WO2000066105A2 - Treatment of epilepsy with imino sugars - Google Patents
Treatment of epilepsy with imino sugars Download PDFInfo
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- WO2000066105A2 WO2000066105A2 PCT/US2000/011584 US0011584W WO0066105A2 WO 2000066105 A2 WO2000066105 A2 WO 2000066105A2 US 0011584 W US0011584 W US 0011584W WO 0066105 A2 WO0066105 A2 WO 0066105A2
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the invention relates to methods for the treatment of epilepsy.
- it relates to the formulation and administration of a pharmaceutical compound which is an imino sugar or derivative thereof.
- Epilepsy can be defined generally as intermittent neuronal dysfunction resulting from sudden, disorderly discharges of CNS neurons. With the exception of cerebrovascular disease and migraine, epilepsy is the most prevalent human neurological disorder and afflicts about 2-3 million people in the U.S. population and about 15-20% of all epileptics are refractory to most medications.
- Seizures are a symptom of epilepsy and can be either convulsive (with overt motor manifestations) or non-convulsive (without motor involvement).
- Epileptic seizures are often described as generalized, involving the cortices of both hemispheres, or as partial, involving a specific cortical region. Partial seizures can be further categorized as simple (without loss of consciousness), or complex (consciousness impaired).
- Generalized or partial seizures that occur without signs of organic brain disorder are often described as idiopathic epilepsy; whereas similar seizure types that occur from definable brain injury, disease, or neurostructural abnormality are often described as symptomatic or acquired epilepsy (1-3).
- the invention provides a method of treating epilepsy by the administration of imino sugars and derivatives thereof in amounts which inhibit or reduce the frequency of epileptic seizures in individuals afflicted with epilepsy.
- X is an unsaturated straight chain aliphatic hydrocarbon, and O or S may optionally substituted for carbon at any position on (CH 2 ) n X; a saturated or unsaturated branched aliphatic hydrocarbon, an aromatic hydrocarbon or substituted derivative thereof, a cyclic hydrocarbon or substituted derivative thereof, -O-Y, -S-Y, -Y-OH, -Y-NH 2 , -Y-COOH, -Y-CON-Y or -Y-COO-R; wherein Y is a saturated or unsaturated straight-chain or branched aliphatic hydrocarbon, an aromatic hydrocarbon or derivative thereof, and R is hydrogen, or a saturated or unsaturated hydrocarbon that is a straight chain aliphatic hydrocarbon, branched aliphatic hydrocarbon, aromatic hydrocarbon or a substituted derivative thereof, a cyclic hydrocarbon or substituted derivative thereof, and n is an integer less than or equal to 16.
- the term "derivative" is intended to mean the addition of short chain alkyl and alkoxy groups with 1-6 carbon atoms and hydroxyl groups as substituents on -(CH 2 )nX.
- Preferred compounds are N-alkyl derivatives between 5 and 16 carbons, more preferably between 9 and 16 carbons.
- a particularly preferred compound is N-nonyl DNJ.
- Amino and imino compounds used as starting materials in the preparation of long chain N-alkylated compounds are commercially available (Sigma, St. Louis, Missouri, US; Cambridge Research Biochemicals, Norwich, Cheshire, UK; Toronto Research Chemicals, Ontario, CA) or can be prepared by known synthetic methods.
- Long chain N-alkylated compounds can be prepared by reductive alkylation of amino or imino compounds.
- the amino or imino compound can be exposed to long chain aldehyde and reducing agent (e.g., sodium cyanoborohydride) to N-alkylate the amine.
- the compound can be a long chain N-alkylated imino sugar.
- the imino sugar can be, for example, deoxynorjirimycin (DNJ) or derivatives, enantiomers, or stereoisomers thereof.
- the compound can be prepared stereospecifically using a stereospecific amino or imino compound as a starting material.
- the compound can be purified out of a mixture of products after synthesis.
- the compounds can be purified, for example, by crystallization or chromatographic methods.
- the compounds can be combined with pharmaceutically acceptable carriers and the like for administration.
- N-nonyl deoxymojirimycin (NN- DNJ) is administered to individuals in need of treatment in effective dosages to prevent epileptic seizures.
- Suitable dosages can be determined easily in accordance with the present invention. In general, such dosages are expected to be between about 50 mg/kg/day and 10 gm/kg/day, between about 100 mg/kg/day and 1 gm/kg/day, or between about 250 mg/kg/day and 800 mg/kg/day. Moreover, serum concentrations can be monitored to achieve a steady-state trough level effective to reduce the number and/or severity of epileptic symptoms.
- compositions that are useful in the present invention may be administered as an oral, ophthalmic, suppository, aerosol, topical, or other formulation, with the preferred route of administration being oral.
- the compositions may be in the physical form of a solid, powder, tablet or lozenge, capsule, liquid or solution, gel, emulsion, suspension, syrup, or the like.
- such compositions may contain pharmaceutically-acceptable carriers and other ingredients known to facilitate administration and/or enhance uptake (e.g., saline, dimethyl sulfoxide).
- the compositions may be administered according to the present invention in a single dose or in multiple doses which are administered several times per day, or on a daily, weekly, or irregular basis.
- N-nonyl deoxymojirimycin (NN-DNJ)
- Drug treatment was initiated after week 0, where all mice experienced generalized seizures. The drug was administered in the food and the mice were tested for seizure susceptibility once per week as described in the text. Drug treatment was suspended after week three of treatment. The difference in number of seizure free mice between the treated and control groups was significant at P ⁇ 0.01** and P ⁇ 0.05* as determined by the Fisher exact test.
- the EL (epilepsy) mouse has been one of the most extensively studied mouse models of idiopathic epilepsy (6).
- the trigger for seizure induction in EL mice is emotional stress or fear which is also thought to initiate many human idiopathic epilepsies.
- the seizures in El mice originate in or near the parietal lobe and then spread quickly to the hippocampus and to other brain regions (7-9).
- the seizures are also accompanied b EEG abnormalities (synchronized spike wave complexes at 3-4 spikes/sec, vocalization (squeaking), incontinence, loss of postural equilibrium, excessive salivation, and head, limb, and chewing automatisms (10-14).
- mice from Dr. Jiro Suzuki were housed in plastic cages with Sanichip bedding that was changed once per week. The mice were kept on a 12 hour light/dark cycle with food (Agway Prolab Rat, Mouse, Hamster 3000) and water provided ad libitum. All mice were maintained in the Boston College Animal Care Facility and the procedures for their use were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee. Drug Treatment
- mice females betwee 10-12 months of age were divided into two groups (control and treated) and were housed three per cage.
- the mice in the treated groups received NN-DNJ administered as a powder in ground mouse chow (Prolab, Agway), as described by Platt et al. (18, 19).
- the NN- DNJ and mouse chow diet was mixed thoroughly, stored in an air-tight container at room temperature, and was used with a week.
- the treated mice received 500 mg NN-DNJ per kg body weight per day.
- the control mice received ground mouse chow alone.
- the diets were provided ad libitum and were administered in glass scintillation vials that were fixed to the cage bottom. Water was also provided ad libitum. Seizure Test
- the seizure test was performed as described by Todorova et al. (20) and involved two handling trials (A and B) that were separated by 30 min. In each trial, a mouse was held by the tail for 30 sec about 10-15 cm above the bedding of its home cage. The test was repeated once per week. Mice were undisturbed (no cage changing) for one week prior to testing and all testing was performed between 1 and 6 PM. Seizure Phenotype
- mice were characterized as seizure susceptible if they experienced a generalized seizure. This involved loss of postural equilibrium and consciousness together with excessive salivation, head, limb and chewing/swallowing automatisms. An erect forward-arching Straub tail was also observed in most mice having generalized seizure. Mice that expressed vocalization or twitching, which did not progress to generalized seizure, were not considered seizure susceptible.
- the Fisher exact test was used to evaluate the significance of NN-DNJ treatment on seizure susceptibility.
- mice were highly seizure susceptible prior to drug treatment (week 0). But 33% (2/6) of the NN-DNJ-treated mice were seizure free after one week, while 100% of the mice (6/6) were seizure free after two weeks of NN-DNJ treatment. The mice remained seizure free for an additional week (week 3) after which the drug treatment was terminated. Remarkably, the treated mice remained mostly seizure free for two weeks following suspension of treatment (weeks 4 and 5).
- the EL mice tolerated the drug well and maintained body weight and temperature similar to that observed in the untreated controls. Furthermore, no behavioral abnormalities (ataxia, lethargy, somnolence, tremor, or nervousness) were seen in the treated mice. In contrast to the NN-DNJ- treated mice, the untreated control mice were highly seizure susceptible aver all weeks. Occasionally, EL mice will not seize on a given test as was seen for two of the control mice at week 3 (Fig. 1). Nevertheless, the difference in seizure frequency between the control and drug-treated mice at week three was significant.
Abstract
Imino sugars, in particular N-nonyl deoxymojirimycin (N-nonyl DNJ), and derivatives thereof are used for the treatment of epilepsy.
Description
TREATMENT OF EPILEPSY WITH IMINO SUGARS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to methods for the treatment of epilepsy. In particular, it relates to the formulation and administration of a pharmaceutical compound which is an imino sugar or derivative thereof.
2. Background Information
Epilepsy can be defined generally as intermittent neuronal dysfunction resulting from sudden, disorderly discharges of CNS neurons. With the exception of cerebrovascular disease and migraine, epilepsy is the most prevalent human neurological disorder and afflicts about 2-3 million people in the U.S. population and about 15-20% of all epileptics are refractory to most medications.
Seizures are a symptom of epilepsy and can be either convulsive (with overt motor manifestations) or non-convulsive (without motor involvement). Epileptic seizures are often described as generalized, involving the cortices of both hemispheres, or as partial, involving a specific cortical region. Partial seizures can be further categorized as simple (without loss of consciousness), or complex (consciousness impaired). Generalized or partial seizures that occur without signs of organic brain disorder are often described as idiopathic epilepsy; whereas similar seizure types that occur from definable brain injury, disease, or neurostructural abnormality are often described as symptomatic or acquired epilepsy (1-3). Although inheritance is implicated in most idiopathic epilepsies, little is known about the genetic or biochemical mechanisms involved.
DESCRIPTION OF THE INVENTION It is an object of the invention to provide methods and compositions for the treatment of epilepsy. In particular, the invention provides a method of
treating epilepsy by the administration of imino sugars and derivatives thereof in amounts which inhibit or reduce the frequency of epileptic seizures in individuals afflicted with epilepsy.
The scope of the invention includes the use of imino sugars of the formula
wherein X is an unsaturated straight chain aliphatic hydrocarbon, and O or S may optionally substituted for carbon at any position on (CH2)nX; a saturated or unsaturated branched aliphatic hydrocarbon, an aromatic hydrocarbon or substituted derivative thereof, a cyclic hydrocarbon or substituted derivative thereof, -O-Y, -S-Y, -Y-OH, -Y-NH2, -Y-COOH, -Y-CON-Y or -Y-COO-R; wherein Y is a saturated or unsaturated straight-chain or branched aliphatic hydrocarbon, an aromatic hydrocarbon or derivative thereof, and R is hydrogen, or a saturated or unsaturated hydrocarbon that is a straight chain aliphatic hydrocarbon, branched aliphatic hydrocarbon, aromatic hydrocarbon or a substituted derivative thereof, a cyclic hydrocarbon or substituted derivative thereof, and n is an integer less than or equal to 16.
As used herein, the term "derivative" is intended to mean the addition of short chain alkyl and alkoxy groups with 1-6 carbon atoms and hydroxyl groups as substituents on -(CH2)nX. Preferred compounds are N-alkyl derivatives between 5 and 16 carbons, more preferably between 9 and 16 carbons. A particularly preferred compound is N-nonyl DNJ.
The synthesis of a variety of imino sugars is known in the art. Methods of synthesizing DNJ derivatives are known and are described, for example, in U.S. Patent Nos. 5,622,972, 5,200.523, 5,043,273, 4,994,572, 4,246,345, 4,266,025, 4,405,714, and 4,806,650. Methods of synthesizing other imino sugar derivatives are known and are described, for example, in U.S. Patent
Nos. 4,861 ,892, 4,894,388, 4,910,310, 4,996,329, 5,011 ,929, 5,013,842, 5,017,704, 5,580,884, 5,286,877, and 5,100,797.
Amino and imino compounds used as starting materials in the preparation of long chain N-alkylated compounds are commercially available (Sigma, St. Louis, Missouri, US; Cambridge Research Biochemicals, Norwich, Cheshire, UK; Toronto Research Chemicals, Ontario, CA) or can be prepared by known synthetic methods. Long chain N-alkylated compounds can be prepared by reductive alkylation of amino or imino compounds. For example, the amino or imino compound can be exposed to long chain aldehyde and reducing agent (e.g., sodium cyanoborohydride) to N-alkylate the amine. In particular, the compound can be a long chain N-alkylated imino sugar. The imino sugar can be, for example, deoxynorjirimycin (DNJ) or derivatives, enantiomers, or stereoisomers thereof. The compound can be prepared stereospecifically using a stereospecific amino or imino compound as a starting material. Alternatively, the compound can be purified out of a mixture of products after synthesis. The compounds can be purified, for example, by crystallization or chromatographic methods. The compounds can be combined with pharmaceutically acceptable carriers and the like for administration.
In a particularly preferred embodiment, N-nonyl deoxymojirimycin (NN- DNJ) is administered to individuals in need of treatment in effective dosages to prevent epileptic seizures.
Suitable dosages can be determined easily in accordance with the present invention. In general, such dosages are expected to be between about 50 mg/kg/day and 10 gm/kg/day, between about 100 mg/kg/day and 1 gm/kg/day, or between about 250 mg/kg/day and 800 mg/kg/day. Moreover, serum concentrations can be monitored to achieve a steady-state trough level effective to reduce the number and/or severity of epileptic symptoms.
Pharmaceutical compositions that are useful in the present invention may be administered as an oral, ophthalmic, suppository, aerosol, topical, or other formulation, with the preferred route of administration being oral. The compositions may be in the physical form of a solid, powder, tablet or lozenge, capsule, liquid or solution, gel, emulsion, suspension, syrup, or the like. In addition to the compound, such compositions may contain
pharmaceutically-acceptable carriers and other ingredients known to facilitate administration and/or enhance uptake (e.g., saline, dimethyl sulfoxide). The compositions may be administered according to the present invention in a single dose or in multiple doses which are administered several times per day, or on a daily, weekly, or irregular basis.
BRIEF DESCRIPTION OF THE DRAWING Figure 1. Influence of N-nonyl deoxymojirimycin (NN-DNJ) on seizure susceptibility in epileptic EL mice. Drug treatment was initiated after week 0, where all mice experienced generalized seizures. The drug was administered in the food and the mice were tested for seizure susceptibility once per week as described in the text. Drug treatment was suspended after week three of treatment. The difference in number of seizure free mice between the treated and control groups was significant at P<0.01** and P<0.05* as determined by the Fisher exact test.
The EL Mouse as an Experimental Epilepsy Model
Since human and murine nervous systems respond similarly to seizure provoking stimuli (4), and can display common neurostructural abnormalities (5), it is thought that mechanisms of naturally occurring spontaneous epilepsies are similar in these two species.
The EL (epilepsy) mouse has been one of the most extensively studied mouse models of idiopathic epilepsy (6). The trigger for seizure induction in EL mice is emotional stress or fear which is also thought to initiate many human idiopathic epilepsies. The seizures in El mice originate in or near the parietal lobe and then spread quickly to the hippocampus and to other brain regions (7-9). The seizures are also accompanied b EEG abnormalities (synchronized spike wave complexes at 3-4 spikes/sec, vocalization (squeaking), incontinence, loss of postural equilibrium, excessive salivation, and head, limb, and chewing automatisms (10-14). The appearance of an erect forward-arching Straub tail in the seizing mice is indicative of spinal cord activation (15). Phenytoin and phenobarbital, the anticonvulsant drugs of choice for treatment of human partial epilepsies, inhibit seizures in EL mice (14, 16, 17). Based on these observations, the EL mouse is considered a
genetic model for human complex partial seizures with secondary generalization (10).
Inbred EIJSuz (EL) mice from Dr. Jiro Suzuki were housed in plastic cages with Sanichip bedding that was changed once per week. The mice were kept on a 12 hour light/dark cycle with food (Agway Prolab Rat, Mouse, Hamster 3000) and water provided ad libitum. All mice were maintained in the Boston College Animal Care Facility and the procedures for their use were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee. Drug Treatment
EL mice (females betwee 10-12 months of age) were divided into two groups (control and treated) and were housed three per cage. The mice in the treated groups received NN-DNJ administered as a powder in ground mouse chow (Prolab, Agway), as described by Platt et al. (18, 19). The NN- DNJ and mouse chow diet was mixed thoroughly, stored in an air-tight container at room temperature, and was used with a week. The treated mice received 500 mg NN-DNJ per kg body weight per day. The control mice received ground mouse chow alone. The diets were provided ad libitum and were administered in glass scintillation vials that were fixed to the cage bottom. Water was also provided ad libitum. Seizure Test
The seizure test was performed as described by Todorova et al. (20) and involved two handling trials (A and B) that were separated by 30 min. In each trial, a mouse was held by the tail for 30 sec about 10-15 cm above the bedding of its home cage. The test was repeated once per week. Mice were undisturbed (no cage changing) for one week prior to testing and all testing was performed between 1 and 6 PM. Seizure Phenotype
Mice were characterized as seizure susceptible if they experienced a generalized seizure. This involved loss of postural equilibrium and consciousness together with excessive salivation, head, limb and chewing/swallowing automatisms. An erect forward-arching Straub tail was also observed in most mice having generalized seizure. Mice that expressed
vocalization or twitching, which did not progress to generalized seizure, were not considered seizure susceptible. Statistical Analysis
The Fisher exact test was used to evaluate the significance of NN-DNJ treatment on seizure susceptibility.
The results (shown in Figure 1) showed that the imino sugar NN-DNJ significantly inhibited seizure susceptibility in the EL mice. All mice were highly seizure susceptible prior to drug treatment (week 0). But 33% (2/6) of the NN-DNJ-treated mice were seizure free after one week, while 100% of the mice (6/6) were seizure free after two weeks of NN-DNJ treatment. The mice remained seizure free for an additional week (week 3) after which the drug treatment was terminated. Remarkably, the treated mice remained mostly seizure free for two weeks following suspension of treatment (weeks 4 and 5).
The EL mice tolerated the drug well and maintained body weight and temperature similar to that observed in the untreated controls. Furthermore, no behavioral abnormalities (ataxia, lethargy, somnolence, tremor, or nervousness) were seen in the treated mice. In contrast to the NN-DNJ- treated mice, the untreated control mice were highly seizure susceptible aver all weeks. Occasionally, EL mice will not seize on a given test as was seen for two of the control mice at week 3 (Fig. 1). Nevertheless, the difference in seizure frequency between the control and drug-treated mice at week three was significant.
The results demonstrate that the administration of imino sugars should be effective in the treatment of epilepsy and the inhibition of epileptic seizures. In general, the effectiveness of an antiepileptic drug encompasses both efficacy and tolerability (21). Efficacy involves the reduction in seizure frequency and/or severity, whereas tolerability involves the incidence and magnitude of adverse side effects. The most common reasons for patient noncompliance with antiepileptic drug therapy include too frequent dosing and the onset of adverse side effects related to drug concentration (22). The results of the study described hereinabove show that NN-DNJ has a high efficacy against seizures in EL mice after two weeks of treatment and that the efficacy persisted for two weeks following termination of treatment. Moreover, the drug was well tolerated since the treated mice showed no obvious
behavioral abnormalities or weight loss. These results indicate that NN-DNJ and other imino sugars and derivatives thereof should be effective drugs for the treatment of human epilepsy.
References cited herein are listed below for convenience and are hereby incorporated by reference, along with provisional U.S. Appln. No. 60/132,125.
REFERENCES
1. Wolf (1994) Historical aspects: The concept of idiopathy. In: Malafosse et al. (eds). Idiopathic generalized epilepsies: clinical, experimental, and genetic aspects. London: John Libbey, 3-6.
2. Delgado Escueta et al. (1986) Looking for epilepsy genes: Clinical and molecular genetic studies. Adv. Neurol. 44:77-95.
3. Hauser (1982) Genetics and clinical characteristics of seizures. In: Anderson et al. (eds.) Genetic Basis of the Epilepsies. New York: Raven Press, 3-9.
4. Krall et al. (1978) Antiepileptic drug development: I. History and a program for progress. Epilepsia 19:393-408.
5. Ribak (1991) Epilepsy and the cortex. In: Peters (ed.) Cerebral Cortex. New York: Plenum, 427-483.
6. Seyfried et al. (1999) Genetics of the EL mouse: A multifactorial epilepsy model. In: Genton et al. (eds.) Genetics of Focal Epilepsies, London: J. Libby, 229-238.
7. Kasamo et al. (1992) The depth EEG and the multiunit activity in the hippocampal CA1 region during the epileptic seizure of an EL mouse: Involvement of the hippocampal neurons in seizure manifestations. Neurosciences 18 (Suppl. 2):129-136.
8. Suzuki et al. (1991) Initiation, propagation and generalization of paroxysmal discharges in an epileptic mutant animal. Jpn. J. Psychiatry Neurol. 45:271-274.
9. Ishida et al. (1993) Epileptic seizure of EL mouse initiates at the parietal cortex: Depth EEG observation in freely moving condition using buffer amplifier. Brain Res. 608:52-57.
10. Seyfried et al. (1992) Genetic and biochemical correlates of epilepsy in the EL mouse. Neurosciences 18 (Suppl. 2):9-20.
11. Kurokawa et al. (1966) Metabolic studies on ep mouse, a special strain with convulsive predisposition. Prog. Brain Res. 21 :112-129.
12. Naruse and Kurokawa (1992) The beginnings of studies on EL mice. Neurosciences 18 (Suppl. 2): 1-3.
13. Suzuki (1976) Paroxysmal discharges in the electroencephalogram of the EL mouse. Experientia 32:336-338.
14. Suzuki and Nakamoto (1977) Seizure patterns and electroencephalograms of EL mouse. Electroencephalogr. Clin. Neurophysiol. 43:229- 311.
15. Hasegawa et al. (1990) Dopamine D2 receptors and spinal cord excitation in mice. Eur. J. Pharmacol. 184:207-212.
16. Matsumoto et al. (1983) Effects of phenytoin on convulsions and brain 5-hydroxytryptamine levels of EL mice. IRCS Med. Sci. 11 :837.
17. Nagatomo et al. (1996) Relationships between convulsive seizures ans serum and brain concentrations of phenobarbital and zonisamide in mutant inbred strain EL. Brain Res. 731 :190-198.
18. Platt et al. (1997) Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276:428-431.
19. Platt et al. (1997) Extensive glyosphingolipid depletion in the liver and lymphoid organs of mice treated with N-butyldeoxynojirimycin. J. Biol. Chem. 272:19365-19372.
20. Todorova et al. (1997) New procedure for seizure induction in epileptic EL mice. Epilepsia. 38:37.
21. Chadwick (1997) Monotherapy clinical trials of new antiepileptic drugs: Design, indications, and controversies. Epilepsia 38:S16-S20.
22. Cramer and Mattson (1997) Monitoring compliance with antiepileptic drug therapy. In: Cramer and Spilker (eds.) Patient Compliance in Medical Practice and Clinical Trials. New York: Raven Press, 123-138.
Claims
1. Use of a pharmaceutical composition comprising an imino sugar, imino sugar derivative, or salt thereof to treat epilepsy in an individual in need of such treatment.
2. Use according to claim 1 wherein said imino sugar is represented by the formula
wherein X is an unsaturated straight chain aliphatic hydrocarbon, wherein O or S may be optionally substituted for carbon at any position on (CH2)nX; a saturated or unsaturated branched aliphatic hydrocarbon; an aromatic hydrocarbon or substituted derivative thereof; a cyclic hydrocarbon or substituted derivative thereof; or is represented by -O-Y, -S-Y, -Y-OH, -Y-NH2, -Y-COOH, -Y-CON-Y or -Y-COO-R; wherein Y is a saturated or unsaturated straight-chain or branched aliphatic hydrocarbon, an aromatic hydrocarbon or derivative thereof, and R is hydrogen, or a saturated or unsaturated hydrocarbon that is a straight chain aliphatic hydrocarbon, branched aliphatic hydrocarbon, aromatic hydrocarbon or a substituted derivative thereof, a cyclic hydrocarbon or substituted derivative thereof, and n is an integer between 0 and 16.
3. Use according to claim 2 wherein (CH2)nX is a straight-chain or branched alkyl group of 1-16 carbons.
4. Use according to claim 3 wherein (CH2)nX is a straight-chain or branched alkyl group of 5-16 carbons.
5. Use according to claim 2 wherein said imino sugar contains at least one C5-C-16 substituent.
6. Use according to claim 1 wherein said imino sugar is 1- deoxynojirimycin (DNJ) or a derivative thereof.
7. Use according to claim 1 wherein said imino sugar is N-nonyl DNJ (NN-DNJ) or a derivative thereof.
8. Use according to any one of claims 1-7 wherein said individual is a mammal.
9. Use according to claim 8 wherein said mammal is a human.
10. Use according to any one of claims 1-9 wherein said imino sugar is administered such that one or more symptoms of epilepsy are reduced in severity.
11. Use according to any one of claims 1 -9 wherein said imino sugar is administered such that one or more symptoms of epilepsy are reduced in frequency.
12. Use according to any one of claims 1-9 wherein said imino sugar is administered such that one or more symptoms of epilepsy continue to be suppressed after treatment is discontinued.
13. Use according to claim 12 wherein one or more symptoms are suppressed for at least about one week after treatment is discontinued.
14. Use according to any of the preceding claims wherein the compound or composition is administered orally.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13212599P | 1999-04-30 | 1999-04-30 | |
| US60/132,125 | 1999-04-30 |
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| WO2000066105A2 true WO2000066105A2 (en) | 2000-11-09 |
| WO2000066105A3 WO2000066105A3 (en) | 2001-07-19 |
| WO2000066105A9 WO2000066105A9 (en) | 2001-08-09 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103953A1 (en) * | 2008-02-18 | 2009-08-27 | Summit Corporation Plc | Treatment of energy utilization disease |
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| WO1994021230A1 (en) * | 1993-03-19 | 1994-09-29 | Cellegy Pharmaceuticals, Inc. | Method and compositions for disrupting the epithelial barrier function |
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| WO2000062780A1 (en) * | 1999-04-20 | 2000-10-26 | Oxford Glycosciences (Uk) Limited | Use of glucosylceramide synthesis inhibitors in therapy |
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| EP0350012A2 (en) * | 1988-07-08 | 1990-01-10 | Meiji Seika Kaisha Ltd. | Antiviral composition |
| WO1994021230A1 (en) * | 1993-03-19 | 1994-09-29 | Cellegy Pharmaceuticals, Inc. | Method and compositions for disrupting the epithelial barrier function |
| US5798366A (en) * | 1993-05-13 | 1998-08-25 | Monsanto Company | Method for treatment of CNS-involved lysosomal storage diseases |
| WO2000062780A1 (en) * | 1999-04-20 | 2000-10-26 | Oxford Glycosciences (Uk) Limited | Use of glucosylceramide synthesis inhibitors in therapy |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103953A1 (en) * | 2008-02-18 | 2009-08-27 | Summit Corporation Plc | Treatment of energy utilization disease |
| US10842784B2 (en) | 2008-02-18 | 2020-11-24 | Vida Pharma Limited | Treatment of energy utilization disease |
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| WO2000066105A9 (en) | 2001-08-09 |
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