WO1997010816A1 - METHODS OF TREATING β-AMYLOID-ASSOCIATED CONDITIONS - Google Patents
METHODS OF TREATING β-AMYLOID-ASSOCIATED CONDITIONS Download PDFInfo
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- WO1997010816A1 WO1997010816A1 PCT/US1996/015046 US9615046W WO9710816A1 WO 1997010816 A1 WO1997010816 A1 WO 1997010816A1 US 9615046 W US9615046 W US 9615046W WO 9710816 A1 WO9710816 A1 WO 9710816A1
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- compound
- amyloid
- serotonin
- amyloid peptide
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- 0 *C(COc1c2)(c1ccc2C#N)C(C=C1)=CCC1F Chemical compound *C(COc1c2)(c1ccc2C#N)C(C=C1)=CCC1F 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N CN(C)CC(C1(CCCCC1)O)c(cc1)ccc1OC Chemical compound CN(C)CC(C1(CCCCC1)O)c(cc1)ccc1OC PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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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
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
Definitions
- 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states.
- R.W. Fuller BIOLOGY OF SEROTONERGIC TRANSMISSION, 221 (1982); D.J. Boullin, SEROTONIN IN MENTAL ABNORMALITIES 1:316 (1978); J. Barchas, et al.. Serotonin and Behavior.(1 73). Serotonin plays an important role in peripheral systems as well.
- serotonin For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists.
- serotonergic systems are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting.
- Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid”) appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For reviews, see, Alzheimer's Disease. (B. Reisberg, ed., The Free Press 1983).]
- ⁇ -amyloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein (APP).
- APP amyloid precursor protein
- ⁇ -Amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al.. Nature (London). 325:733-736 (1987). These peptides, however, vary as to their amino-termini. C. Hilbich, et al.. Journal of Molecular Biology. 218:149-163 (1991).
- cells have alternative mechanisms for processing amyloid precursor protein which can result in the formation of the ⁇ -amyloid protein and subsequently, the senile plaques.
- This invention provides methods for the treatment of Alzheimer's disease and other conditions associated with ⁇ -amyloid peptide in mammals. Specifically, this invention provides methods of using selective serotonin reuptake inhibitors as a treatment for Alzheimer's disease and these other conditions.
- This invention provides a method for treating a physiological disorder associated with ⁇ -amyloid peptide in a mammal which comprises administering to a mammal in need thereof an effective amount of a composition having serotonin reuptake inhibition activity.
- ⁇ -amyloid peptide naturally occurs as a series of peptides which are 39 to 43 amino adds long, with the shorter, more soluble forms being present in cerebrovascular deposits and the longer forms being found primarily in senile plaques.
- the primary structure of the 43 amino acid long peptide ( ⁇ l-43) is depicted in SEQ ID NO:l:
- ⁇ -amyloid peptide comprising amino-truncated, carboxy-truncated, or internal deletions, or any combination of these, as well as conservative variants of these peptides, may be employed in this invention so long as that peptide fragment demonstrates the requisite neurotoxicity.
- SEQ ID NO:l and SEQ ID NO:2 are referred to as ⁇ -amyloid peptide throughout this document, in the body of literature concerning this field, this peptide is alternatively referred to as ⁇ -amyloid protein, amyloid ⁇ peptide, amyloid ⁇ A4, ⁇ protein, amyloid A4, ⁇ -peptide, and other such names.
- treating includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
- effective amount refers to the amount of compound necessary to treat physiological effects or disorders associated with ⁇ -amyloid peptide, or inhibit amyloidogenic production or deposition, or treat Alzheimer's Disease, as the case may be.
- ⁇ -amyloid peptide includes diseases related to the inappropriate or undesirable deposition of ⁇ -amyloid peptide, and as such includes Alzheimer's Disease (including familial Alzheimer's Disease), Down's Syndrome, advanced aging of the brain, hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D), and the like.
- the compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
- R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
- the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
- the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
- the priority of groups is based upon their atomic number (in order of decreasing atomic number).
- the skilled practitioner can proceed by one of two routes.
- the practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers.
- a commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active acid or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al.. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
- the practitioner of this invention may also choose an enantiospecific protocol for the preparation of these compounds.
- a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation.
- These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
- some of the compounds employed in the methods of the present invention also have the capacity for (E)-(Z) isomerism.
- this system the group of higher priority bonded to one of the carbon atoms sharing the double bond is compared to the group of higher priority bonded to the other carbon atom sharing the double bond. If the two groups of higher priority are on the same side of the double bond, the alkene is designated (Z) (zusammen). If the two groups of higher priority are on opposite sides of the double bond the alkene is designated (E) (enthafen).
- all asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
- This invention also encompasses methods employing the pharmaceutically acceptable salts of the compounds described herein.
- a compound employed in this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
- Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
- This invention also encompasses methods employing the pharmaceutically acceptable solvates of the compounds described herein. Many of these compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
- solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
- solvents such as water, methanol, ethanol and acetonitrile
- pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
- solvents such as water, methanol, ethanol and acetonitrile
- solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
- Inhibitors of serotonin uptake increase serotonin action on postsynaptic receptors on target neuron, and increase serotonergic neurotransmission, resulting in functional consequences that are mostly subtle, i.e., not detectable by gross observation, but are detectable by various specific techniques.
- serotonin uptake inhibitors reduce aggressive behavior, decrease food uptake, decrease alcohol drinking in rats, decrease rapid-eye-movememt sleep, potentiate morphine analgesia, and the like.
- Serotonin uptake inhibitors are used clinically in the treatment of mental depression, bulimia, and obsessive-compulsive disorder. They are also reported to be effective as appetite suppressant drugs in the treatment of obesity, in borderline personality disorder, trichotillomania, panic disorder, and attention deficit hyperactivity disorder. See, e.g.. R.W. Fuller, Advances in Biosciences. 85:255-270 (1992).
- serotonin uptake inhibitors have been reported to have therapeutic benefit in premenstrual syndrome, diabetic neuropathy, chronic pain, and in postanoxic intention myoclonus.
- duloxetine which has activity as a reuptake inhibitor of both serotonin and norepinephrine. This compound has the structure
- Venlafaxine is known in the literature as a serotonin and norepinephrine reuptake inhibitor. This compound has the structure
- milnacipran ⁇ (Z) l-phenyl-l-diethylaminocarbonyl-2- aminomethylcyclopropane hydrochloride ⁇ is taught in United States Patent 4,478,836, the entire contents of which are herein incorporated by reference.
- the structure of milnacipran is as follows.
- Milnacipran is known to increase the availability of serotonin, norepinephrine, and dopamine.
- Another serotonin reuptake inhibitor which may be employed in the methods of the present invention is citalopram, a compound having the structure
- indalpine a compound having the structure
- Sertraline is another serotonin reuptake inhibitor which may be employed in the methods of the present invention.
- This compound having the chemical name (lS-cis)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine, has the following structure.
- Sertraline may be prepared as described in United States Patent 4,536,518, the entire contents of which are herein incorporated by reference.
- An additional such inhibitor which may be employed in the methods of the present invention is zimeldine, a compound of the structure
- Another such compound is imipramine, a compound having the structure
- the selective serotonin reuptake inhibitors are a series of compounds which act as serotonin reuptake inhibitors but act in a selective manner. Selective serotonin reuptake inhibitors are especially preferred in the methods of the present invention.
- One such compound is fluoxetine, a compound having the structure
- fluoxetine refers to any acid addition salt or the free base, and includes either the racemic mixture or either of the enantiomers.
- Another compound belonging to this class of therapeutics is femoxetine, a compound having the structure
- Another such compound is paroxetine, a compound having the structure
- the above groups of compounds are only illustrative of the serotonin reuptake inhibitors which are currently under development or are frequently employed in serotonin receptor studies. This listing of groups of compounds is not meant to be comprehensive, the methods of the present invention may employ any serotonin reuptake inhibitor and is not limited to any particular class of compound.
- the biological activities of the compounds of the present invention are evaluated employing an initial screening assay which rapidly and accurately measures the inhibition of ⁇ -amyloid peptide in a whole cell assay.
- Two cell lines (human kidney cell line 293 and Chinese hamster ovary cell Une CHO) are stably transfected with the gene for APP751 containing the double mutation Lys65i-Met ⁇ 5 2 to Asn ⁇ 5i-Leu 6 52 (APP-751 numbering) commonly called the Swedish mutation using the method described in Citron, et al.. Nature 360:672-674 (1992).
- the transfected cell lines are designated as 293 751 SWE and CHO 751 SWE, and are plated in Corning 96 well plates at 2.5xl0 4 or lxlO 4 cells per well respectively in Dulbecco's minimal essential media (DMEM) plus 10% fetal bovine serum.
- DMEM Dulbecco's minimal essential media
- the media are removed and replaced with 200 ⁇ l per well of media. After a two hour pretreatment period, the media are again removed and replaced with fresh media containing the test compound and the cells are incubated for an additional two hours.
- CO 2 carbon dioxide
- MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide
- results ofthe ⁇ -amyloid peptide ELISA are fit to a standard curve and expressed as ng/ml ⁇ -amyloid peptide. In order to normalize for cytotoxicity, these ⁇ -amyloid peptide results are divided by the MTT results and expressed as a percentage of the results from a drug-free control.
- serotonin reuptake inhibitors have shown significant inhibition of ⁇ -amyloid peptide production without demonstrating increased cytotoxicity.
- selective serotonin reuptake inhibitors are especially preferred.
- compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
- These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
- Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
- the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
- the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the active compounds are generally effective over a wide dosage range.
- dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg day, in single or divided dose, is especially preferred.
- the amount of the compound actually administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
- Hard gelatin capsules containing the following ingredients are prepared:
- Quantity Ingredient (mg/capsule)
- the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
- a tablet formula is prepared using the ingredients below:
- Quantity Ingredient (mg/tablet)
- a dry powder inhaler formulation is prepared containing the following components:
- the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
- Tablets each containing 30 mg of active ingredient, are prepared as follows:
- Quantity Ingredient (mg/tablet)
- the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
- the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
- Capsules each containing 40 mg of medicament are made as follows:
- Quantity Ingredient mg/capsule
- Suppositories each containing 25 mg of active ingredient are made as follows:
- the active ingredient(s) is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
- Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
- Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
- the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
- Capsules each containing 15 mg of medicament, are made as follows:
- the active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
- An intravenous formulation may be prepared as follows:
- a topical formulation may be prepared as follows:
- Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
- the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 °C.
- the solution is cooled to about 50-55°C and the medicament is slowly admixed.
- the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
- Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
- the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
- the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.
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Abstract
This invention provides a method for treating a physiological disorder associated with β-amyloid peptide in a mammal which comprises administering to a mammal in need thereof an effective amount of a composition having serotonin reuptake inhibition activity.
Description
Title
METHODS OF TREATING β-AMYLOID - ASSOCIATED CONDITIONS Priority Claim
This application claims the benefit of U.S. Provisional Application No. 60/004178, filed September 22, 1995.
Background of the Invention
Since the discovery of serotonin (5-hydroxytryptamine, 5- HT) over four decades ago, the cumulative results of many diverse studies have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R.A. O'Brien, Serotonin in Mental Abnormalities. 1:41 (1978); H.W.M. Steinbusch, HANDBOOK OF
CHEMICAL NEUROANATOMY, Volume 3, Part II, 68 (1984); N.E. Anden, et al.. Acta Phvsiologica Scandinavia. 67:313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H.W.M. Steinbusch, supra.
With such a diffuse system, it is not surprising that 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states. R.W. Fuller, BIOLOGY OF SEROTONERGIC TRANSMISSION, 221 (1982); D.J. Boullin, SEROTONIN IN MENTAL ABNORMALITIES 1:316 (1978); J. Barchas, et al.. Serotonin and Behavior.(1 73). Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is
synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists. In particular, serotonergic systems are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting. M.D. Gershon, et al.. THE PERIPHERAL ACTIONS OF 5- HYDROXYTRYPTAMINE, 246 (1989); P.R. Saxena, et al.. Journal of Cardiovascular Pharmacology. 15:Supplement 7 (1990).
Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid") appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For reviews, see, Alzheimer's Disease. (B. Reisberg, ed., The Free Press 1983).]
While there is no general agreement as to the chemical nature of neurofibrillary tangles, the major constituent of both the amyloid plaque cores and the amyloid of the congophilic angiopathy has been shown to be a 4500 Dalton protein originally termed β-protein or amyloid A4. Throughout this document this protein is referred to as β- amyloid peptide or protein. β-amyloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein (APP). Different splice forms of the amyloid precursor protein are encoded by a widely expressed gene. see, e.g.. K. Beyreuther and B. Muller-Hill, Annual Reviews in Biochemistrv. 58:287-307 (1989). β-Amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al.. Nature (London). 325:733-736 (1987). These peptides, however, vary as to
their amino-termini. C. Hilbich, et al.. Journal of Molecular Biology. 218:149-163 (1991).
Because senile plaques are invariably surrounded by dystrophic neurites, it was proposed early that β-amyloid peptide is involved in the loss of neuronal cells that occurs in Alzheimer's disease. B. Yankner and co-workers were the first to demonstrate that synthetic β-amyloid peptide could be neurotoxic in vitro and in vivo. B.A. Yankner, et al.. Science. 245:417 (1989); See, also. N.W. Kowall, et al.. Proceedings of the National Academy of Sciences. U.S.A.. 88:7247 (1991). Other research groups, however, were unable to consistently demonstrate direct toxicity with β-amyloid peptide. See, e.g.. Neurobiologv of Aging. 13:535 (K. Kosik and P. Coleman, eds. 1992). Even groups receiving β-amyloid peptide from a common source demonstrate conflicting results. D. Price, et al.. Neurobiologv of Aging. 13:623-625 ( 1991)(and the references cited therein).
As mentioned supra, cells have alternative mechanisms for processing amyloid precursor protein which can result in the formation of the β -amyloid protein and subsequently, the senile plaques.
Because of the debilitating effects of Alzheimer's disease there continues to exist a need for effective treatments. This invention provides methods for the treatment of Alzheimer's disease and other conditions associated with β-amyloid peptide in mammals. Specifically, this invention provides methods of using selective serotonin reuptake inhibitors as a treatment for Alzheimer's disease and these other conditions.
Summary of the Invention
This invention provides a method for treating a physiological disorder associated with β-amyloid peptide in a mammal which comprises administering to a mammal in need thereof an effective amount of a composition having serotonin reuptake inhibition activity.
Detailed Description and Preferred Embodiments
β-amyloid peptide naturally occurs as a series of peptides which are 39 to 43 amino adds long, with the shorter, more soluble forms being present in cerebrovascular deposits and the longer forms being found primarily in senile plaques. F. Prelli, et al.. Journal of Neurochemistry- 51:648-651 (1988). The primary structure of the 43 amino acid long peptide (βl-43) is depicted in SEQ ID NO:l:
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gin 15 Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 30 He He Gly Leu Met Val Gly Gly Val Val He Ala Thr 43
Even though the full length peptide of SEQ ID NO:l: has sufficient solubility in water for the following experiments, for the purposes of convenience, a more water-soluble form of the peptide is often desired. For that reason, the following examples were performed using peptides containing just the first 40 amino acids of the β-amyloid peptide (βl-40). The sequence of this preferred peptide is SEQ ID NO:2:
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gin 15 Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 30 He He Gly Leu Met Val Gly Gly Val Val 40
It is understood by those in the art that other fragments of β-amyloid peptide, comprising amino-truncated, carboxy-truncated, or internal deletions, or any combination of these, as well as conservative variants of these peptides, may be employed in this invention so long as that peptide fragment demonstrates the requisite neurotoxicity. While the peptide of SEQ ID NO:l and SEQ ID NO:2 are referred to as β-amyloid peptide throughout this document, in the body of literature concerning this field, this peptide is alternatively referred to as β-amyloid protein, amyloid β peptide, amyloid βA4, β protein, amyloid A4, β-peptide, and other such names. The term "treating" (or "treat") as used herein includes its generally accepted meaning which encompasses prohibiting,
preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration. The term "effective amount" as used herein refers to the amount of compound necessary to treat physiological effects or disorders associated with β-amyloid peptide, or inhibit amyloidogenic production or deposition, or treat Alzheimer's Disease, as the case may be.
The term "physiological disorder associated with β-amyloid peptide" includes diseases related to the inappropriate or undesirable deposition of β-amyloid peptide, and as such includes Alzheimer's Disease (including familial Alzheimer's Disease), Down's Syndrome, advanced aging of the brain, hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D), and the like. The compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120. In addition to the (R)-(S) system, the older D-L system may be used in this document to denote absolute configuration, especially
with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes. The practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active acid or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al.. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of these compounds. Such a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation. These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
In addition to the (R)-(S) system of stereochemistry, some of the compounds employed in the methods of the present invention also have the capacity for (E)-(Z) isomerism. In this system the group of higher priority bonded to one of the carbon atoms sharing the double bond is compared to the group of higher priority bonded to the other carbon atom sharing the double bond. If the two groups of higher priority are on the same side of the double bond, the alkene is designated (Z) (zusammen). If the two groups of higher priority are on opposite sides of the double bond the alkene is designated (E) (entgegen). As noted supra, all asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
This invention also encompasses methods employing the pharmaceutically acceptable salts of the compounds described herein. A compound employed in this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
This invention also encompasses methods employing the pharmaceutically acceptable solvates of the compounds described herein. Many of these compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate. The term "serotonin reuptake inhibitor'' refers to a composition which inhibits the serotonin transporter on membranes of serotonin neurons. These uptake inhibitors increase the concentration of serotonin within the synaptic cleft by blocking its removal via the membrane transporter. Inhibitors of serotonin uptake increase serotonin action on postsynaptic receptors on target neuron, and increase serotonergic neurotransmission, resulting in functional consequences that are mostly subtle, i.e., not detectable by gross observation, but are detectable by various specific techniques.
For instance, serotonin uptake inhibitors reduce aggressive behavior, decrease food uptake, decrease alcohol drinking in rats, decrease rapid-eye-movememt sleep, potentiate morphine analgesia, and the like. R.W. Fuller, Journal of Clinical Psychiatry. 53:35-45 (1992). Serotonin uptake inhibitors are used clinically in the treatment of mental depression, bulimia, and obsessive-compulsive disorder. They are also reported to be effective as appetite suppressant drugs in the treatment of obesity, in borderline personality disorder,
trichotillomania, panic disorder, and attention deficit hyperactivity disorder. See, e.g.. R.W. Fuller, Advances in Biosciences. 85:255-270 (1992). In addition, serotonin uptake inhibitors have been reported to have therapeutic benefit in premenstrual syndrome, diabetic neuropathy, chronic pain, and in postanoxic intention myoclonus. Id.- One such compound is duloxetine which has activity as a reuptake inhibitor of both serotonin and norepinephrine. This compound has the structure
and the chemical name (S) N-methyl-3-(l-naphthalenyloxy)-3-(2- thienyDpropanamine. This compound is usually administered as the hydrochloride salt. The preparation of this compound is described in United States Patent 4,956,388, the entire contents of which is herein incorporated by reference. The term "duloxetine" as employed herein refers to any acid addition salt or the free base of the molcule.
Venlafaxine is known in the literature as a serotonin and norepinephrine reuptake inhibitor. This compound has the structure
and is referred to as l-[(2-dimethylamino)-l-4- methoxyphenyl)ethyl]cyclohexanol. This compound is taught in United States Patent 4,761,501, the entire contents of which is herein incorporated by reference.
Milnacipran {(Z) l-phenyl-l-diethylaminocarbonyl-2- aminomethylcyclopropane hydrochloride} is taught in United States Patent 4,478,836, the entire contents of which are herein incorporated by reference. The structure of milnacipran is as follows.
Milnacipran is known to increase the availability of serotonin, norepinephrine, and dopamine.
Another serotonin reuptake inhibitor which may be employed in the methods of the present invention is citalopram, a compound having the structure
and the chemical name l-[3-(dimethylamino)propyl]-l-4-fluorophenyl)- l,3-dihydro-5-isobenzofurancarbonitrile. This compound may be prepared as described in United States Patent 4,136,193, the entire contents of which are herein incorporated by reference.
Another serotonin reuptake inhibitor which may be employed in the methods of the present invention is fiuvoxamine, a compound having the structure
and the chemical name 5-methoxy-l-[4-(trifluoromethyl)phenyl]-l- pentanone 0-(2-aminoethyl)oxime. This compound may be prepared as described in United States Patent 4,085,225, the entire contents of which are herein incorporated by reference.
Another compound belonging to this class of therapeutics is indalpine, a compound having the structure
and the chemical name 3-[2-(4-piperidinyl)ethyl]-lH-indole. This compound may be prepared as described in United States Patent 4,064,255, the entire contents of which are herein incorporated by reference.
Sertraline is another serotonin reuptake inhibitor which may be employed in the methods of the present invention. This compound, having the chemical name (lS-cis)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine, has the following structure.
Sertraline may be prepared as described in United States Patent 4,536,518, the entire contents of which are herein incorporated by reference.
An additional such inhibitor which may be employed in the methods of the present invention is zimeldine, a compound of the structure
having the chemical name (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3- pyridinyl)-2-propen-l-amine. This compound may be prepared as described in United States Patent 3,928,369, the entire contents of which are herein incorporated by reference.
Another such compound is imipramine, a compound having the structure
and the chemical name 10,ll-dihydro-N,N-dimethyl-5- dibenz[b,f]azepine-5-propanamine. This compound is prepared as described in United States Patent 2,554,736, the entire contents of which is herein incorporated by reference.
The selective serotonin reuptake inhibitors (SSRI's) are a series of compounds which act as serotonin reuptake inhibitors but act in a selective manner. Selective serotonin reuptake inhibitors are especially preferred in the methods of the present invention.
One such compound is fluoxetine, a compound having the structure
and the chemical name N-methyl-3-(4-trifluoromethylphenoxy)-3- phenylpropylamine. This compound is prepared as described in United States Patent 4,314,081 which is herein incorporated by reference. Throughout this document the term "fluoxetine" refers to any acid addition salt or the free base, and includes either the racemic mixture or either of the enantiomers.
Another compound belonging to this class of therapeutics is femoxetine, a compound having the structure
and the chemical name (3R- trans )-3-[(4-methoxyphenoxy)methyl]- 1- methyl-4-phenylpiperidine. This compound may be prepared as described in United States Patent 3,912,743, the entire contents of which are herein incorporated by reference.
Another such compound is paroxetine, a compound having the structure
and the chemical name trans-(-)-3-[(l,3-benzodioxol-5-yloxy)methyl]-4-(4- fluorophenyDpiperidine. This compound is prepared as described in United States Patents 3,912,743 and 4,007, 196, the entire contents of which are herein incorporated by reference.
The above groups of compounds are only illustrative of the serotonin reuptake inhibitors which are currently under development or are frequently employed in serotonin receptor studies. This listing of groups of compounds is not meant to be comprehensive, the methods of the present invention may employ any serotonin reuptake inhibitor and is not limited to any particular class of compound.
The biological activities of the compounds of the present invention are evaluated employing an initial screening assay which rapidly and accurately measures the inhibition of β-amyloid peptide in a whole cell assay.
β-Amvloid Peptide Production Inhibition (Cellular Assay)
Two cell lines (human kidney cell line 293 and Chinese hamster ovary cell Une CHO) are stably transfected with the gene for APP751 containing the double mutation Lys65i-Metβ52 to Asnβ5i-Leu652 (APP-751 numbering) commonly called the Swedish mutation using the method described in Citron, et al.. Nature 360:672-674 (1992). The transfected cell lines are designated as 293 751 SWE and CHO 751 SWE, and are plated in Corning 96 well plates at 2.5xl04 or lxlO4 cells per well respectively in Dulbecco's minimal essential media (DMEM) plus 10% fetal bovine serum. Following overnight incubation at 37°C in an incubator equilibrated with 10% carbon dioxide (CO2), the media are removed and replaced with 200 μl per well of media. After a two hour pretreatment period, the media are again removed and replaced with fresh media containing the test compound and the cells are incubated for an additional two hours.
After treatment, plates are centrifuged at 1200 rpm for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 μl of conditioned media are transferred into an ELISA plate precoated with antibody 266 against β- amyloid peptide( 13-28) and stored at 4°C overnight. An ELISA assay employing labelled antibody 6C6 (against β-amyloid peptide-1-16) is run the next day to measure the amount of β-amyloid peptide produced. Cytotoxic effects of the compounds are measured by a modification of the method of Hansen, et al.. Journal of Immunological Methods. 119:203-210 (1989). To the cells remaining in the tissue culture plate, is added 25 μl of a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) stock solution (5 mg/ml) to a final concentration of 1 mg/ml. Cells are incubated at 37°C for one hour, and cellular activity is stopped by the addition of an equal volume of MTT
lysis buffer (20% w/v sodium dodecylsulfate in 50% DMF, pH 4.7).
Complete extraction is achieved by overnight shaking at room temperature. The difference in the OD562nm and the OD650nm is measured in a UVmaχ micropiate reader as an indicator of the cellular viability.
The results ofthe β-amyloid peptide ELISA are fit to a standard curve and expressed as ng/ml β-amyloid peptide. In order to normalize for cytotoxicity, these β-amyloid peptide results are divided by the MTT results and expressed as a percentage of the results from a drug-free control.
In addition to the above assay, a similar assay employing IMR32 cells possessing endogenous wild-type APP is employed in a similar manner.
In repeated experiments using the above assays, serotonin reuptake inhibitors have shown significant inhibition of β-amyloid peptide production without demonstrating increased cytotoxicity. Especially preferred are the selective serotonin reuptake inhibitors.
In another assay to better study the effects of the above- described compounds on whole animals some of the above compounds are administered in vivo to guinea pigs by an intraperitoneal route at 1 mg/kg/day. The individual compound being tested is administered in four 0.25 mg/kg doses separated by one hour. One hour after the last of the four injectons, the amount of β-amyloid peptide in the cerebrospinal fluid is measured and compared to control animals in which no such compound is administered.
While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds
employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compounds are generally effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
Formvilation Preparation I
Hard gelatin capsules containing the following ingredients are prepared:
Quantity Ingredient (mg/capsule)
Active Ingredient(s) 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Formulation Preparation 2
A tablet formula is prepared using the ingredients below:
Quantity Ingredient (mg/tablet)
Active Ingredient(s) 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3
A dry powder inhaler formulation is prepared containing the following components:
Ingredient Weight %
Active Ingredient(s) 5
Lactose 95
The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Formulation Preparation 4
Tablets, each containing 30 mg of active ingredient, are prepared as follows:
Quantity Ingredient (mg/tablet)
Active Ingredient(s) 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc O mg
Total 120 mg
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
Formulation Preparation 5
Capsules, each containing 40 mg of medicament are made as follows:
Quantity Ingredient (mg/capsule)
Active Ingredient(s) 40.0 mg
Starch 109.0 mg
Magnesium stearate 1.0 mg
Total 150.0 mg
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6
Suppositories, each containing 25 mg of active ingredient are made as follows:
Ingredient Amount
Active Ingredient(s) 25 mg
Saturated fatty acid glycerides to 2,000 mg
The active ingredient(s) is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Preparation 7
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
Ingredient Amount
Active Ingredient(s) 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Formulation Preparation 8
Capsules, each containing 15 mg of medicament, are made as follows:
Quantity
Ingredient (mg/capsule)
Active Ingredient(s) 15.0 mg
Starch 407.0 mg
Magnesium stearate 3.0 mg
Total 425.0 mg
The active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9
An intravenous formulation may be prepared as follows:
Ingredient Quantity
Active Ingredient(s) 250.0 mg
Isotonic saline 1000 ml
Formulation Preparation 10
A topical formulation may be prepared as follows:
Ingredient Ouantitv
Active Ingredient(s) 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Formulation Preparation 11
Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:
Quantity Ingredient Per Tablet
Active Ingredient(s) 10.0 mg
Glycerol 210.5 mg
Water 143.0 mg
Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg
Polyvinylpyrrolidone 15.5 mg
Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 °C. When the polymers have gone into solution, the solution is cooled to about 50-55°C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by
reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
The type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.
Claims
1. A method of treating a physiological disorder associated with β-amyloid peptide which comprises administering to a mammal in need thereof an effective amount of a composition having activity as a serotinin reuptake inhibitor.
2. A method as claimed in Claim 1 wherein said serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor.
3. A method as claimed in Claim 2 wherein said selective serotonin reuptake inhibitor is fluoxetine.
4. A serotonin reuptake inhibitor as employed in any one of Claims 1 to 3, for use in treating a physiological disorder associated with β-amyloid peptide.
5. The use of a serotonin reuptake inhibitor as employed in any one of Claims 1 to 3, for the manufacture of a medicament for the treatment of a physiological disorder associated with β-amyloid peptide.
6. A pharmaceutical formulation adapted for the treatment of physiological disorder associated with β-amyloid peptide, comprising a serotonin reuptake inhibitor as employed in any one of Claims 1 to 3.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU71139/96A AU7113996A (en) | 1995-09-22 | 1996-09-19 | Methods of treating beta-amyloid-associated conditions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US417895P | 1995-09-22 | 1995-09-22 | |
US60/004,178 | 1995-09-22 |
Publications (1)
Publication Number | Publication Date |
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WO1997010816A1 true WO1997010816A1 (en) | 1997-03-27 |
Family
ID=21709551
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/015046 WO1997010816A1 (en) | 1995-09-22 | 1996-09-19 | METHODS OF TREATING β-AMYLOID-ASSOCIATED CONDITIONS |
Country Status (2)
Country | Link |
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AU (1) | AU7113996A (en) |
WO (1) | WO1997010816A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998002169A2 (en) * | 1996-07-15 | 1998-01-22 | Alza Corporation | Novel formulations for the administration of fluoxetine |
WO2000024392A1 (en) * | 1998-10-26 | 2000-05-04 | Sumitomo Pharmaceuticals Company, Limited | β-AMYLOID FORMATION INHIBITORS |
US6203817B1 (en) | 1997-02-19 | 2001-03-20 | Alza Corporation | Reduction of skin reactions caused by transdermal drug delivery |
WO2002038142A2 (en) * | 2000-11-08 | 2002-05-16 | Massachusetts Institute Of Technology | Serotonergic compositions and methods for treatment of mild cognitive impairment |
US6512010B1 (en) | 1996-07-15 | 2003-01-28 | Alza Corporation | Formulations for the administration of fluoxetine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5372813A (en) * | 1992-12-22 | 1994-12-13 | The Regents, University Of California | Substituted 6-nitroquipazines, methods of preparation, and methods of use |
-
1996
- 1996-09-19 AU AU71139/96A patent/AU7113996A/en not_active Abandoned
- 1996-09-19 WO PCT/US1996/015046 patent/WO1997010816A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5372813A (en) * | 1992-12-22 | 1994-12-13 | The Regents, University Of California | Substituted 6-nitroquipazines, methods of preparation, and methods of use |
Non-Patent Citations (3)
Title |
---|
BRITISH JOURNAL OF CLINICAL PRACTICE, November/December 1994, Vol. 48, No. 6, GOTTFRIES, C.G., "Therapy Options in Alzheimer's Disease", pages 327-330. * |
JOURNAL OF CLIN. PSYCHIATRY, April 1994, Vol. 55, No. 4, GELDMACHER, D.S. et al., "Fluoxetine in Dementia of the Alzheimer's Type: Prominent Adverse Effects and Failure to Improve Cognition", page 161. * |
JOURNAL OF NEURAL TRANSMISSION, 1995, Vol. 9, TOHGI, H. et al., "Indoleamine Concentrations in Cerebrospinal Fluid from Patients with Alzheimer Type and Binswanger Type Dementias Before and After Administration of Citalopram, a Synthetic Serotonin Uptake Inhibitor", pages 121-131. * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998002169A2 (en) * | 1996-07-15 | 1998-01-22 | Alza Corporation | Novel formulations for the administration of fluoxetine |
WO1998002169A3 (en) * | 1996-07-15 | 1998-03-12 | Alza Corp | Novel formulations for the administration of fluoxetine |
US6512010B1 (en) | 1996-07-15 | 2003-01-28 | Alza Corporation | Formulations for the administration of fluoxetine |
US7011844B2 (en) | 1996-07-15 | 2006-03-14 | Alza Corporation | Formulations for the administration of fluoxetine |
US6203817B1 (en) | 1997-02-19 | 2001-03-20 | Alza Corporation | Reduction of skin reactions caused by transdermal drug delivery |
WO2000024392A1 (en) * | 1998-10-26 | 2000-05-04 | Sumitomo Pharmaceuticals Company, Limited | β-AMYLOID FORMATION INHIBITORS |
WO2002038142A2 (en) * | 2000-11-08 | 2002-05-16 | Massachusetts Institute Of Technology | Serotonergic compositions and methods for treatment of mild cognitive impairment |
WO2002038142A3 (en) * | 2000-11-08 | 2003-08-14 | Massachusetts Inst Technology | Serotonergic compositions and methods for treatment of mild cognitive impairment |
Also Published As
Publication number | Publication date |
---|---|
AU7113996A (en) | 1997-04-09 |
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