CA2131754A1 - Prostaglandin e derivatives in the treatment of dementia - Google Patents
Prostaglandin e derivatives in the treatment of dementiaInfo
- Publication number
- CA2131754A1 CA2131754A1 CA002131754A CA2131754A CA2131754A1 CA 2131754 A1 CA2131754 A1 CA 2131754A1 CA 002131754 A CA002131754 A CA 002131754A CA 2131754 A CA2131754 A CA 2131754A CA 2131754 A1 CA2131754 A1 CA 2131754A1
- Authority
- CA
- Canada
- Prior art keywords
- prostaglandin
- derivatives
- human
- derivative
- dementia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention pertains to the novel use of prostaglandin E derivatives in the treatment of dementia.
A method is described of treating dementia in human beings which comprises administering to the human being a therapeutic amount of a prostaglandin E derivative, alone or in combination with antiinflammatory agents which inhibit the synthesis of prostaglandins.
A method is described of treating dementia in human beings which comprises administering to the human being a therapeutic amount of a prostaglandin E derivative, alone or in combination with antiinflammatory agents which inhibit the synthesis of prostaglandins.
Description
2l3l754 PR08T~T~NnIN E DERIVATIVES IN THE TREATMENT OF DEMENTIA
Technical Field This invention pertains to the novel use of prostaglandin E derivatives in the treatment of dementia (Alzheimer disease) in human beings.
Background Art An increasing body of evidence now supports the principle of autodestruction of neurons in dementia of the Alzheimer type. This autodestruction appears to occur as a result of toxic activity of reactive microglial cells.
The evidence is of three types:
1) postmortem studies of Alzheimer tissue demonstrating the presence of a plethora of inflammatory proteins, along with reactive microglia, in lesioned areas (McGeer et al., 1993);
Technical Field This invention pertains to the novel use of prostaglandin E derivatives in the treatment of dementia (Alzheimer disease) in human beings.
Background Art An increasing body of evidence now supports the principle of autodestruction of neurons in dementia of the Alzheimer type. This autodestruction appears to occur as a result of toxic activity of reactive microglial cells.
The evidence is of three types:
1) postmortem studies of Alzheimer tissue demonstrating the presence of a plethora of inflammatory proteins, along with reactive microglia, in lesioned areas (McGeer et al., 1993);
2) multiple epidemiological studies showing that people taking antiinflammatory agents for other medical reasons, or suffering from chronic conditions where antiinflammatory agents are routinely prescribed, have a lower incidence of Alzheimer disease than age-matched populations (Jenkinson et al. 1989; McGeer et al. 1990; Broe et al. 1990; Li et al. 1992; Breitner et al.
1994; Myllykangas-Luosujarvi and Isomaki, 1994);
and, 3) the arrest of Alzheimer dementia in a pilot clinical trial of one nonsteroidal antiinflammatory drug (NSAID), indomethacin (Rogers et al. 1993).
The mechanism of action of steroids and NSAIDs is believed to be inhibition of prostaglandin synthesis.
Prostaglandins are generally considered to be mediators of inflammation (Constantinides, 1994). An important clinical application of prostaglandin E derivatives, especially misoprostol, is to prevent the gastrointestinal toxicity 213175~
_ - 2 caused by NSAIDs (Graham et al. 1988). Since NSAIDs appear to be effective in the prevention (as evidenced by epidemiological studies) and treatment (as evidenced by the clinical trial of indomethacin) of dementia, and since prostaglandin E derivatives antagonize the effects of NSAIDs on the gastrointestinal tract, it would be counterintuitive to propose prostaglandin E derivatives for the treatment of dementia. These compounds are found to be increased in inflammatory disease states and in experimental models of inflammation. According to current teaching, their administration would be anticipated to worsen, rather than ameliorate dementia. However, we have found that prostaglandin E derivatives act in an opposite fashion to inflammatory mediators on the respiratory burst activity of monocyte derived phagocytes. In this key aspect of inflammation, which is a plausible reason for the toxic action of reactive microglia on neurons, they suppress activity as does the NSAID indomethacin.
Accordingly, they would be appropriate derivatives for the treatment of dementia, alone or in combination with steroids and NSAIDs.
SummarY of the Invention The invention pertains to a method of treating dementia in human beings which comprises administering to the human being a therapeutic amount of a substance selected from the prostaglandin E series and its derivatives. These would include, but would not be limited to, prostaglandin E1 and its analogs, rioprostil and misoprostol, and prostaglandin E2 and its derivatives, enprostil, arbaprostil and trimoprostil. These may be administered alone, or in combination with antiinflammatory adrenocorticosteroids and their derivatives or NSAIDs of the cyclooxygenase inhibiting class. Examples of the former would be prednisone and dexamethasone, while examples of the latter would be indomethacin and ketoprofen.
_ - 3 The dosage of each agent will vary. For each patient, it will be the dosage that is required to inhibit microglial action in brain, but not to induce side effects such as diarrhoea. Daily doses of a prostaglandin E
derivative can range from 50 micrograms to 1 gram per 50 kilograms body weight. The composition can comprise a prostaglandin E derivative, a suitable NSAID or adrenocortical steroid, or derivative thereof, and a therapeutically acceptable carrier.
Best Mode(s) For Carryinq Out the Invention Adrenocortical steroids are thought to exert their antiinflammatory effects primarily by inducing synthesis of lipocortin (Flower and Blackwell, 1979).
Lipocortin inhibits phospholipase A2 which controls the breakdown of lipids in the cell membrane to form arachidonic acid. NSAIDs are thought to exert their antiinflammatory effects by inhibiting the enzyme cyclooxygenase which converts arachidonic acid to prostaglandins (Vane, 1971). Thus, each of these classes of antiinflammatory agents has the same end effect of limiting the availability of prostaglandins. The initial stable prostaglandin H2 product is convertible into prostaglandins of the D, E, F, G and I series. Numerous derivatives result, and the physiological actions of each are as yet unclear.
Prostaglandins are generally considered to be promoters of inflammation. In particular, prostaglandin E
derivatives cause vasodilation, increased permeability of capillary endothelium and greatly potentiated pain of inflammation (Constantinides, 1994). Current teaching, therefore, would suggest that one of the reasons why antiinflammatory drugs are effective in Alzheimer disease would be suppression of prostaglandin derivatives generally, and prostaglandin E derivatives particularly.
2131 7S~
In multiple sclerosis, a disease considered to be a prime example of inflammation of the brain, prostaglandin E levels are elevated and are considered to be indicative of the level of inflammation (Merrill et al.). In experimental models involving central nervous system tissue, astrocytes are thought to play a prominent role in the initiation of inflammatory responses in the central nervous system on the basis of interleukin-1 induction of prostaglandin E (Hartung et al.). In experimental uveitis, induction of prostaglandins, including prostaglandin E
derivatives, is regarded as a measure of severity of inflammation, and the antiinflammatory action of indomethacin is interpreted as being due, at least in part, to suppression of prostaglandin E production (Fleischer et al.). Prostaglandin E2 is found in neurons but not glial cells in brain (Fujimoto et al.). Binding sites for prostaglandin E1 and prostaglandin E2 derivatives occur throughout the brain and are of moderate density in the entorhinal cortex, hippocampus, and other areas particularly prone to Alzheimer disease pathology (Matsumara et al.). However, prostaglandins are not altered in the postmortem cerebral cortex of Alzheimer disease patients (Iwamoto et al.). deposits are thought to consolidate in an aggregated form, and the aggregated BAP
is believed to be toxic to neurons (Hardy & Allsop, 1991).
How this toxicity is produced is uncertain. There is evidence that BAP activates cultured microglia, as well as cultured peritoneal macrophages (Klegeris et al., Schedule A). This activation caused an increase in respiratory burst activity (Klegeris et al., Schedule A). Since respiratory burst activity produces toxic oxygen species, this is a plausible explanation for the association of reactive microglia in consolidated amyloid deposits with damaged neuronal processes which are found in such plaques.
213175~
_ - 5 We therefore examined the effects of indomethacin, an agent known to be effective in the treatment of Alzheimer disease, and prostaglandin E on the respiratory burst of peritoneal macrophages following stimulation by opsonized zymosan. Brain microglia and peritoneal macrophages behave in comparable fashion to such stimulation (Klegeris & McGeer, Schedule B). We find that indomethacin at a concentration of 2 x 10-4M reduced the activity to 75% of that obtained when opsonized zymosan was given alone (see Schedule C). Prostaglandin E2 at a concentration of 2 x 10-~ reduced the activity to 80% of that obtained with opsonized zymosan alone (see Schedule C). Thus, in this assay, prostaglandin E2 had a comparable effect to indomethacin, indicating that these two agents act in the same direction in inhibiting activated macrophages, demonstrating that prostaglandin E derivatives will be effective in the treatment of dementia.
The preferred method of treatment for dementia according to the present invention comprises administering a supplement to the prostaglandin E defensive derivatives in the brain in order to reduce the toxic actions of microglia on neurons. The prostaglandin E derivatives can be given alone or in combination with steroids and/or NSAIDs to enhance the effects of these latter agents. The helpful effects of these overall prostaglandin synthesis inhibitors outweigh their harmful action in suppressing prostaglandin E production. Thus, the preferred embodiment could be a combination of a prostaglandin E derivative with a steroidal, or nonsteroidal inhibitor of prostaglandin production.
Prostaglandin E derivatives, by themselves or in combination with a steroidal or nonsteroidal inhibitor of prostaglandin production, may be packaged as a pharmaceutical agent for the treatment of dementia. In which case, the labelling on the package can indicate that 213175~
_ - 6 the pharmaceutical agent can be used for treatment of dementia.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
REFERENCES
P.L. McGeer, T. Kawamata, D.G. Walker, H. Akiyama, I.
Tooyama, and E.G. McGeer, "Microglia in degenerative neurological disease", Glia 1993;7:84-92.
M.I. Jenkinson, M.R. Bliss, A.T. Brain, and D.L. Scott, "Rheumatoid arthritis and senile dementia of the Alzheimer type", British Journal of Rheumatology 1989;28:86-88.
P.L. McGeer, J. Rogers, E.G. McGeer, and J. Sibley, "Does anti-inflammatory treatment protect against Alzheimer disease?", Lancet 1990;335:1037.
G.A. Broe, A.S. Henderson, H. Creasey, et al., "A
case-control study of Alzheimer's disease in Australia", Neurology 1990;40:1698-1707.
G. Li, Y.C. Shen, Y. T. Li, C.H. Chen, Y.W. Zhau, and J. M.
Silverman, "A case-controlled study of Alzheimer's disease in China", Neurology 1992;42:1481-1488.
J.C.S. Breitner, B.A. Gau, K.A. Welsh, et al. "Inverse association of anti-inflammatory treatments and Alzheimer's disease", Neurology 1994;44:227-232.
21317~
R. Myllykangas-Luosujarvi and H. Isomaki, "Alzheimer's disease and rheumatoid arthritis", British Journal of Rheumatology 1994;33:501-502.
J. Rogers, L.C. Kirby, S.R. Hempelman, et al., "Clinical trial of indomethacin in Alzheimer's disease", Neurology 1993;43:1609-1611.
P. Constantinides, "General Pathobiology", Appleton &
Lange, Norwalk, Connecticut, 1994D.Y. Graham, N.M. Agrawal, and S.H. Roth, "Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial", Lancet, December 3, 1988, 1277-1280.
R.J. Flower and G.J. Blackwell, "Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation", Nature 1979;278:456-459.
J.R. Vane, "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs", Nature 1971;
231:232-235.
J.E. Merrill, S.R. Strom, G.W. Ellison, and L.W. Myers, "In vitro study of mediators of inflammation in multiple sclerosis", Journal of Clinical Immunology 1989;9:84-96.
H.P. Hartung, B. Schafer, K. Heininger, and K.V. Toyka, "Recombinant interleukin-l beta stimulates eicosanoid production in rat primary culture astrocytes", Brain Research 1989;489:113-119.
L.N. Fleisher, J.B. Ferrell, M.G. Smith, and M.C. McGahan, "Lipid mediation of tumor necrosis factor-alpha-induced uveitis", Investigative Ophthalmology and Visual Science 1991;32:2393-2399.
21317erj4 _ - 8 N. Fujimoto, T. Kaneko, N. Eguchi, Y. Urade, N. Mizuno, and O. Hayaishi, "Biochemical and immunohistochemical demonstration of a tightly bound form of prostaglandin E2 in the rat brain", Neuroscience 1991;49:591-606.
K. Matsumura, Y. Watanabe, K. Imai-Matsumura, et al., "Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography", Brain Research 1992j581:292-298.
N. Iwamoto, K. Kobayashi, and K. Kosaka, "The formation of prostaglandins in the postmortem cerebral cortex of Alzheimer-type dementia patients", Journal of Neurology 1989;236:80-84.
J. Hardy and D. Allsop, "Amyloid deposition as the central event in the aetiology of Alzheimer's disease", Trends in Pharmacology 1991;12:383-388.
A. Klegeris, D.G. Walker, and P.L. McGeer, "Activation of macrophages by Alzheimer b amyloid peptide", Biochemical and Biophysical Research Communications 1994jl99(2):984-991 (Schedule A).
A. Klegeris and P.L. McGeer , "Comparison of respiratory burst activity between rat brain microglia and peritoneal macrophages", Journal of Neuroimmunology 1994; 53 (Schedule B).
1994; Myllykangas-Luosujarvi and Isomaki, 1994);
and, 3) the arrest of Alzheimer dementia in a pilot clinical trial of one nonsteroidal antiinflammatory drug (NSAID), indomethacin (Rogers et al. 1993).
The mechanism of action of steroids and NSAIDs is believed to be inhibition of prostaglandin synthesis.
Prostaglandins are generally considered to be mediators of inflammation (Constantinides, 1994). An important clinical application of prostaglandin E derivatives, especially misoprostol, is to prevent the gastrointestinal toxicity 213175~
_ - 2 caused by NSAIDs (Graham et al. 1988). Since NSAIDs appear to be effective in the prevention (as evidenced by epidemiological studies) and treatment (as evidenced by the clinical trial of indomethacin) of dementia, and since prostaglandin E derivatives antagonize the effects of NSAIDs on the gastrointestinal tract, it would be counterintuitive to propose prostaglandin E derivatives for the treatment of dementia. These compounds are found to be increased in inflammatory disease states and in experimental models of inflammation. According to current teaching, their administration would be anticipated to worsen, rather than ameliorate dementia. However, we have found that prostaglandin E derivatives act in an opposite fashion to inflammatory mediators on the respiratory burst activity of monocyte derived phagocytes. In this key aspect of inflammation, which is a plausible reason for the toxic action of reactive microglia on neurons, they suppress activity as does the NSAID indomethacin.
Accordingly, they would be appropriate derivatives for the treatment of dementia, alone or in combination with steroids and NSAIDs.
SummarY of the Invention The invention pertains to a method of treating dementia in human beings which comprises administering to the human being a therapeutic amount of a substance selected from the prostaglandin E series and its derivatives. These would include, but would not be limited to, prostaglandin E1 and its analogs, rioprostil and misoprostol, and prostaglandin E2 and its derivatives, enprostil, arbaprostil and trimoprostil. These may be administered alone, or in combination with antiinflammatory adrenocorticosteroids and their derivatives or NSAIDs of the cyclooxygenase inhibiting class. Examples of the former would be prednisone and dexamethasone, while examples of the latter would be indomethacin and ketoprofen.
_ - 3 The dosage of each agent will vary. For each patient, it will be the dosage that is required to inhibit microglial action in brain, but not to induce side effects such as diarrhoea. Daily doses of a prostaglandin E
derivative can range from 50 micrograms to 1 gram per 50 kilograms body weight. The composition can comprise a prostaglandin E derivative, a suitable NSAID or adrenocortical steroid, or derivative thereof, and a therapeutically acceptable carrier.
Best Mode(s) For Carryinq Out the Invention Adrenocortical steroids are thought to exert their antiinflammatory effects primarily by inducing synthesis of lipocortin (Flower and Blackwell, 1979).
Lipocortin inhibits phospholipase A2 which controls the breakdown of lipids in the cell membrane to form arachidonic acid. NSAIDs are thought to exert their antiinflammatory effects by inhibiting the enzyme cyclooxygenase which converts arachidonic acid to prostaglandins (Vane, 1971). Thus, each of these classes of antiinflammatory agents has the same end effect of limiting the availability of prostaglandins. The initial stable prostaglandin H2 product is convertible into prostaglandins of the D, E, F, G and I series. Numerous derivatives result, and the physiological actions of each are as yet unclear.
Prostaglandins are generally considered to be promoters of inflammation. In particular, prostaglandin E
derivatives cause vasodilation, increased permeability of capillary endothelium and greatly potentiated pain of inflammation (Constantinides, 1994). Current teaching, therefore, would suggest that one of the reasons why antiinflammatory drugs are effective in Alzheimer disease would be suppression of prostaglandin derivatives generally, and prostaglandin E derivatives particularly.
2131 7S~
In multiple sclerosis, a disease considered to be a prime example of inflammation of the brain, prostaglandin E levels are elevated and are considered to be indicative of the level of inflammation (Merrill et al.). In experimental models involving central nervous system tissue, astrocytes are thought to play a prominent role in the initiation of inflammatory responses in the central nervous system on the basis of interleukin-1 induction of prostaglandin E (Hartung et al.). In experimental uveitis, induction of prostaglandins, including prostaglandin E
derivatives, is regarded as a measure of severity of inflammation, and the antiinflammatory action of indomethacin is interpreted as being due, at least in part, to suppression of prostaglandin E production (Fleischer et al.). Prostaglandin E2 is found in neurons but not glial cells in brain (Fujimoto et al.). Binding sites for prostaglandin E1 and prostaglandin E2 derivatives occur throughout the brain and are of moderate density in the entorhinal cortex, hippocampus, and other areas particularly prone to Alzheimer disease pathology (Matsumara et al.). However, prostaglandins are not altered in the postmortem cerebral cortex of Alzheimer disease patients (Iwamoto et al.). deposits are thought to consolidate in an aggregated form, and the aggregated BAP
is believed to be toxic to neurons (Hardy & Allsop, 1991).
How this toxicity is produced is uncertain. There is evidence that BAP activates cultured microglia, as well as cultured peritoneal macrophages (Klegeris et al., Schedule A). This activation caused an increase in respiratory burst activity (Klegeris et al., Schedule A). Since respiratory burst activity produces toxic oxygen species, this is a plausible explanation for the association of reactive microglia in consolidated amyloid deposits with damaged neuronal processes which are found in such plaques.
213175~
_ - 5 We therefore examined the effects of indomethacin, an agent known to be effective in the treatment of Alzheimer disease, and prostaglandin E on the respiratory burst of peritoneal macrophages following stimulation by opsonized zymosan. Brain microglia and peritoneal macrophages behave in comparable fashion to such stimulation (Klegeris & McGeer, Schedule B). We find that indomethacin at a concentration of 2 x 10-4M reduced the activity to 75% of that obtained when opsonized zymosan was given alone (see Schedule C). Prostaglandin E2 at a concentration of 2 x 10-~ reduced the activity to 80% of that obtained with opsonized zymosan alone (see Schedule C). Thus, in this assay, prostaglandin E2 had a comparable effect to indomethacin, indicating that these two agents act in the same direction in inhibiting activated macrophages, demonstrating that prostaglandin E derivatives will be effective in the treatment of dementia.
The preferred method of treatment for dementia according to the present invention comprises administering a supplement to the prostaglandin E defensive derivatives in the brain in order to reduce the toxic actions of microglia on neurons. The prostaglandin E derivatives can be given alone or in combination with steroids and/or NSAIDs to enhance the effects of these latter agents. The helpful effects of these overall prostaglandin synthesis inhibitors outweigh their harmful action in suppressing prostaglandin E production. Thus, the preferred embodiment could be a combination of a prostaglandin E derivative with a steroidal, or nonsteroidal inhibitor of prostaglandin production.
Prostaglandin E derivatives, by themselves or in combination with a steroidal or nonsteroidal inhibitor of prostaglandin production, may be packaged as a pharmaceutical agent for the treatment of dementia. In which case, the labelling on the package can indicate that 213175~
_ - 6 the pharmaceutical agent can be used for treatment of dementia.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
REFERENCES
P.L. McGeer, T. Kawamata, D.G. Walker, H. Akiyama, I.
Tooyama, and E.G. McGeer, "Microglia in degenerative neurological disease", Glia 1993;7:84-92.
M.I. Jenkinson, M.R. Bliss, A.T. Brain, and D.L. Scott, "Rheumatoid arthritis and senile dementia of the Alzheimer type", British Journal of Rheumatology 1989;28:86-88.
P.L. McGeer, J. Rogers, E.G. McGeer, and J. Sibley, "Does anti-inflammatory treatment protect against Alzheimer disease?", Lancet 1990;335:1037.
G.A. Broe, A.S. Henderson, H. Creasey, et al., "A
case-control study of Alzheimer's disease in Australia", Neurology 1990;40:1698-1707.
G. Li, Y.C. Shen, Y. T. Li, C.H. Chen, Y.W. Zhau, and J. M.
Silverman, "A case-controlled study of Alzheimer's disease in China", Neurology 1992;42:1481-1488.
J.C.S. Breitner, B.A. Gau, K.A. Welsh, et al. "Inverse association of anti-inflammatory treatments and Alzheimer's disease", Neurology 1994;44:227-232.
21317~
R. Myllykangas-Luosujarvi and H. Isomaki, "Alzheimer's disease and rheumatoid arthritis", British Journal of Rheumatology 1994;33:501-502.
J. Rogers, L.C. Kirby, S.R. Hempelman, et al., "Clinical trial of indomethacin in Alzheimer's disease", Neurology 1993;43:1609-1611.
P. Constantinides, "General Pathobiology", Appleton &
Lange, Norwalk, Connecticut, 1994D.Y. Graham, N.M. Agrawal, and S.H. Roth, "Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial", Lancet, December 3, 1988, 1277-1280.
R.J. Flower and G.J. Blackwell, "Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation", Nature 1979;278:456-459.
J.R. Vane, "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs", Nature 1971;
231:232-235.
J.E. Merrill, S.R. Strom, G.W. Ellison, and L.W. Myers, "In vitro study of mediators of inflammation in multiple sclerosis", Journal of Clinical Immunology 1989;9:84-96.
H.P. Hartung, B. Schafer, K. Heininger, and K.V. Toyka, "Recombinant interleukin-l beta stimulates eicosanoid production in rat primary culture astrocytes", Brain Research 1989;489:113-119.
L.N. Fleisher, J.B. Ferrell, M.G. Smith, and M.C. McGahan, "Lipid mediation of tumor necrosis factor-alpha-induced uveitis", Investigative Ophthalmology and Visual Science 1991;32:2393-2399.
21317erj4 _ - 8 N. Fujimoto, T. Kaneko, N. Eguchi, Y. Urade, N. Mizuno, and O. Hayaishi, "Biochemical and immunohistochemical demonstration of a tightly bound form of prostaglandin E2 in the rat brain", Neuroscience 1991;49:591-606.
K. Matsumura, Y. Watanabe, K. Imai-Matsumura, et al., "Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography", Brain Research 1992j581:292-298.
N. Iwamoto, K. Kobayashi, and K. Kosaka, "The formation of prostaglandins in the postmortem cerebral cortex of Alzheimer-type dementia patients", Journal of Neurology 1989;236:80-84.
J. Hardy and D. Allsop, "Amyloid deposition as the central event in the aetiology of Alzheimer's disease", Trends in Pharmacology 1991;12:383-388.
A. Klegeris, D.G. Walker, and P.L. McGeer, "Activation of macrophages by Alzheimer b amyloid peptide", Biochemical and Biophysical Research Communications 1994jl99(2):984-991 (Schedule A).
A. Klegeris and P.L. McGeer , "Comparison of respiratory burst activity between rat brain microglia and peritoneal macrophages", Journal of Neuroimmunology 1994; 53 (Schedule B).
Claims (7)
1) A method of treating dementia in a human being in need thereof which comprises administering to said human being on a daily basis a sufficient amount of a prostaglandin E
derivative to inhibit toxic actions of microglial cells in brain tissue but insufficient to induce unwanted side effects in said human.
derivative to inhibit toxic actions of microglial cells in brain tissue but insufficient to induce unwanted side effects in said human.
2 ) A method as claimed in claim 1 wherin the drug is selected from the group consisting of prostaglandin E1 and its analogs, rioprostil and misoprostol, or prostaglandin E2 and its derivatives, enprostil, arbaprostil and trimoprostil, and therapeutically acceptable salts thereof.
3) A method as claimed in claim 2 wherein the daily dosage is from 50 micrograms to 1 gram of substance per 50 kilograms of body weight of the human being.
4) A method as claimed in claim 1 wherein the prostaglandin derivative is combined with a therapeutically effective dose of an adrenocorticosteroid capable of inhibiting production of prostaglandins in the body, including, but not limited to, cortisol, cortisone, dexamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone or any of their derivatives.
5) A method as claimed in claim 1 wherein the prostaglandin derivative is combined with a nonsteroidal antiinflammatory drug capable of inhibiting production of prostaglandins in the body at a dosage sufficient to inhibit brain cyclooxygenase.
6 ) A method as in claim 5 where misoprostol at a dose of micrograms to 800 micrograms is combined with indomethacin at a dose of 25 milligrams to 150 milligrams per 50 kilograms of body weight on a daily basis.
7) An article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for treating dementia in a human being, and wherein the packaging material comprises a label which indicates that the pharmaceutical agent can be used for treating dementia, and wherein said pharmaceutical agent comprises a prostaglandin E derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002131754A CA2131754A1 (en) | 1994-09-09 | 1994-09-09 | Prostaglandin e derivatives in the treatment of dementia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002131754A CA2131754A1 (en) | 1994-09-09 | 1994-09-09 | Prostaglandin e derivatives in the treatment of dementia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2131754A1 true CA2131754A1 (en) | 1996-03-10 |
Family
ID=4154292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002131754A Abandoned CA2131754A1 (en) | 1994-09-09 | 1994-09-09 | Prostaglandin e derivatives in the treatment of dementia |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2131754A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001002855A1 (en) * | 1999-07-01 | 2001-01-11 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| EP1669756A2 (en) * | 1999-07-01 | 2006-06-14 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| WO2008036678A2 (en) * | 2006-09-19 | 2008-03-27 | Braincells, Inc. | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
-
1994
- 1994-09-09 CA CA002131754A patent/CA2131754A1/en not_active Abandoned
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001002855A1 (en) * | 1999-07-01 | 2001-01-11 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| US6596474B1 (en) | 1999-07-01 | 2003-07-22 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| EP1669756A2 (en) * | 1999-07-01 | 2006-06-14 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| EP1669756A3 (en) * | 1999-07-01 | 2006-12-20 | Scios Inc. | Prevention and treatment of amyloid-associated disorders |
| WO2008036678A2 (en) * | 2006-09-19 | 2008-03-27 | Braincells, Inc. | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
| WO2008036678A3 (en) * | 2006-09-19 | 2008-10-30 | Braincells Inc | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |