WO1995017154A2 - Use of thalidomide for treating neurocognitive disorders - Google Patents
Use of thalidomide for treating neurocognitive disorders Download PDFInfo
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- WO1995017154A2 WO1995017154A2 PCT/US1994/014743 US9414743W WO9517154A2 WO 1995017154 A2 WO1995017154 A2 WO 1995017154A2 US 9414743 W US9414743 W US 9414743W WO 9517154 A2 WO9517154 A2 WO 9517154A2
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- thalidomide
- acid
- inflammatory
- steroidal anti
- mammal
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- 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
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- 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
- A61K31/60—Salicylic acid; Derivatives thereof
Definitions
- the present invention is directed to compositions, and methods for alleviating the symptoms associated with neurocognitive disorders, i.e., senile dementia of the Alzheimer's type.
- the present invention is directed to a method for treating Alzheimer's disease with thalidomide.
- senile dementia is treated with thalidomide in conjunction with nonsteroidal anti-inflammatory carboxylic acids selected from the group consisting of the aryl acetic acids, the aryl propionic acids, the salicyiates, the ferramic acids, the biphenyl carboxylic acids and the diphenylether carboxylic acids.
- Thalidomide N- phthalidoglutarimide
- Thalidomide was first synthesized in 1953 by researchers at Chemie Grunenthal in Germany. It was marketed in Europe in 1956 as a sedative/hypnotic drug. Thalidomide is orally administered. It is poorly absorbed in humans. When 100 to 200 milligrams (mg) of thalidomide is ingested by humans, a maximal blood concentration of 0.9 to 1.5 mg/liter is attained 4 to 6 hours later. Thalidomide is extensively distributed throughout the body but does not selectively localize in any tissue. Thalidomide breaks down by spontaneous hydrolysis; however, the hydrolytic cleavage in serum is much slower than in vitro at pH 7.4. This may be due to thalidomide being highly bound to plasma proteins.
- Thalidomide metabolites are renally excreted.
- racemic thalidomide has not been toxic.
- side effects in humans have included somnolence, teratogenicity and, upon extended administration, peripheral neuropathy.
- the teratogenic potential of thalidomide resulted in a variety of malformations of fetuses (phocomelia) and the subsequent removal of thalidomide from the market.
- the mechanism of the teratogenic effect is not known; however, it will occur when thalidomide is taken between the 35th and 50th day of the menstrual age of the embryo.
- thalidomide has exhibited an immunomodulatory effect which has resulted in its therapeutic use in the following conditions: rheumatoid arthritis, acute and chronic graft versus host disease, aphthosis, cold hemagglutinin disease, colitis, cutaneous lupus erythematosus, erythema nodosum leprosum, erythema multiform, histiocytosis, immune complex vasculitis, Jessner- Kanofs disease, lichen planus, pemphigoid disorders, photodermatoses, prurigo nodularis, pyoderma gangrenosum, sarcoidosis and Weber Christian's disease.
- Thalidomide has been shown to reduce HIV production in peripheral blood mononuclear cells of HIV-infected patients. Thalidomide also inhibited HIV expression from infected cells lines induced with tumor necrosis factor alpha (Schauf et al.. Intl. Sci. Conference on Antimicrobial Aoents and Chemotherapy. Anaheim, California, 1992).
- Alzheimer's disease is the fourth leading cause of death in Americans over the age of 65.
- the etiology of Alzheimer's disease may be familial in 50% of cases and sporadic in the other 50%.
- T ⁇ UTE SHEET (RULE 26) disease is divided into three clinical stages. Stage one is characterized by a memory loss and emotional instability. The frequency of misdiagnosis at this stage is high. In the second stage, patient confusion increases and although patients are ambulatory, they are at significant risk for falls and accidents. In the last stage of the disease , patients begin to lose control over bodily functions. They become completely dependent on caregivers and are at high risk for development of pneumonia, malnutrition and pressure necrosis of the skin. The patient ultimately goes into a coma and dies. Senile dementia of the Alzheimer's type is characterized by a degenerative process in which there is a loss of cells from the cerebral cortex, hippocampus and subcortical structures.
- beta-amyloid peptide is a 40 to 42 amino acid peptide derived from a larger amyloid precursor protein.
- beta-amyloid peptide is a 40 to 42 amino acid peptide derived from a larger amyloid precursor protein.
- Alzheimer's disease exhibit many of the classical markers of immune-mediated damage. These have included increased numbers of microglia (cells believed to be the functional equivalent to macrophages in the central nervous system) (Stryren et al., Exp. Neurel.. 110:93. 1990) and astrocytes expressing inflammatory reactants interleukin 1 and alpha 1 antichymotrypsin (Abraham et al., Cell. 52:487, (1988). Complement proteins of the classical pathway have been immunohistochemically detected in Alzheimer's brain tissue and are most often associated with the beta amyloid plaques. Rogers et al., (Prgc. Nat. Acad. Sci..).
- EET RULE 26 by enzyme-linked immunosorbent assay and cytotoxicity bioassay.
- the authors reported elevated levels of tumor necrosis factor in Alzheimer's patients compared to controls and indicated elevated circulating tumor necrosis factor may be derived from the local central nervous system inflammatory reaction found in Alzheimer's patients and may account for some of the systemic manifestations of Alzheimer's disease such as weight loss.
- thalidomide has an inhibitory effect on the synthesis of tumor necrosis factor alpha, a mediator of the inflammatory reaction and which is elevated in the sera of Alzheimer's patients (Fillit, Neurosci. Lett., 129:318, 1991).
- Corder et al (Sci 261: 921, 1993) have discovered an association between Alzheimer's disease and the apolipoprotein E locus on human chromosome 19.
- Apolipoprotein E is a protein that transports cholesterol through the blood stream. APOE has three alleles, APOE-12, APOE- ⁇ 3 and APOE-14.
- APOE-14 allele may either have an active pathogenic role in Alzheimer's disease development or may only be closely linked on chromosome 19 to a gene that does. However it is unusual in the case of a genetic linkage for the APOE gene dose to be correlated with development of Alzheimer's disease.
- APOE-4 binds more rapidly and tighter to beta amyloid than other APOE's and it is hypothesized that APOE-4 causes soluble circulating beta-amyloid to become insoluble upon binding to it and thereby facilitating beta-amyloid deposition in brain tissue resulting in plaque formation. Soluble beta-amyloid also binds to another apolipoprotein, APOJ. It has been hypothesized that binding to APOJ protects beta-amyloid's solubility and that the amount of APOE-4 versus APOJ is in a delicate balance in the brain with Alzheimer's disease developing if the APOE gene dose is able to shift the balance in favor of APOE-4.
- APOE-4 also binds to the neurofibrillary tangles found in the brain tissue of patients with Alzheimer's disease. The significance of this is not clear at this time.
- Progress of Alzheimer's disease is believed to be attributed to degeneration of certain nerve tracts in the central nervous system, resulting in the loss of associated functions.
- Pathological studies indicate that brains of Alzheimer's patients have loss of several neurotransmitter systems, related to different functions, but the system which is implicated the most is the cholinergic system.
- Studies show that several important cholinergic tracts innervating the cortical and hippocampal regions degenerate. Although this particular degeneration may not account for all the symptoms of Alzheimer's, it may account for the cognitive and memory deficits, which are some of the most difficult symptoms for patients and their families to deal with.
- the prior art is silent regarding the treatment of cognitive disorders with thalidomide.
- the primary object of the present invention is the treatment of neurocognitive disorders by administering thalidomide to a patient in need of such treatment.
- Another object of the present invention is to provide a therapeutic method for alleviating the symptoms of cognitive decline by administering a therapeutically effective amount of thalidomide.
- An additional object of the present invention is to treat Alzheimer's disease with a therapeutically effective amount of thalidomide.
- Another object of the present invention is to treat Alzheimer's disease or neurocognitive disorders with thalidomide in combination with other drugs.
- a further object of the invention is to treat Alzheimer's disease with a pharmaceutical composition comprising thalidomide and a non-steroidal anti-inflammatory carboxylic acid.
- Still another object of the invention is to treat Alzheimer's disease with a pharmaceutical composition comprising thalidomide and a separate pharmaceutical composition comprising a non-steroidal anti- inflammatory carboxylic acid.
- Another object of the invention is to treat Alzheimer's disease with pharmaceutical composition comprising thalidomide and a steroidal anti-inflammatory.
- Still another object of the invention is to treat Alzheimer's disease with a pharmaceutical composition comprising thalidomide and separate pharmaceutical composition comprising a steroidal anti- inflammatory carboxylic acid.
- the present inventor has now discovered a method for treating central nervous system or peripheral nervous system cholinergic deficit states in a mammal.
- the method comprises administering to a mammal an amount of thalidomide alone or in combination with compounds selected from the group consisting of tacrine, non-steroidal anti-inflammatory carboxylic acids (NSAIDs), b-amyloid inhibitors and pentoxyphylline effective in the treatment of cholinergic deficit states and for a time sufficient to achieve a suitable blood level to treat said cholinergic deficit state.
- NSAIDs non-steroidal anti-inflammatory carboxylic acids
- b-amyloid inhibitors b-amyloid inhibitors
- pentoxyphylline pentoxyphylline
- EET RULE 26 The present inventor has also discovered a pharmaceutical composition of matter for treating said cholinergic deficit states in a mammalian organism in need of such treatment, said composition comprising a unit dosage amount of thalidomide alone or in combination with the above mentioned compounds and pharmaceutically acceptable carrier.
- the present invention deals with a method for treating a central nervous system or peripheral nervous system cholinergic deficit state in a mammalian organism in need of such treatment, said method comprising administering to said mammal an amount of thalidomide effective in the treatment of a cholinergic deficit state and for a time sufficient to achieve a suitable blood level to treat said cholinergic deficit state.
- the present invention relates to a method of treating the symptoms of cognitive decline in a mammal which comprises administering to a mammal affected with said cognitive decline a therapeutically effective amount of thalidomide.
- the present invention provides a method of treating a mammal suffering from cognitive decline with thalidomide and independently with other agents selected from the group consisting of tacrine, non-sterodial anti-inflammatory agents, sterodial anti-inflammatory agents, b-amyloid inhibitors and/or pentoxyphylline.
- the invention also provides a method for treating the symptoms of cognitive decline in a mammal which comprises administering to a mammal affected with said cognitive decline a therapeutically effective amount of a mixture of thalidomide with a compound selected from the group consisting of tacrine, non- steroidal anti-inflammatory carboxylic acids (NSAIDs), b-amyloid inhibitors and pentoxyphylline.
- NSAIDs non- steroidal anti-inflammatory carboxylic acids
- b-amyloid inhibitors b-amyloid inhibitors
- pentoxyphylline pentoxyphylline
- the present invention further provides a method for treating Alzheimer's disease in a mammal, said method comprising administering to said mammal a therapeutically effective amount of thalidomide.
- the therapeutically effective amounts of thalidomide are typically 30 mg to 1000 mg and preferably 100 mg to 500 mg.
- thalidomide When thalidomide is used in combination with NSAIDs or sterodial anti-inflammatories (SAIDs), the amount of thalidomide is typically in the range of about 30 mg to about 1000 mg while the NSAIDs are present in the range of about 200 mg to 800 mg and the SAIDs are present in the range of 10 mg to 60 mg.
- an effective combination for treating Alzheimer's is a gelatin capsule containing 200 mg of thalidomide and 200 mg of ibuprofen given three times daily. Two capsules each containing the active ingredient may also be prescribed.
- thalidomide alone or with the other active materials mentioned above will vary depending, for example, on the condition for which the drug is administered and the size and kind of the mammal.
- the thalidomide can be employed in any amount effective in the treatment of central nervous system or peripheral nervous system cholinergic deficit states. The symptoms of these states, including senile dementia of the Alzheimer's type are improved.
- typical effective amounts of thalidomide for use in the unit dose compositions of the present invention range from about 30 mg to 1000 mg per 24 hours; however greater amounts may be employed, if desired. This range is based on administration to a 70 Kg human. A preferred amount is 100 mg to 800 mg. The more preferred range contains about 100 mg to 500 mg of thalidomide per 24 hours.
- thalidomide may be given alone or in combination with other drugs which are also useful in the treatment of central nervous system or peripheral nervous system cholinergic deficit states.
- a typical formulation contains from about 100 mg to 500 mg of thalidomide and from about 100 mg to 300 mg of tacrine. The formulations are administered over a 24 hour period.
- thalidomide is combine with NSAIDs or steroidal anti-inflammatories, a typical formulation contains from about 100 mg to about 500 mg of thalidomide, and from about 100 mg to 800 mg of NSAIDs or 10 mg to 60 mf of SAID.
- the preferred non-steroidal anti-inflammatory is selected from the group consisting of aryl propionic acids, aryl acetic acids, biphenyl carboxylic acids, diphenyiether carboxylic acids, the salicylates, and the fenamic acids.
- the propionic acid derivatives which may be used comprise: ibuprofen, ibuprofen aluminum, indoprofen, ketoprofen, naproxen, benoxaprogen, flurbiprofen, fenoprofen, fenbufen, pirprogen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, fluprofen, and bucloxic acid.
- Structurally related propionic acid derivatives having similar analgesic and anti- inflammatory properties are also intended to be included in this group.
- ⁇ as defined herein are nonnarcotic analgesics/non-sterodial anti-infiammatory drugs having a free -CH(CH 3 )COOH or -CH 2 CH 2 COOH group (which optionally can be in the form of pharmaceutically acceptable salt group, e.g. -CH(CH 3 )COO " Na * or -CH 2 CH 2 COO ' Na * ), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
- a free -CH(CH 3 )COOH or -CH 2 CH 2 COOH group which optionally can be in the form of pharmaceutically acceptable salt group, e.g. -CH(CH 3 )COO " Na * or -CH 2 CH 2 COO ' Na *
- acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, suiindac, tolmetin, zomepirac, didofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac,
- SUBST ⁇ TE SHEET (RULE 26) tiopinac, zidometacin, acematacin, fentiazac, clidanac, oxpinac, and fenflozic acid.
- Structurally related acetic add derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
- acetic acid derivatives as defined herein are non-narcotic analgesics/non-sterodidal anti- inflammatory drugs having a free -CH 2 COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH 2 COO " Na * ), typically attached directly to a ring system.
- a free -CH 2 COOH group which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH 2 COO " Na *
- fenamic acid derivatives which may be used comprise: mefanamic acid, meclofe ⁇ amic acid, flufenamic acid, niflumic acid, and tolfenamic acid. Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
- fenamic acid derivatives as defined herein are non-narcotic analgesic/non-steroidal anti- inflammatory drugs which contain the basic structure:
- the biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
- biphenylcarboxylic acid derivatives as defined herein are non-narcotic analgesics/non- steroidal anti-inflammatory drugs which contain the basic structure:
- Typical acids include ibuprofen, diflunisol, fenoprotenin acid, mecfofenic add, mefenamic acid, naproxen, suiindac, indomethacin, tolmetin, fenbufen, ketoprofen, indoprofen, fluprofen, benozaprofen, pirprofen, miroprofen, thioxaprofen, aspirin, choiine magnesium salicylate as well as those NSAIDs disclosed in the "Physicians Desk Reference" (1992 edition) whose contents are incorporated by reference herewith.
- the preferred steroidals are predniso ⁇ e, prednisolone etc.
- thalidomide can be combined with or administered with b-amyloid inhibitors and with pentoxyphylline.
- the amount of thalidomide is typically from about 100 mg to about 500 mg and the amount of the o-amyloid inhibitors is from about 50 mg to 1000 mg. In the case of pentoxyphylline, the amounts are in the range of about 50 mg to 500 mg.
- apolipoprotein E may refer to apolipoprotein E2, E3 or E4 or any combination thereof.
- thalidomide is combined with agents that suppress or reduce expression of apolipoprotein E alleles on chromosome 19.
- thalidomide is administered with or combined with agents that eliminate or reduce the level of apolipoprotein E in the circulatory system.
- thalidomide is administered with or combined with agents that ameliorate the effect of apolipoprotein E or apolipoprotein E and amyloid deposits in the fo ⁇ m of extracellular senile plaques, vascular amyloid deposits and neurofibrillary tangles, in the brain.
- Thalidomide is also administered with or combined with apolipoprotein J, which may prevent deposition of beta amyloid into brain tissue.
- SUBST ⁇ JTE SHEET (RULE 26) Additionally thalidomide is administered with or combined with agents that facilitate and/or maintain the solubility of beta amyloid.
- Thalidomide is further administered with or combined with agents that prevent or reduce binding or reduce avidity of binding between apolipoprotein E and beta amylid.
- Thalidomide is also administered with or combined with agents that prevent deposition of amyloid deposits in the brain.
- thalidomide is administered with or combined with agents that stimulate produdion of apolipoprotein J.
- Thalidomide with agents that prevent or reduce apolipoprotein E from binding to neurofibrillary tangles in brain tissue.
- Thalidomide with agents that reduce or prevent development of neurofibrillary tangles in brain tissue.
- Thalidomide with agents that prevent or reduce production of TAU protein, a component of neurofibrillary tangles.
- each compound selected will depend on the weight of the mammal and the disease state.
- One skilled in the art can adjust the dosage forms to achieve the desired therapeutic levels.
- the compound of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the adive component, either thalidomide alone or in combination with other compounds.
- the compounds of the present invention are administered orally, intramuscularly or subcutaneously.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also ad as diluents, flavoring agents, solubiiizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the earner is a finely divided solid which is in a mixture with the finely divided adive component.
- the adive component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the adive compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, ladose, pedin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluiose, a low melting wax, cocoa butter, and the like.
- the term "preparation" is intended to include the formulation of the adive compound with encapsulating material as a carrier providing a capsule in which the adive component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similariy, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- SUBST ⁇ UTE SHEET (RULE 26)
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
- the adive component is dispersed homogeneously therein, as by stirring.
- the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
- liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions suitable for oral use can be prepared by dissolving the adive component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided adive component in water with viscous material, such as natural or synthetic gums, resins, methycellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- viscous material such as natural or synthetic gums, resins, methycellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the adive component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the pharmaceutical preparation is preferably in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the adive component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage fo ⁇ m can be a
- SUBSTTTUTE SHEET (RULE 26) capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- time-release formulations include a lower concentration of peak serum absorption which substantially reduces the adverse side effeds and toxicity of the compound administered.
- a reduced frequency of administration results, which substantially improves patient compliance. A frequency of administration of every 12 or 24 hours would be preferred.
- more constant serum concentration of thalidomide would result thereby allowing a more consistent relief of symptoms.
- EXAMPLE 1 500 mg of thalidomide are mixed with 200 mg of ibuprofen. The adive ingredients are triturated and q.s. with ladose to seleded capsules size.
- EXAMPLE 2 500 mg of thalidomide are mixed with 375 mg of naproxen. The adive ingredients are triturated and q.s. with ladose to seleded capsule size.
- EXAMPLE 3 250 mg of thalidomide are mixed with 100 mg of tacrine. The adive ingredients are triturated and q.s. with ladose to seleded capsule size.
- EXAMPLE 4 Pinched off nerve endings (symptoms) from whole rat brain are first incubated in the presence of the precursor 3 H-Choline, which is converted intracellularly to 3 H-Acetylcholine (ACh). The release of ACh from synaptosomes is quantitated under low [K] and high. [K] conditions intended to simulate physiological stimulation. The thalidomide or combinations with other drugs are tested under the above conditions.
- Baseline registration of EEG (eledroencephalogram), psychometric testing (short term memory), assessment of P-300 potential by audiometric testing.
- phase 1 to 3 is followed by a period of at least one week before starting the next one. Every patient undergoes all 3 phases.
- Thalidomide 250 mg four times daily.
- Saline physiological concentration.
- the memory test consists in the memorization of a list of neutral words.
- the investigator reads the words; then a dispersion phase ensued, consisting in the performance of some arithmetical tasks.
- the subjed is then asked to repeat as many words from the list as he/she could remember The words used in each case were different, in order to avoid learning.
- the stimulus seleded for this test is an auditive one, since audiometric testing of this potential has proven to be easy to perform and reliable.
- the mechanisms involved in the process of the hearing itself produce some bioeledric adivity diredly related to the stimulus itself.
- the perception process is more complex that the mere "hearing” and even after the stimulus has been removed, bioeledric adivity related to it can be observed, as a form of 'echoes.' These 'echoes' are the evoked potentials.
- P-300 is a positive wave that can be observed 300 milliseconds after the first peak due to stimulus, and it is known to be related with the conscious processing of it, namely with the attention devoted to it.
- EEG Monitoring starts one week after administration.
- SUBST ⁇ UTE SHEET (RULE 26 Changes are defined as any variation in amplitude (potential) or in topographical distribution of the bands and are studied subjed by subjed, comparing the pattern obtained after injedion of the produds versus baseline recording and versus placebo.
- ADAS alzheimer's Disease Assessment Scale
- the alzheimer's Disease Assessment Scale provides a composite assessment of all of the common symptoms of Alzheimer's disease. Evaluates cognitive and noncognitive behaviors. Scale is divided into two sedions: an 11-team cognitive subscale that rates mood, vegetative fundions, agitation, delusions, hallucinations, and concentration and distractibility. Scores on the cognitive subscale range from 0-70 and on the noncognitive subscale from 0-50, with the higher scores indicating poorer performance. Used in longitudinal investigations and clinical trails. In clinical trials, only the cognitive subscale is typically used as a primary outcome measure. Score on the ADAS have been shown to correlate moderately with neurochemical markers or Alzheimer's disease. Some training required to administer the ADAS.
- MMSE Mini-Mental State Examination
Abstract
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Priority Applications (2)
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AU13751/95A AU1375195A (en) | 1993-12-23 | 1994-12-22 | Use of thalidomide for treating neurocognitive disorders |
EP95904954A EP0735874A1 (en) | 1993-12-23 | 1994-12-22 | Use of thalidomide for treating neurocognitive disorders |
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US08/172,155 | 1993-12-23 | ||
US08/172,155 US5434170A (en) | 1993-12-23 | 1993-12-23 | Method for treating neurocognitive disorders |
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WO1997048391A2 (en) * | 1996-06-21 | 1997-12-24 | Advanced Research And Technology Institute | Methods and compositions comprising r-ibuprofen |
WO1998024433A1 (en) * | 1996-12-05 | 1998-06-11 | Rhone-Poulenc Rorer S.A. | Application of thalidomide to the treatment of parkinson's disease and parkisonian syndromes |
WO1998052563A1 (en) * | 1997-05-21 | 1998-11-26 | Shionogi & Co., Ltd. | REMEDIES FOR DEMENTIA OF ALZHEIMER TYPE CONTAINING η-SULTAM DERIVATIVES |
EP0908176A1 (en) * | 1997-10-06 | 1999-04-14 | Grünenthal GmbH | Intravenous administration form of thalidomide for the therapy of immunologic diseases |
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Also Published As
Publication number | Publication date |
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AU1375195A (en) | 1995-07-10 |
WO1995017154A3 (en) | 1995-07-13 |
EP0735874A1 (en) | 1996-10-09 |
US5434170A (en) | 1995-07-18 |
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