The term “mitigating refers to reduction or elimi 0026 FIG. 1, panels A-G shows that lithium prevents oxi nation of one or more symptoms of that pathology or disease, dized/nitrated alpha-synuclein accumulation in multiple and/or a reduction in the rate or delay of onset or severity of brain regions. Examples are shown of OB (panels A, CandE) one or more symptoms of that pathology or disease, and/or and striatum (panels B, D and F). Mean density-SEM after the prevention of that pathology or disease. background correction (a.u. arbitrary unit) (panel G). One 0022. As used herein, the phrase “consisting essentially way ANOVA, the Dunnett's post hoc test (n=6 each); *. of refers to the genera or species of active pharmaceutical p-0.05, **, p<0.01, n.s., not significant compared to no agents included in a method or composition, as well as any lithium group--PQ/MB (black bars). Cont: no lithium without excipients inactive for the intended purpose of the methods or PQ/MB injection. Size bar: 250 um. Abb.: GL, glomerular compositions. In some embodiments, the phrase “consisting layer: GCL, granule cell later; St, striatum: SNpc. Substantia essentially of expressly excludes the inclusion of one or Nigra pars compacta, HP, hippocampus; CX, cortex. more additional active agents other than the active agents 0027 FIG. 2, panels A-G shows that lithium prevents described herein (e.g., receptor antagonists such as oxidized/nitrated alpha-synuclein accumulation (oxi/nit loxapine and/or loxapine analogues, and/or cyproheptadine C-Syn, 16 kD) in multiple brain regions of neuronal human and/or cyproheptadine analogues). A53T mutant expressing mice chronically exposed to 0023 The terms “subject,” “individual,” and “patient” PQ/MB. Examples of Western blot analysis of high salt (panel interchangeably refer to a mammal, preferably a human or a A) and RIPA (panel B) soluble extracts are displayed and non-human primate, but also domesticated mammals (e.g., densitometric analyses in oxi/nit C.-syn Western blots shown canine or feline), laboratory mammals (e.g., mouse, rat, rab in BS (panel C), OB (panel D), Cx (panel E), Cb (panel F), and bit, hamster, guinea pig) and agricultural mammals (e.g., St (panel G) of high salt samples, normalized for B-actin equine, bovine, porcine, Ovine). In various embodiments, the loading. *, p<0.05, **, p<0.01 versus vehicle with PQ/MB Subject can be a human (e.g., adult male, adult female, ado (black bars) as assessed by one-way ANOVA, the Dunnett's lescent male, adolescent female, male child, female child) post hoc test (n=3-6 per group). Abb.: BS, Brain stem; OB, under the care of a physician or other health worker in a olfactory bulb. Cx, cortex; Cb, cerebellum; St, striatum: Li, hospital, psychiatric care facility, as an outpatient, or other lithium treatment; PO/MB, paraquat/maneb treated group. clinical context. In certain embodiments the Subject may not 0028 FIG. 3, panels A-G shows that lithium prevents be under the care or prescription of a physician or other health oxidized/nitrated alpha-synucleinaccumulation in mitral (ar worker. rows in panels A and D) and Purkinje cells (arrows in panels US 2013/001 7274 A1 Jan. 17, 2013

Band E). Panels A, B, and C: vehicle-treated group; Panels D. expressing cell line recently created by our E. and F: lithium-treated group. Panels C and F are enlarge laboratory. In vivo lithium administration (0.255% lithium ments of panels B and E, respectively. Panel G. Oxidized/ chloride) delivered in feed to 9 month old pan-neuronal nitrated alpha-synuclein positive cells were stereologically human alpha-synuclein expressing transgenic mice over a 3 counted and reported as meant-SEM (n-6-7 each). **, p<0.01 month period was sufficient to prevent accumulation of oxi Versus controls as assessed by paired t-test. Bar: 75um. dized/nitrated alpha-synuclein in multiple brain regions pre 0029 FIG. 4, panels A-I, shows that lithium protects viously shown to occur as a consequence of paraquat/maneb against neuronal cell death in several brain regions. Mitral administration in these transgenics. This included in the cells (panels A and D) and Purkinje cells (panels B and E) glomerular layer, mitral cells, and the granule cell layer of the were specifically labeled with anti-5HT2A receptor antibody olfactory bulb (OB), the striatum (ST), the substantia nigra and SNpc DA neurons (panels C and F) with anti-TH anti pars compacta (SNpc), in Purkinje cells of the cerebellum body. Total cell numbers were stereologically counted fol (Cb), and the cortex (FIGS. 1-3). lowing specific cell labeling (panel G. mitral cells; H. 0040 Lithium was found to not only prevent alpha-sy Purkinje cells; panel I, SNpc DA cells) and reported as nuclein accumulation in various brain regions, but also to meaniSEM (n=6-7 each). *, p<0.05, **, p<0.01 versus protect against neuronal cell loss in this model (FIG. 4). vehicle control as assessed by paired t-test. Bar: 100 um. Importantly, this dosage has previously been demonstrated to 0030 FIG. 5 shows hindlimb clasping studies. result in sera lithium levels in the low therapeutic range (0.65 0031 FIG. 6 shows results of a hindlimb clasping test as a 0.8 mM) in mice independent of strain with no effect on motor function of treatment. Three days of tests were combined. function. 0032 FIG. 7 shows an analysis of the hindlmib clasping 0041. In addition, low dose lithium when used in combi tests for each treatment. The average instances of hindlimb nation with SINEMETR) was shown provide a synergistic clasping are shown for each treatment. Clasping counted for improvement in locomotor behavior compared to 10 seconds for 3 consecutive days was combined for data SINEMETR) alone. Moreover this improvement does not analysis (MeaniSEM, unpaired t-test: *: p<0.05, *: p<0.01, appear to be associated with dyskinesias observed at higher n=7, 9, 6, 6, and 9 in order above). lithium dosages previously used in humans. Accordingly it is 0033 FIG. 8A illustrates striatum samples taken for mea believed that lithium used in combination with L-DOPA and/ surement of dopamine levels within the striatum via or a levodopa/carbidopa combination can show Substantially hydroxylase (TH) staining. FIG. 8B shows TH+ staining in improved long term benefit to a Subject under Such treatment. the striatum for four treatments (no MPTP-saline, MPTP 0042. As indicated above, in view of these, and other data, saline, MPTP-lithium, and MPTP-lithium-i-SINEMETR). it is believed that chronic administration of lithium in low 0034 FIG. 9 illustrates the effect of treatment on therapeutic doses or Sub-therapeutic dosages can be used be TH+Density in ST. Results are evaluated using a one way used to inhibit the onset and/or rate of progression and/or ANOVA, Dunnett's test: *: p<0.05, *: p<0.01, compared severity of one or more symptoms of Parkinson's disease with MPTP+Sal (ii), n=6-8 each group. and/or of a Parkinson's-plus condition. It is also contem 0035 FIG. 10 illustrates the effect of treatment on TH+ plated that the chronic low-therapeutic or sub-therapeutic cell count in SNpc. One way ANOVA, Dunnett's test: *: p<0.05, *: p<0.01, compared with MPTP+Sal (it), n=6-8 dose lithium can be used in conjunction with certain other each group. agents (e.g., L-DOPA and/or derivatives thereof) to achieve 0036 FIG. 11 shows the results of an N27 AT-cell, 20 S improved efficacy in the treatment or prophylaxis of Parkin proteasomal assay. One way ANOVA, Dunnett's test: *: p<0. son's disease or a Parkinson's-plus condition. 0043. In addition, combined formulations are contem 05, **: p<0.01, compared with No Li+MPP+(), n=6-8 each plated, especially (but not limited to) combination formula group. tions of lithium and levodopa/carbidopa (e.g., SINEMETR) DETAILED DESCRIPTION combinations. 0037. In various embodiments methods of slowing the Pharmaceutical Formulation. onset and/or inhibiting the onset and/or severity of one or more symptoms of Parkinson's Disease and/or a “Parkin 0044. In various embodiments the methods described sons-plus disease are provided. In certain embodiments the herein contemplate administering low dosage (e.g., low methods involve the administration of low dose lithium alone, therapeutic dosage, or sub-therapeutic dosage) lithium alone or in combination with one or more pharmacological agents for the treatment or prophylaxis of Parkinson's disease or in (e.g., L-DOPA). combination with one or more additional agents. Such addi 0038. In particular it is believed that chronic low dosage tional agents include, but are not limited to L-DOPA, L-car administration of lithium alone, or in combination with cer bidopa, L-DOPA/carbidopa combinations, DOPMAOB tain other agents affords a neuroprotective effect and can be inhibitors, dopamine agonists, and the like. Particularly used to inhibit the onset and/or rate of progression and/or where the second agent comprises L-DOPA or a derivative severity of one or more symptoms of Parkinson's disease thereof administration of additional agents can include and/or of a Parkinson's-plus condition. administration of one or more DOPA decarboxylase inhibi 0.039 Our recent data indicate that that chronic lithium tors (DDCIs) and/or one or more catechol-O-methyl trans administration can prevent both oxidative stress-induced ferase (COMT) inhibitors alpha-synuclein accumulation and neuronal cell death in PD 0045 Lithium. models at dosages in the low therapeutic range and it is 0046 Lithium is available in a wide number of pharma believed in the Sub-therapeutic range. Lithium administration ceutical formulations. Typically, lithium is provided as a salt was initially found to protect against in vitro cell death in a e.g., lithium carbonate (LiCo), lithium citrate (Li-CHO), hydrogen peroxide treated, stable human alpha-synuclein lithium sulfate (LiSO), lithium chloride (LiCl), and the like. US 2013/001 7274 A1 Jan. 17, 2013

0047. In various embodiments the lithium can be provided include, for example, one or more additional agents include, as an orally administered formulation, e.g., fluid, caplet, cap a DOPA decarboxylase inhibitor (DDCI) or aromatic Sule, gelcap, tablet, and the like, as an injectable, as a depot L-amino acid decarboxylase inhibitor (DDCI), and/or a cat formulation, as a timed-release or slow-release formulation, echol-O-methyl transferase (COMT) inhibitor. as an inhalable composition, and the like. 0058. In various embodiments peripheral DDCIs inca 0048. In certain embodiments, the lithium will be pro pable of crossing the blood-brain-barrier (BBB) can be used vided at a dosage that produces a low therapeutic serum in conjunction with the L-DOPA to block the peripheral con concentration. In certain embodiments the low-therapeutic version of L-DOPA into dopamine and thereby reduce dosage will be a dosage that provides an average serum con adverse side effects. Illustrative DDCIs include, but are not centration ranging from about 0.4 mM to about 1.2 mM, limited to benserazide (e.g., MADOPARR, PROLOPAR), preferably from about 0.4 mM to about 1.0 mM, more pref MODOPARR, MADOPARKOR), NEODOPASOL(R), erably from about 0.4 mM to about 0.8 mM, and most pref EC-DOPARYL(R), etc.), carbidopa (e.g., LODOSYNR, erably from about 0.4 mM to about 0.6 mM. SINEMETR, PARCOPAR, ATAMETR, STALEVOR), etc.), 0049. In certain embodiments the lithium is provided as a methyldopa (e.g., ALDOMETR), ALDORIL(R), Subtherapeutic dosage. An illustrative Sub-therapeutic dosage DOPAMETR, DOPEGYTR), etc.), and the like. produces a serum lithium concentration ranging from about 0059 A typical illustrative dosage of combinations of 0.05 mM up to about 0.39 mM. In certain embodiments the L-DOPA and DDCIs (e.g., SINEMETR, etc.) is SINEMETR Sub-therapeutic dosage produces a serum lithium concentra 25:100 t.i.d. with 100 mg of levodopa TID (300 mg per day). tion range from a low of about 0.1 mM, or about 0.15 mM, or A typical maintenance dose is between about 300 mg/day up about 0.2 mM, to a high of about 0.3 mM, or about 0.34 mM, to 800 mg 1-dopaper day. The bottom of the therapeutic range or about 0.46 mM, or about 0.39 mM. is 280 mg/day of SINEMETR) (L-DOPA). Accordingly, in 0050. The particular dosage administered to a subject can certain embodiments, a subtherapeutic dosage is below 280 vary with the formulation. Typically the serum lithium is mg/day, preferably below about 270 mg/day, or below about monitored in the Subject according to methods well known to below about 260 mg/day, or below about 250 mg/day, or those of skill in the art until the optimal administered dosage below about 240 mg/day, or below about 230 mg/day, or is identified. below about 220 mg/day, or below about 210 mg/day, or 0051 Lithium is also available as a nutritional supplement below about 200 mg/day. in the form of lithium orotate. In certain embodiments the use 0060 Catechol-O-Methyl Transferase (COMT) Inhibitors of lithium orotate is expressly excluded. 0061. In various embodiments the L-DOPA/lithium are 0052 L-3,4-dihydroxyphenylalanine (L-DOPA). administered in conjunction with a COMT inhibitor. A 0053. In certain embodiments the chronic low dosage COMT inhibitor is nagent that inhibits the action of catechol lithium can be administered in conjunction with one or addi O-methyl transferase. This is involved in degrading tional agents. One Such agent comprises L-3,4-dihydrox neurotransmitters. Illustrative pharmaceutical examples yphenylalanine (L-DOPA) and/or a derivative thereof. Illus include, but are not limited to entacapone, tolcapone, and trative L-DOPA derivatives include, but are not limited to nitecapone. L-DOPA amides (see, e.g., Zhou et al. (2010) Eur: J. Med. 0062. It is noted that all of the foregoing active agents are Chem., 45(9):4035-4542, which is incorporated herein by commercially available as pharmaceutical formulations and, reference for the compounds described therein), L-DOPA in certain embodiments, the use of Such formulations is con esters (see, e.g., PCT Publication WO/1986/004579, which is templated. incorporated herein by reference for the compounds 0063 MAOB Inhibitors. described therein), glycosyl derivatives of L-DOPA (see, e.g., 0064. In certain embodiments administration of one or Bonina, et al. (2003).J. Targeting, 11(1): 25-36, which more MAOB inhibitors in conjunction with lithium is con is incorporated herein by reference for the compounds templated for the treatment or prophylaxis of PD. In certain described therein), hydrogen sulfide-releasing L-DOPA embodiments selective MAOB inhibitors are contemplated, derivatives (see, e.g., Lee et al. (2010) J. Biol. Chem., 285 while in other embodiments, non-selective MAOB inhibitors (23): 17318-17328, which is incorporated herein by reference are contemplated. Illustrative MAOB inhibitor(s) include, but for the compounds described therein), and the like. are not limited to selegiline (e.g., DEPRENYL(R), 0054. In certain embodiments the L-DOPA can be admin ELDEPRYL(R), EMSAMR), JUMEXR, JUMEXALR CAR istered in standard therapeutic dosages for PD. In certain BEXR, ELDEPRYL(R), MOVERGANR); APTAPRYL(R), embodiments the L-DOPA can be administered in a low ANIPRYL(R); ELDEPRINE(R); PLURIMENR), desmeth therapeutic dose. ylselegiline, pargyline (EUDATINR, SUPIRDYL(R), EUTO 0055. In certain embodiments it is believed that the low NYL(R), see, e.g., U.S. Pat. No. 3,155,584, which is incorpo dose lithium can act additively or even synergistically with rated herein by reference), rasagiline R(+)N-propargyl the L-DOPA. Thus, in certain embodiments it is contemplated laminoindan (e.g., AZILECTR), 3-N-phenylacetylamino-2, that the L-DOPA can be administered in sub-therapeutic 5-piperidinedione, caroxyazone, AGN-1135 (see, e.g., WO doses. In certain embodiments L-DOPA is administered in a 92/21333), MDL 72195 (see, e.g., WO 92/21333), J 508 (see, Subtherapeutic dosage of less than 0.5 mg/day, or less than e.g., WO 92/21333), lazabemide (e.g., PAKIOR), TEM about 0.4 mg/day, or less than about 0.3 mg/day, or less than PIUM(R), also see, e.g., WO 2000/045846), millacemide (see, about 0.2 mg/day. e.g., WO 00/45846), IFO (see, e.g., WO 00/45846), mofe 0056 Dopa Decarboxylase Inhibitors (DDCIs) giline (see, e.g., WO 00/45846), and 5-(4-(4,4,4-trifluorobut 0057. In certain embodiments, particularly where the oxy)phenyl)-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)- L-DOPA/lithium are administered in conjunction with the one (see, e.g., PCT/FR2000/000193 (WO 2000/045846)), lithium administration of one or more additional agents in D-deprenyl, ladostigil, millacemide, mofegiline, and the like. conjunction with the L-DOPA are contemplated. Such agents In certain embodiments, prodrugs or metabolites of the US 2013/001 7274 A1 Jan. 17, 2013

MAOB inhibitors are contemplated. Typically the metabolite peutic doses) and the other active agents as described herein has substantially the same or better selective MAO-B inhibi in therapeutic doses, low therapeutic doses, or Subtherapeutic tor activity as its unmetabolized form. doses). 0065. In certain embodiments, a prodrug of a MAOB 0076. The combined formulations contemplated herein inhibitor comprises a derivatized MAOB inhibitor that is can comprise each of the component agents (e.g., lithium, metabolized in vivo into the active inhibitory agent. Prodrugs L-DOPA, etc.) the “native' form or, if desired, in the form of typically have substantially the same or better therapeutic salts, esters, amides, prodrugs, derivatives, and the like, pro value than the underivatized MAOB inhibitor(s). vided the salt, ester, amide, prodrug or derivative is Suitable 0.066. In certain embodiments the MAOB inhibitor can be pharmacologically, e.g., effective in the present method(s). administered in standard therapeutic dosages for PD. In cer Salts, esters, amides, prodrugs and other derivatives of the tain embodiments the MAOB inhibitor can be administered in agents described herein can be prepared using standard pro a low therapeutic doses. cedures known to those skilled in the art of synthetic organic 0067. In certain embodiments it is believed that the low chemistry and described, for example, by March (1992) dose lithium can act additively or even synergistically with Advanced Organic Chemistry, Reactions, Mechanisms and the MAOB inhibitor(s). Thus, in certain embodiments it is Structure, 4th Ed. N.Y. Wiley-Interscience. contemplated that the MAOB inhibitor(s) can be adminis 0077. For example, acid addition salts are prepared from tered in Sub-therapeutic doses. the free base using conventional methodology that typically 0068 Illustrative doses for MAOB inhibitors are for rasa involves reaction with a suitable acid. Generally, the base giline monotherapy 1 mg daily in combination with L-Dopa form of the drug is dissolved in apolar organic solvent such as 0.5-1.0 mg daily. Accordingly, in certain embodiments, Sub methanol or and the acid is added thereto. The result therapeutic MAOB inhibitor (rasagiline) dose is less than 0.5 ing salt either precipitates or can be brought out of solution by mg/day, or less than about 0.4 mg/day, or less than about 0.3 addition of a less polar solvent. Suitable acids for preparing mg/day, or less than about 0.2 mg/day. Similarly, selegiline is acid addition salts include both organic acids, e.g., acetic typically administered at 1.25-2.5 mg per day on mainte acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, nance. Sub therapeutic dosages are less than 1.25 mg/day, malic acid, malonic acid. Succinic acid, maleic acid, fumaric preferably less than about 1.2 mg/day, or less than about 1.1 acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mg/day, or less than about 1.0 mg/day, or less than about 0.9 mandelic acid, methanesulfonic acid, ethanesulfonic acid, mg/day, or less than about 0.8 mg/day, or less than about 0.7 p-toluenesulfonic acid, Salicylic acid, and the like, as well as mg/day, or less than about 0.6 mg/day, or less than about 0.5 inorganic acids, e.g., hydrochloric acid, hydrobromic acid, mg/day, or less than about 0.4 mg/day. Sulfuric acid, nitric acid, phosphoric acid, and the like. An 0069 Dopamine Agonists. acid addition salt may be reconverted to the free base by treatment with a suitable base. Certain addition salts include 0070. In certain embodiments administration of one or are halide salts, such as may be prepared using hydrochloric more MAOB inhibitors in conjunction with lithium is con templated for the treatment or prophylaxis of PD. Dopamine or hydrobromic acids. Conversely, basic salts are prepared in agonists include bromocriptine (e.g., PARLODEL(R), caber a similar manner using a pharmaceutically acceptable base goline (e.g., DOSTINEX(R), pergolide (e.g., PERMAX(R), Such as sodium hydroxide, potassium hydroxide, ammonium pramipexole (e.g., MIRAPEXR, SIFROL(R), ropinirole (e.g., hydroxide, calcium hydroxide, trimethylamine, or the like. REQUIPR), piribedil, (e.g., APOKYNR), Illustrative basic salts include alkali metal salts, e.g., the rigotine (e.g., NEUPROR), quinagolide (e.g., NORPRO Sodium salt, and copper salts. 0078. In certain embodiments for the preparation of salt LAC(R), fenoldopam, and lisuride. forms of basic drugs, the pKa of the counterion is preferably 0071. In certain embodiments the dopamine agonist(s) can at least about 2 pH lower than the pKa of the drug. Similarly, be administered in standard therapeutic dosages for PD. In for the preparation of salt forms of acidic drugs, the pKa of the certain embodiments the dopamine agonist(s) can be admin counterion is preferably at least about 2 pH higher than the istered in a low therapeutic doses. pKa of the drug. This permits the counterion to bring the 0072. In certain embodiments it is believed that the low solution's pH to a level lower than the pHmax to reach the salt dose lithium can act additively or even synergistically with plateau, at which the solubility of salt prevails over the solu the dopamine agonist(s). Thus, in certain embodiments it is bility of free acid or base. The generalized rule of difference contemplated that the dopamine agonist(s) can be adminis in pKa units of the ionizable group in the active pharmaceu tered in Sub-therapeutic doses. tical ingredient (API) and in the acid or base is meant to make 0073. A typical dosage for bromocriptine (PARLODEL(R), the proton transfer energetically favorable. When the pKa of CYCLOSETR) is about 1.25 mg-100 mg per day on mainte the API and counterion are not significantly different, a solid nance. Contemplated subtherapeutic dosages are below 100 complex may form but may rapidly disproportionate (e.g., mg/day, preferably below about 90 mg/day, or below about 80 break down into the individual entities of drug and counte mg/day, or below about 70 mg/day, or below about 60 mg/day, rion) in an aqueous environment. or below about 50 mg/day. 0079 Preferably, the counterion is a pharmaceutically 0074 Combined Formulations. acceptable counterion. Suitable anionic salt forms include, 0075. In certain other embodiments, use of combined for but are not limited to acetate, benzoate, benzylate, bitartrate, mulations (e.g., formulations comprising lithium and bromide, carbonate, chloride, citrate, edetate, edisylate, esto L-DOPA and/or an L-DOPA derivative, and/or a MAOB late, fumarate, gluceptate, gluconate, hydrobromide, hydro inhibitor and/or a dopamine agonist, and optionally a COMT chloride, iodide, lactate, lactobionate, malate, maleate, man inhibitor or a DDCI) are contemplated. In certain embodi delate, mesylate, methyl bromide, methyl sulfate, mucate, ments the combined formulation is designed to administer the napsylate, nitrate, pamoate (embonate), phosphate and lithium in low doses (e.g., low therapeutic doses or subthera diphosphate, Salicylate and disalicylate, Stearate. Succinate, US 2013/001 7274 A1 Jan. 17, 2013

sulfate, tartrate, tosylate, triethiodide, Valerate, and the like, and on the particular physio-chemical characteristics of the while suitable cationic salt forms include, but are not limited active agent(s) comprising the formulation. to aluminum, benZathine, calcium, ethylene diamine, lysine, I0085. In certain embodiments the excipients are prefer magnesium, meglumine, potassium, procaine, Sodium, ably sterile and generally free of undesirable matter. These tromethamine, Zinc, and the like. compositions may be sterilized by conventional, well-known 0080 Preparation of esters typically involves functional sterilization techniques. ization of hydroxyl and/or carboxyl groups which may be 0.086 Invarious embodiments the combined formulations present within the molecular structure of the drug (e.g., described herein can be compounded in, or attached to, for L-DOPA). The esters are typically acyl-substituted deriva example through covalent, hydrophobic and electrostatic tives of free alcohol groups, i.e., moieties that are derived interactions, a drug carrier, drug delivery system and from carboxylic acids of the formula RCOOH where R is advanced drug delivery system in order to further enhance alky, and preferably is lower alkyl. Esters can be reconverted stability of the compound, increase bioavailability, increase to the free acids, if desired, by using conventional hydro solubility, decrease adverse effects, and/or increase patient genolysis or hydrolysis procedures. compliance or any combination thereof. Examples of carri 0081 Amides and prodrugs can also be prepared using ers, drug delivery systems and advanced drug delivery sys techniques known to those skilled in the art or described in the tems include, but are not limited to, polymers, for example pertinent literature. For example, amides may be prepared cellulose and derivatives, polysaccharides, for example dex from esters, using Suitable amine reactants, or they may be tran and derivatives, starch and derivatives, poly(vinyl alco prepared from an anhydride or an acid chloride by reaction hol), acrylate and methacrylate polymers, polylactic and with ammonia or a lower alkylamine. Prodrugs are typically polyglycolic acid and block co-polymers thereof, polyethyl prepared by covalent attachment of a moiety that results in a ene glycols, carrier proteins, for example albumin, gels, for compound that is therapeutically inactive until modified by an example, thermogelling systems, for example block co-poly individual's metabolic system. meric systems well known to those skilled in the art, micelles, 0082. The combined formulations contemplated herein liposomes, microspheres, nanoparticulates, liquid crystals can be useful for parenteral, topical, oral, nasal (or otherwise and dispersions thereof, polymeric micelles, multiple emul inhaled), rectal, or local administration such as by intracere sions, self-emulsifying, self-microemulsifying, cyclodex broVentricular pump, by aerosol administration, or transder trins and derivatives thereof, and dendrimers. mally, for prophylactic and/or therapeutic treatment of one or I0087. The combined formulations contemplated herein more of the pathologies/indications described herein (e.g., to can comprise each of the component agents (e.g., lithium, mitigate the onset, progression, or severity of one or more L-DOPA, etc.) the “native' form or, if desired, in the form of symptoms of Huntington's disease). In various embodiments salts, esters, amides, prodrugs, derivatives, and the like, pro the combination formulations are formulated as injectables vided the salt, ester, amide, prodrug or derivative is Suitable for injection, delivery via an implanted catheter, and the like. pharmacologically, i.e., effective in the present method(s). The pharmaceutical compositions can be administered in a Salts, esters, amides, prodrugs and other derivatives of the variety of unit dosage forms depending upon the method of agents described herein can be prepared using standard pro administration. Suitable unit dosage forms, include, but are cedures known to those skilled in the art of synthetic organic not limited to powders, tablets, pills, capsules, lozenges, Sup chemistry and described, for example, by March (1992) positories, patches, nasal sprays, injectables, implantable Sus Advanced Organic Chemistry, Reactions, Mechanisms and tained-release formulations, lipid complexes, etc. Structure, 4th Ed. N.Y. Wiley-Interscience. 0083. The components (active agents) comprising the I0088 For example, acid addition salts are prepared from combined formulations described herein of this invention are the free base using conventional methodology that typically typically each combined with a separate or the same pharma involves reaction with a suitable acid. Generally, the base ceutically acceptable carrier (excipient) to form a pharmaco form of the drug is dissolved in apolar organic solvent such as logical composition. Pharmaceutically acceptable carriers methanol or ethanol and the acid is added thereto. The result can contain one or more physiologically acceptable com ing salt either precipitates or can be brought out of solution by pound(s) that act, for example, to stabilize the composition or addition of a less polar solvent. Suitable acids for preparing to increase or decrease the absorption of the active agent(s). acid addition salts include both organic acids, e.g., acetic Physiologically acceptable compounds can include, for acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, example, carbohydrates, such as glucose, Sucrose, or dex malic acid, malonic acid. Succinic acid, maleic acid, fumaric trans, , such as ascorbic acid or , acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, chelating agents, low molecular weight proteins, protection mandelic acid, methanesulfonic acid, ethanesulfonic acid, and uptake enhancers such as lipids, compositions that reduce p-toluenesulfonic acid, Salicylic acid, and the like, as well as the clearance or hydrolysis of the active agent(s), or excipi inorganic acids, e.g., hydrochloric acid, hydrobromic acid, ents or other stabilizers and/or buffers. Sulfuric acid, nitric acid, phosphoric acid, and the like. An 0084. Other physiologically acceptable compounds acid addition salt may be reconverted to the free base by include Wetting agents, emulsifying agents, dispersing agents treatment with a suitable base. Certain addition salts include or preservatives that are particularly useful for preventing the are halide salts, such as may be prepared using hydrochloric growth or action of microorganisms. Various preservatives or hydrobromic acids. Conversely, basic salts are prepared in are well known and include, for example, phenol and ascorbic a similar manner using a pharmaceutically acceptable base acid. One skilled in the art would appreciate that the choice of Such as sodium hydroxide, potassium hydroxide, ammonium pharmaceutically acceptable carrier(s), including a physi hydroxide, calcium hydroxide, trimethylamine, or the like. ologically acceptable compound depends, for example, on Illustrative basic salts include alkali metal salts, e.g., the the route of administration of the combined formulation(s) Sodium salt, and copper salts. US 2013/001 7274 A1 Jan. 17, 2013

0089. In certain embodiments for the preparation of salt 0094. The components (active agents) comprising the forms of basic drugs, the pKa of the counterion is preferably combined formulations described herein of this invention are at least about 2 pH lower than the pKa of the drug. Similarly, typically each combined with a separate or the same pharma for the preparation of salt forms of acidic drugs, the pKa of the ceutically acceptable carrier (excipient) to form a pharmaco counterion is preferably at least about 2 pH higher than the logical composition. Pharmaceutically acceptable carriers pKa of the drug. This permits the counterion to bring the can contain one or more physiologically acceptable com solution's pH to a level lower than the pH to reach the salt pound(s) that act, for example, to stabilize the composition or plateau, at which the solubility of salt prevails over the solu to increase or decrease the absorption of the active agent(s). bility of free acid or base. The generalized rule of difference Physiologically acceptable compounds can include, for in pKa units of the ionizable group in the active pharmaceu example, carbohydrates, such as glucose, Sucrose, or dex tical ingredient (API) and in the acid or base is meant to make trans, antioxidants, such as ascorbic acid or glutathione, the proton transfer energetically favorable. When the pKa of chelating agents, low molecular weight proteins, protection the API and counterion are not significantly different, a solid and uptake enhancers such as lipids, compositions that reduce complex may form but may rapidly disproportionate (i.e., the clearance or hydrolysis of the active agent(s), or excipi break down into the individual entities of drug and counte ents or other stabilizers and/or buffers. rion) in an aqueous environment. 0.095 Other physiologically acceptable compounds 0090 Preferably, the counterion is a pharmaceutically include Wetting agents, emulsifying agents, dispersing agents acceptable counterion. Suitable anionic salt forms include, or preservatives that are particularly useful for preventing the but are not limited to acetate, benzoate, benzylate, bitartrate, growth or action of microorganisms. Various preservatives bromide, carbonate, chloride, citrate, edetate, edisylate, esto are well known and include, for example, phenol and ascorbic late, fumarate, gluceptate, gluconate, hydrobromide, hydro acid. One skilled in the art would appreciate that the choice of chloride, iodide, lactate, lactobionate, malate, maleate, man pharmaceutically acceptable carrier(s), including a physi delate, mesylate, methyl bromide, methyl sulfate, mucate, ologically acceptable compound depends, for example, on napsylate, nitrate, pamoate (embonate), phosphate and the route of administration of the combined formulation(s) diphosphate, Salicylate and disalicylate, Stearate. Succinate, and on the particular physio-chemical characteristics of the sulfate, tartrate, tosylate, triethiodide, Valerate, and the like, active agent(s) comprising the formulation. while suitable cationic salt forms include, but are not limited 0096. In certain embodiments the excipients are prefer to aluminum, benZathine, calcium, ethylene diamine, lysine, ably sterile and generally free of undesirable matter. These magnesium, meglumine, potassium, procaine, Sodium, compositions may be sterilized by conventional, well-known tromethamine, Zinc, and the like. sterilization techniques. 0091 Preparation of esters typically involves functional 0097. In various embodiments the combined formulations ization of hydroxyl and/or carboxyl groups which may be described herein can be compounded in, or attached to, for present within the molecular structure of the drug (e.g., example through covalent, hydrophobic and electrostatic L-DOPA). The esters are typically acyl-substituted deriva interactions, a drug carrier, drug delivery system and tives of free alcohol groups, i.e., moieties that are derived advanced drug delivery system in order to further enhance from carboxylic acids of the formula RCOOH where R is stability of the compound, increase bioavailability, increase alky, and preferably is lower alkyl. Esters can be reconverted solubility, decrease adverse effects, and/or increase patient to the free acids, if desired, by using conventional hydro compliance or any combination thereof. Examples of carri genolysis or hydrolysis procedures. ers, drug delivery systems and advanced drug delivery sys 0092 Amides and prodrugs can also be prepared using tems include, but are not limited to, polymers, for example techniques known to those skilled in the art or described in the cellulose and derivatives, polysaccharides, for example dex pertinent literature. For example, amides may be prepared tran and derivatives, starch and derivatives, poly(vinyl alco from esters, using Suitable amine reactants, or they may be hol), acrylate and methacrylate polymers, polylactic and prepared from an anhydride or an acid chloride by reaction polyglycolic acid and block co-polymers thereof, polyethyl with ammonia or a lower alkylamine. Prodrugs are typically ene glycols, carrier proteins, for example albumin, gels, for prepared by covalent attachment of a moiety that results in a example, thermogelling systems, for example block co-poly meric systems well known to those skilled in the art, micelles, compound that is therapeutically inactive until modified by an liposomes, microspheres, nanoparticulates, liquid crystals individual's metabolic system. and dispersions thereof, polymeric micelles, multiple emul 0093. The combined formulations contemplated herein sions, self-emulsifying, self-microemulsifying, cyclodex can be useful for parenteral, topical, oral, nasal (or otherwise inhaled), rectal, or local administration such as by intracere trins and derivatives thereof, and dendrimers. broVentricular pump, by aerosol administration, or transder mally, for prophylactic and/or therapeutic treatment of one or Administration. more of the pathologies/indications described herein (e.g., to 0098. In various embodiments the methods described mitigate the onset, progression, or severity of one or more herein are applied therapeutically to Subjects diagnosed as symptoms of Huntington's disease). In various embodiments having Parkinson's disease or prophylactically to Subjects the combination formulations are formulated as injectables identified as at risk for PD. for injection, delivery via an implanted catheter, and the like. 0099 Various medical organizations have created diag The pharmaceutical compositions can be administered in a nostic criteria to ease and standardize the diagnostic process, variety of unit dosage forms depending upon the method of especially in the early stages of the disease. The most widely administration. Suitable unit dosage forms, include, but are known criteria come from the UK Parkinson's Disease Soci not limited to powders, tablets, pills, capsules, lozenges, Sup ety Brain Bank and the US National Institute of Neurological positories, patches, nasal sprays, injectables, implantable Sus Disorders and Stroke. The PD Society Brain Bank criteria tained-release formulations, lipid complexes, etc. require A) Bradykinesia and at least one of the following: US 2013/001 7274 A1 Jan. 17, 2013

muscular rigidity, 4-6 HZ resting tremor, or postural instabil 0107 Criteria for PROBABLE diagnosis of Parkinson's ity not caused by primary visual, vestibular, cerebellar or disease include: At least 3 of the 4 features in Group A are proprioceptive dysfunction. B) Features that exclude Parkin present and: sons disease as the cause of Parkinsonism include 1) History 0108) None of the features in Group B is present (note: of repeated Strokes with stepwise progression of parkinsonian symptom duration of at least 3 years is needed to meet features; 2) History of repeated head injury; 3) History of this requirement); and definite encephalitis; 4) Neuroleptic treatment at onset of 0.109 Substantial and sustained response to levodopa or symptoms; 5) More than 1 affected relative; 5) Sustained a dopamine agonist has been documented. remission; 6) Strictly unilateral features after 3 years; 7) 0110. Criteria for DEFINITE diagnosis of Parkinson's Supranuclear gaze palsy; 8) Cerebellar signs; 9) Early severe disease include: All criteria for POSSIBLE Parkinson disease autonomic involvement; 10) Early severe dementia with dis are met; and histopathological confirmation of the diagnosis turbances of memory, language and praxis; 11) Babinski's is obtained at autopsy. sign; 12) Presence of a cerebral tumour or communicating 0111. In humans, olfactory dysfunction often precedes the hydrocephalus on computed tomography scan: 13) Negative onset of cardinal motor (as well as non-motor) symptoms of response to large doses of levodopa (if malabsorption PD (Fornaietal. (2008) Amyotroph Lateral Scler 9:123-124). excluded); or 14) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri PD-associated olfactory deficits include various degrees of dine (MPTP) exposure. C) Features that support a diagnosis loss in odor detection, discrimination and identification. As of Parkinson's disease (three or more required for diagnosis Such, olfactory deficits may be a potential pre-symptomatic or of definite Parkinson's disease: 1) Unilateral onset; 2) Rest early diagnostic marker for the disorder and, in certain tremor present; 3) Progressive disorder; 4) Persistent asym embodiments the methods described herein are contemplated metry affecting the side of onset most; 5) Excellent (70 for use in subjects diagnosed as at risk for PD via olfactory 100%) response to levodopa; 6) Severe levodopa-induced deficits. chorea; 7) Levodopa response for 25 years; 8) Clinical course 0.112. In certain embodiments the effectiveness of treat of 210 years. ment can be determined by comparing a baseline measure of 0100 Criteria of diagnosis of Parkinson disease (Gelb et a parameter of the disease before administration of the agent al, 1999) commissioned and supported by the Advisory (s) described herein (e.g., low dose lithium and, optionally Council of the National Institute of Neurological Disorders one or more additional agents such as L-DOPA) is com and Stroke, US National Institutes of Health are as follows: menced to the same parametera one or more time points after 0101 Grouping of clinical features of Parkinson's disease administration of the active agent(s). Illustrative parameters according to diagnostic utility are shown in Table 1 that can be measured include one or more of the motor, cognitive, or psychiatric symptoms described above, and/or TABLE 1. degree of cell death. Mitigation of one or more of the symp toms and/or a decline or reversal of neural cell death indicates Grouping of features characteristic of Parkinson's disease. partial, substantial, or full efficacy. GROUPA: Features characteristic of Parkinson's disease: 0113. In certain embodiments effectiveness of treatment Resting tremor; can be evaluated by comparison to the normative time course Bradykinesia; of the pathology in typical similarly situated Subjects (e.g., Rigidity; similar age, severity at first presentation, and the like). Asymmetric onset; 0114. In all of the methods described herein, appropriate GROUP B: Features suggestive of alternative diagnoses: dosages of the active agent(s) (e.g., Li) can readily be deter Features unusual early in the clinical course; mined by those of ordinary skill in the art of medicine by Prominent postural instability in the first 3 years after symptom monitoring serum concentrations and/or by monitoring the onset; Freezing phenomena in the first 3 years; patient for signs of disease amelioration or inhibition, and Hallucinations unrelated to in the first 3 years; increasing or decreasing the dosage and/or frequency of treat Dementia preceding motor symptoms or in the first year; ment as desired and appropriate. Supranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades; EXAMPLES Severe, symptomatic dysautonomia unrelated to medications; Documentation of a condition known to produce Parkinsonism and plausibly connected to the patient's symptoms (such as 0115 The following examples are offered to illustrate, but suitably located focal brain lesions or neuroleptic use within the not to limit the claimed invention. past 6 months); Example 1 0102 Criteria for POSSIBLE diagnosis of Parkinson's Neuroprotective Effects of Low Dose Lithium disease include: At least 2 of the 4 features in Group A are present; at least 1 of these is tremor or bradykinesia and 0116 Lithium administration was initially found to pro either: tect against in vitro cell death in a hydrogen peroxide treated, 0103) None of the features in Group B is present; or stable human alpha-synuclein expressing dopaminergic cell 0104 Symptoms have been present for less than 3 years, line recently created by our laboratory. In vivolithium admin and none of the features in Group B is present to date; and istration (0.255% lithium chloride) delivered in feed to 9 either: month old pan-neuronal human alpha-synuclein expressing 0105 Substantial and sustained response to levodopa or transgenic mice over a 3 month period was Sufficient to pre a dopamine agonist has been documented; or vent accumulation of oxidized/nitrated alpha-synuclein in 0106 Patient has not had an adequate trial of levodopa multiple brain regions previously shown to occur as a conse or dopamine agonist. quence of paraquat/maneb administration in these transgen US 2013/001 7274 A1 Jan. 17, 2013

ics. This included in the glomerular layer, mitral cells, and the I0128. The hind limb clasping data provide a measure of granule cell layer of the olfactory bulb (OB), the striatum abnormal involuntary movement (AIM) in the test animals. (ST), the Substantia nigra pars compacta (SNpc), in Purkinje Hind limb clasping is a typical AIM in Parkinson's Disease cells of the cerebellum (Cb), and the cortex (see, FIGS. 1-3). models and is similar to dyskinesia in PD. 0117 Lithium was found to not only prevent alpha-sy I0129 Hindlimb clasping data (% of hindlimb clasping and nuclein accumulation in various brain regions, but also to a hindlimb clasping severity index) are shown in FIG. 6 and protect against neuronal cell loss in this model (FIG. 4). an analysis of the hindlimb clasping data is provided in FIG. Importantly, this dosage has previously been demonstrated to 7. Use of low dose lithium and a combination of low dose result in sera lithium levels in the low therapeutic range (0.65 lithium and SINEMETR) appears to significantly reduce 0.8 mM) in mice independent of strain with no effect on motor hindlimb clasping (e.g., Parkinson's associated dyskinesia). function. 0.130. Without being bound by a particular theory it is Example 2 believed that the protective effects of low dose lithium can be mediated by one or both of two potential mechanisms. In the Investigation of Combination of Lithium and first mechanism, lithium may suppress 20S proteasomal SINEMETR) to Reduce L-DOPA-Induced activity for cytoprotection. In the second mechanism, lithium Dyskinesia (LID) may up-regulate TH expression in the ST resulting in cell protection against MPTP, mediated by calpain inhibition. 0118 SINEMETR) is used in the treatment of Parkinson's These hypotheses were tested. disease. SINEMETR) comprises a combination of carbidopa and levodopa. Short term side effects for SINEMETR) include 0131 FIG. 9 illustrates the effect of treatment on TH+ nausea, vomiting, heart rhythm disturbance, while long term density in ST, while FIG. 10 illustrates the effect of treatment side effects include dyskinesia (involuntary movement), rest on TH+ cell count in Substantia nigra pars compacta (SNpc). lessness, and confusion. In both cases, SINEMETR) appears to upregulate TH+ 0119) Dyskinesia is a movement disorder that consists of expression. Without being bound to a particular theory, it is effects including diminished Voluntary movements and the believed that low dose lithium up-regulates TH levels in the presence of involuntary movements, similar to tics or chorea. nigrostriatum which acts to attenuate motor deficits as a con Dyskensia in Parkinson's patients ranges from a slight tremor sequence of decreased dopamine levels in addition to lithi of the hands to uncontrollable movement of most commonly, um's ability to provide neuroprotection against MPTP neu the upper body. In certain presentations, it can also be seen in rotoxicity the lower extremities. (0132 FIG. 11 shows the results of an N27 AT-cell, 20 S 0120 Approximately, 30% of PD patient experience LID proteasomal assay for each of the treatments. As shown in the after 4-6 yrs of treatment and almost 90% suffer from this Figure, lithium appears to Suppress 20S proteasomal activity. complication after 9 yrs 0.133 Without being bound by a particular theory, it 0121. In these experiments the combination of lithium (Li) appears that low dose lithium is neuroprotective and when and SINEMETR) was investigated for the ability to reduce used in conjunction with SINEMETR) appears to provide a L-DOPA induced dyskinesia. synergistic improvement in locomotor behavior compared to SINEMETR). Methods and Results. I0134. It is understood that the examples and embodiments 0122. A mouse model of Parkinson's disease (C57BL/6J described herein are for illustrative purposes only and that male mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahy various modifications or changes in light thereofwill be Sug dropyridine (MPTP) (25 mg/ml) for 5 days at 9 months) were gested to persons skilled in the art and are to be included treated as follows for 2 months: within the spirit and purview of this application and scope of (0123. 1) control food (Saline); the appended claims. All publications, patents, and patent (0.124. 2) Lithium food (0.125% LiCl); applications cited herein are hereby incorporated by refer (0.125 3) SINEMETR) IP injection (100 mg/kg ence in their entirety for all purposes. L-DOPA+25 mg/kg. Carbidopa): 0126 4) Lithium-i-SINEMETR); 1: A method of delaying the onset of and/or mitigating the 0127. A hind limb clasping test was performed as illus severity of one or more symptoms of Parkinson's disease in a trated in FIG. 5 as summarized below in Table 2. mammal, said method comprising: administering to a mammal diagnosed as having or as at TABLE 2 risk for Parkinson's disease a chronic low dose of lithium. Hindlimb clasping studies. 2: The method of claim 1, wherein said low dose is a Treatment Treatment Shown. In Subtherapeutic dose. 3: The method of claim 1, wherein said low dose is a low Saline (5x) injection MPTP (5x), followed by FIG. 5, row 1. therapeutic dosage. Saline injection for 2 months MPTP (5x) Before MPTP (5x) injection and FIG. 5, row 2. 4: The method of claim 1, wherein said low dose is a dosage SINEMET (R) SINEMET (R) injection for 2 that results in an average serum concentration below about months O.5 mM. MPTP (5x) Before MPTP (5x) injection and 0.125% FIG. 5, row 3. SINEMET (R) Lithium feeding for 2 months 5-6. (canceled) MPTP Before drugs MPTP (5x) injection, followed by FIG. 5, row 4. Lithium-SINEMET (R) for 2 7: The method of claim 1, wherein said mammal is a months human. 8: The method of claim 7, wherein said human is not under treatment for a neuropsychiatric disorder. US 2013/001 7274 A1 Jan. 17, 2013

9: The method of claim 7, wherein said human is not under 33: The method of claim 32, wherein said MAOB inhibitor treatment for one or more disorders selected from the group comprises one or more agents selected from the group con consisting of mania, Schizophrenia, bipolar disorder, and psy sisting of selegiline, desmethylselegiline, pargyline, rasa chosis. giline, AGN-1135, MDL 72195, J 508, lazabemide, millace 10: The method of claim 7, wherein said mammal is a mide, mofegiline, D-deprenyl, and ladostigil. human diagnosed as having Parkinson's disease. 34: The method of claim 32, wherein said MAOB inhibitor is administered in a sub-therapeutic dose for Parkinson's 11: The method of claim 7, wherein said mammal is a disease. human diagnosed as at risk for Parkinson's disease 35: The method of claim 18, wherein said second agent 12: The method of claim 7, wherein said human is a human comprises a dopamine agonist. 40 years of age or older. 36: The method of claim 35, wherein said dopamine ago 13-14. (canceled) nist comprises one or more agents selected from the group 15: The method of claim 7, wherein said administration is consisting of bromocriptine, , pergolide, prami before the onset of cardinal motor symptoms of Parkinson's pexole, ropinirole, piribedil, apomorphine, rigotine, disease. quinagolide, fenoldopam, and lisuride. 16: The method of claim 7, wherein said administration is 37: The method of claim 35, wherein said dopamine ago to a Subject diagnosed as having olfactory dysfunction. nist is administered in a sub-therapeutic dose for Parkinson's 17: The method of claim 7, wherein said human is diag disease. nosed with one or more conditions selected from the group 38. (canceled) consisting of tremor, bradykinesia, and muscle rigidity. 39: The method of claim 18, wherein said low dose is a 18: A method of delaying the onset of and/or mitigating the Subtherapeutic dose. severity of one or more symptoms of Parkinson's disease in a 40-43. (canceled) mammal, said method comprising: 44: The method of claim 18, wherein said mammal is a administering to a mammal diagnosed as having or as at human. risk for Parkinson's disease a chronic low dose of 45: The method of claim 44, wherein said human is not lithium in conjunction with a second agent comprising under treatment for a neuropsychiatric disorder. one or more pharmaceutically active agents selected 46-48. (canceled) from the group consisting of L-3,4-dihydroxyphenyla 49: The method of claim 44, wherein said human is a lanine (L-DOPA) and/or a derivative thereof, a MAOB human 40 years of age or older. inhibitor, and a dopamine agonist. 50-51. (canceled) 19-22. (canceled) 52: The method of claim 44, wherein said administration is 23: The method of claim 18, wherein said lithium and said before the onset of cardinal motor symptoms of Parkinson's second agent are administered in a combined formulation. disease. 24: The method of claim 18, wherein said method further 53-54. (canceled) comprises administering said lithium, and L-DOPA in con 55: A formulation delaying the onset of and/or mitigating junction with a dopa decarboxylase inhibitor and/or a COMT the severity of one or more symptoms of Parkinson's disease inhibitor and/or pyridoxal phosphate. said formulation comprising: 25: The method of claim 18, wherein said lithium is admin lithium; istered as a lithium salt, and/or said L-DOP is provided as an L-DOPA and/or a derivative thereof, and L-DOPAethyl ester. one or more pharmaceutically acceptable excipients. 26. (canceled) 56: The formulation of claim 55, wherein said formulation 27: The method of claim 18, wherein said L-DOPA is further comprises a dopa decarboxylase inhibitor and/or a administered in a sub-therapeutic dose for Parkinson's dis COMT inhibitor, and/or pyridoxal phosphate. CaSC. 57-58. (canceled) 28: The method of claim 24, wherein said method com 59: The formulation of claim 56, wherein said formulation prises administering a peripheral DOPA decarboxylase comprises a peripheral DOPA decarboxylase inhibitor inhibitor (DDCI). (DDCI). 29: The method of claim 28, wherein said DDCI is selected 60: The formulation of claim 59, wherein said DDCI is from the group consisting of benserazide, (2S)-3-(3,4-dihy selected from the group consisting of benserazide, carbidopa, droxyphenyl)-2-hydrazino-2-methylpropanoic acid (carbi and methyldopa. dopa), and methyldopa. 61. (canceled) 30: The method of claim 24, wherein said method com 62: The formulation of claim 56, wherein said formulation prises administering a catechol-O-methyl transferase comprises a catechol-O-methyl transferase (COMT) inhibi (COMT) inhibitor. tOr. 31: The method of claim 30, wherein said COMT inhibitor 63: The method of claim 62, wherein said COMT inhibitor is selected from the group consisting of entacapone, tolca is selected from the group consisting of entacapone, tolca pone, and nitecapone. pone, and nitecapone. 32: The method of claim 18, wherein said second agent 64. (canceled) comprises a MAOB inhibitor.