US 20110201597A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0201597 A1 CHASE et al. (43) Pub. Date: Aug. 18, 2011 (54) METHOD AND COMPOSITION FOR Publication Classification TREATING ALZHEIMER-TYPE DEMENTA (51) Int. Cl. (76) Inventors: Thomas N. CHASE, Washington, A6II 3/55 (2006.01) DC (US); Kathleen E. A6II 3/445 (2006.01) CLARENCE-SMITH, A6IP 25/28 (2006.01) Washington, DC (US) (52) U.S. Cl. ......................................... 514/215: 514/319 (21) Appl. No.: 13/051,181 (57) ABSTRACT (22) Filed: Mar. 18, 2011 There is described a method for increasing the maximal tol erated dose and thus the efficacy of an acetylcholinesterase Related U.S. Application Data inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by (63) Continuation-in-part of application No. 12/880,395, administration of said AChEI in combination with a non filed on Sep. 13, 2010, Continuation-in-part of appli anticholinergic antiemetic agent, whereby an enhanced ace cation No. PCT/US2010/002475, filed on Sep. 13, tylcholinesterase inhibition in the CNS of said patient is 2010, Continuation-in-part of application No. 12/934, achieved and alleviation of the symptoms of Alzheimer type 140, filed on Sep. 23, 2010, filed as application No. dementia in said patient is thereby improved to a greater PCT/US09/01662 on Mar. 17, 2009. extent. The use of a non-anticholinergic antiemetic agent for (60) Provisional application No. 61/272.382, filed on Sep. the preparation of a pharmaceutical composition for the treat 18, 2009, provisional application No. 61/272.382, ment of Alzheimer type dementia in combination with an acetylcholinesterase inhibitor (AChEI) and pharmaceutical filed on Sep. 18, 2009. compositions comprising (a) a 5HT receptor antagonist, a (30) Foreign Application Priority Data dopamine antagonist, a H1-receptor antagonist, a cannab inoid agonist, aprepitant or casopitant as an antiemetic agent Mar. 27, 2008 (EP) .................................. 08005750.8 and (b) an acetylcholinesterase inhibitor are also described. US 2011/02O 1597 A1 Aug. 18, 2011 METHOD AND COMPOSITION FOR central nervous system (CNS) characterized by progressive TREATING ALZHEMER-TYPE DEMENTA cognitive impairment, a variety of neurobehavioral and/or neuropsychiatric disturbances, and restrictions inactivities of CROSS REFERENCE TO RELATED daily living. APPLICATIONS 0005 Alzheimer's disease is the most common form of 0001. This application is a continuation-in-part of U.S. dementia. Prevalence studies indicated that in 2000 there application Ser. No. 12/880,395, filed on Sep. 13, 2010, tak were about 25 million persons with Alzheimer's disease ing benefit from U.S. Provisional Application No. 61/272, worldwide and this number is expected to increase to 114 382, filed on Sep. 18, 2009, which are incorporated herein in million by 2050 unless an effective preventive or neuropro their entirety. This application also is a continuation-in-part tective therapy emerges. Onset usually occurs in those over of the PCT/US2010/002475 Application filed on 13 Sep. age 65. Clinical signs include progressive cognitive loss and 2010, taking benefit from U.S. Provisional Application No. other associated neurobehavioral disabilities together with a 61/272.382 filed on Sep. 18, 2009. This application also is a declining capability of performing the activities of daily liv continuation-in-part of U.S. application Ser. No. 12/934,140 ing. which is the US national phase of PCT/US09/01662 filed on 0006. The basic cause of sporadic Alzheimer's disease is 13 Mar. 2009, taking benefit from EP Application No. not known, probably because the disease is heterogeneous 08005750.8 filed on Mar. 27, 2008. and involves age-related changes together with a complex interaction of genetic and environmental risk factors. Current FIELD OF THE INVENTION hypotheses advanced to explain the pathophysiology of Alzheimer's disease center on the putative deleterious effects 0002 This invention concerns a method for enhancing the of the two misfolded and aggregated proteins, extracellular maximal efficacy and maximal tolerated dose of an acetyl beta amyloid and intracellular tau. Presumably, as a conse cholinesterase inhibitor in a patient Suffering from dementia quence of the selective neurodegenerative process, the Syn of the Alzheimer type by combining said acetylcholinsterase thesis of the neurotransmitter acetylcholine declines. This inhibitor with an antiemetic agent, or the use of an antiemetic reduction undoubtedly interferes with normal synaptic trans agent Substantially devoid of central anticholinergic activity mission in brain. Drugs that act to correct the acetylcholine for the preparation of pharmaceutical compositions for the deficiency thus constitute the mainstay of current therapy. treatment of Alzheimer type dementias in combination with 0007 Dementias of the Alzheimer type also include cog an acetylcholinesterase inhibitor (AChEI). The invention also nitive impairments associated with Parkinson's disease. One concerns pharmaceutical compositions comprising an anti example is Parkinson's disease dementia, also a chronic pro emetic agent, in particular a serotonin 5HT receptor antago gressive CNS degenerative disorder with relatively late life nist compound in association with an acetylcholinesterase onset, Parkinson's disease itself primarily affects motor func inhibitor to allow increasing and prolonging efficacy and tion. But secondary symptoms include cognitive deteriora decreasing toxicity of these conventional cholinomimetic tion, especially deficits in executive function. treatments such as treatments for dementias in diseases of the 0008 Another dementia of the Alzheimer type that is com Alzheimer type. monly linked to Parkinson's disease is known as dementia with Lewy bodies or Lewy body dementia. Although Lewy DEFINITIONS body dementia is now generally regarded as a separate dis ease, differentiation from Alzheimer's disease and from Par “AChEI(s)''': Acetyl Choline Esterase Inhibitor(s). kinson's disease dementia may be clinically challenging. “CNS: Central Nervous System. Lewy body dementia thus tends to be under-diagnosed or “PNS: Peripheral Nervous System. misdiagnosed as Alzheimer's disease or Parkinson's disease 0003 “IR”: Immediate Release of the active ingredient dementia. The clinical presentation of Lewy body dementia is from a composition. typically one of cortical and Subcortical cognitive impair “ER': Extended Release (including slow release) of the ment, with visuospatial and executive dysfunction more pro active ingredient from a composition. nounced than in Alzheimer's disease. Core clinical features of “Non-anticholinergic' refers to antiemetic medications not primarily regarded as anticholinergic agents; they are entirely Lewy body dementia, in addition to parkinsonism, are cog devoid of anticholinergic activity or have an extremely low nitive decline plus fluctuations in attention and recurrent ability to prevent acetylcholine from acting at its cholinergic visual hallucinations. 0009. Both Parkinson's disease dementia and Lewy body receptor sites. dementia are characterized neuropathologically by the pres “MTD': maximum (or maximal) tolerated dose, i.e. the high ence of cortical Lewy body pathology and Synuclein protein est dose of a drug or treatment that does not cause unaccept deposition. Genetic factors appear to play a role in pathogen able side effects. The maximum tolerated dose is determined esis. Not Surprisingly, the pathology of Parkinson's disease in clinical trials by testing increasing doses on different dementia and Lewy body dementia is heterogeneous and groups of people until the highest dose with acceptable side overlapping, often intermixed with changes of the Alzheimer effects is found (NCI Drug Dictionary). and vascular types. A reduction in brain acetylcholine-medi ated neurotransmission has been linked to the primary clini BACKGROUND OF THE INVENTION cal abnormalities found in both these disorders and drugs 0004 Dementias of the Alzheimer type include, but are acting to stimulate cholinergic transmission now constitute not limited to Alzheimer's disease, Parkinson's disease the main approach to therapy. dementia, and related maladies in humans involving cogni 0010. In addition to the aforementioned disorders, the off tive and behavioral dysfunction such as Lewy body dementia. label administration of drugs that augment CNS cholinergic Most are chronic neurodegenerative disorders of the human transmission for various other cognitive disorders is wide US 2011/02O 1597 A1 Aug. 18, 2011 spread. Some of this use involves cognitive disorders for efficacy can be measured by the degree of improvement in which relatively little clear evidence of cholinergic dysfunc cognitive dysfunction and other neurobehavioral abnormali tion currently exists. Nevertheless, an increasing number of ties associated with these disorders using standardized scales. clinical studies now support a rational extension of AChEI 0016. Unfortunately, however, none of the currently avail treatment to various additional disorders of cognitive func able cholinomimetic medications offers more than modest tion, including but not limited to, vascular dementia, Down clinical benefit for some patients suffering from any of the syndrome, traumatic brain injury and mild cognitive impair aforementioned dementing disorders, even when these medi ment. cations are administered at their maximum safe and tolerated