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Title:  Botulinum toxin therapy for neuropsychiatric disorders
United States Patent: 
7,229,626
Issued: 
June 12, 2007

Inventors: 
Donovan; Stephen (Capistrano Beach, CA)
Assignee:
 Allergan, Inc. (Irvine, CA)
Appl. No.: 
10/806,972
Filed: 
March 22, 2004


 

George Washington University's Healthcare MBA


Abstract

Methods for treating psychiatric disorders include intracranial administration of a therapeutically effective amount of a neurotoxin, such as a botulinum toxin type A, to a human patient.

SUMMARY OF THE INVENTION

The present invention meets this need and provides methods for effectively treating neuropsychiatric disorders by intracranial administration of a neurotoxin which has the characteristics of long duration of activity, low rates of diffusion out of an intracranial site where administered and insignificant systemic effects at therapeutic dose levels.

The following definitions apply herein:

"About" means approximately or nearly and in the context of a numerical value or range set forth herein means .+-.10% of the numerical value or range recited or claimed.

"Local administration" means direct administration of a pharmaceutical at or to the vicinity of a site on or within an animal body, at which site a biological effect of the pharmaceutical is desired. Local administration excludes systemic routes of administration, such as intravenous or oral administration.

"Neurotoxin" means a biologically active molecule with a specific affinity for a neuronal cell surface receptor. Neurotoxin includes Clostridial toxins both as pure toxin and as complexed with one to more non-toxin, toxin associated proteins

"Intracranial" means within the cranium or at or near the dorsal end of the spinal cord and includes the medulla, brain stem, pons, cerebellum and cerebrum.

Methods for treating neuropsychiatric disorders comprise the step of intracranially administering a neurotoxin to a patient. The neurotoxin is administered in a therapeutically effective amount to alleviate at least one symptom of the disorder. The neurotoxin alleviates the symptoms associated with the disorder by reducing secretions of neurotransmitter from the neurons exposed to the neurotoxin.

A suitable neurotoxin may be a neurotoxin made by a bacterium, for example, the neurotoxin may be made from a Clostridium botulinum, Clostridium butyricum, or Clostridium beratti. In certain embodiments of the invention, neuropsychiatric disorders are treated by intracranially administering a botulinum toxin to the patient. The botulinum toxin may be a botulinum toxin type A, type B, type C.sub.1, type D, type E, type F, or type G. The botulinum toxin may be administered in an amount of between about 10.sup.-3 U/kg and about 10 U/kg. The effects of the botulinum toxin may persist for between about 1 month and 5 years.

Other neurotoxins include recombinantly produced neurotoxins, such as botulinum toxins produced by E. coli. In addition or alternatively, the neurotoxin can be a modified neurotoxin, that is a neurotoxin which has at least one of its amino acids deleted, modified or replaced, as compared to a native or the modified neurotoxin can be a recombinant produced neurotoxin or a derivative or fragment thereof. The neurotoxins are still able to inhibit neurotransmitter release.

The neurotoxin is administered to a site within the brain that is believed to be involved in the disorder being treated. The neurotoxin may be administered to a lower brain region, the pontine region, the pedunculopontine nucleus, the locus ceruleus, or the ventral tegmental area, for example. The neurotoxin may alleviate the symptom that is associated with hyperactive neurotransmitter release. The neurotoxin may also restore a balance between two neuronal systems to alleviate the disorder. The neurotoxin administered to the patient may inhibit acetylcholine release from cholinergic neurons, may inhibit dopamine release from dopaminergic neurons, may inhibit the release of norepinephrine from noradrenergic neurons.

The neuropsychiatric disorders treated in accordance with the methods disclosed herein include, and are not limited to, schizophrenia, Alzheimer's disease, mania, and anxiety. The neurotoxin can alleviate a positive symptom associated with the neuropsychiatric disorder, for example schizophrenia, and can alleviate the symptoms within a few hours after administration.

I have surprisingly found that a botulinum toxin, such as botulinum toxin type A, can be intracranially administered in amounts between about 10.sup.-4 U/kg and about 10 U/kg to alleviate a neuropsychiatric disorder experienced by a human patient. Preferably, the botulinum toxin used is intracranially administered in an amount of between about 10.sup.-3 U/kg and about 1 U/kg. Most preferably, the botulinum toxin is administered in an amount of between about 0.1 unit and about 5 units. Significantly, the neuropsychiatric disorder alleviating effect of the present disclosed methods can persist for between about 2 months to about 6 months when administration is of aqueous solution of the neurotoxin, and for up to about five years when the neurotoxin is administered as a controlled release implant.

Another preferred method within the scope of the present invention is a method for improving patient function, the method comprising the step of intracranially administering a neurotoxin to a patient, thereby improving patient function as determined by improvement in one or more of the factors of reduced pain, reduced time spent in bed, increased ambulation, healthier attitude and a more varied lifestyle.

DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that intracranial administration of a neurotoxin can provide significant and long lasting relief from a variety of different neuropsychiatric disorders. Intracranial administration permits a neurotoxin to be locally administered at a site, within a patient's cranium, that has a direct effect on the neurons involved in the disorders, and avoids complications associated with passage of the neurotoxin across the blood brain barrier. Thus, intracranial administration provides greater local dosages of a neurotoxin to a brain area than is achieved with systemic routes of administration, and avoids the non-specificity associated with systemic administration of current therapeutic agents. Indeed, systemic administration of a neurotoxin, such as a botulinum toxin, is contraindicated due to the severe complications (i.e. botulism) which can result from entry of a botulinum toxin into the patient's general circulation.

The neurotoxins used in accordance with the invention disclosed herein are neurotoxins that inhibit transmission of chemical or electrical signals between select neuronal groups that are involved in the neuropsychiatric disorders. The neurotoxins preferably are not cytotoxic to the cells that are exposed to the neurotoxin. The neurotoxin may inhibit neurotransmission by reducing or preventing exocytosis of neurotransmitter from the neurons exposed to the neurotoxin. Or, neurotoxins may reduce neurotransmission by inhibiting the generation of action potentials of the neurons exposed to the toxin. The suppressive effects provided by the neurotoxin should persist for a relatively long period of time, for example, for more than two months, and potentially for several years.

Examples of neurotoxins used to treat neuropsychiatric disorders, include, and are not limited to, neurotoxins made from Clostridium bacteria, such as Clostridium botulinum, Clostridium butyricum and Clostridium beratti. In addition, the neurotoxins used in the methods of the invention may be a botulinum toxin selected from a group of botulinum toxin types A, B, C, D, E, F, and G. In one embodiment of the invention, the neurotoxin administered to the patient is botulinum toxin type A. Botulinum toxin type A is desirable due to its high potency in humans, ready availability, and known use for the treatment of skeletal and smooth muscle disorders when locally administered by intramuscular injection. The present invention also includes the use of (a) neurotoxins obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying, and/or reconstitution; and/or (b) modified or recombinant neurotoxins, that is neurotoxins that have had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made. These neurotoxin variants should retain the ability to inhibit neurotransmission between or among neurons, and some of these variants may provide increased durations of inhibitory effects as compared to native neurotoxins, or may provide enhanced binding specificity to the neurons exposed to the neurotoxins. These neurotoxin variants may be selected by screening the variants using conventional assays to identify neurotoxins that have the desired physiological effects of inhibiting neurotransmission.

Botulinum toxins for use according to the present invention can be stored in lyophilized, vacuum dried form in containers under vacuum pressure or as stable liquids. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized material can be reconstituted with saline or water to create a solution or composition containing the botulinum toxin to be administered to the patient.

Although the composition may only contain a single type of neurotoxin, such as botulinum toxin type A, as the active ingredient to suppress neurotransmission, other therapeutic compositions may include two or more types of neurotoxins, which may provide enhanced therapeutic effects of the disorders. For example, a composition administered to a patient may include botulinum toxin type A and botulinum toxin type B. Administering a single composition containing two different neurotoxins may permit the effective concentration of each of the neurotoxins to be lower than if a single neurotoxin is administered to the patient while still achieving the desired therapeutic effects. The composition administered to the patient may also contain other pharmaceutically active ingredients, such as, protein receptor or ion channel modulators, in combination with the neurotoxin or neurotoxins. These modulators may contribute to the reduction in neurotransmission between the various neurons. For example, a composition may contain gamma aminobutyric acid (GABA) type A receptor modulators that enhance the inhibitory effects mediated by the GABA.sub.A receptor. The GABA.sub.A receptor inhibits neuronal activity by effectively shunting current flow across the cell membrane. GABA.sub.A receptor modulators may enhance the inhibitory effects of the GABA.sub.A receptor and reduce electrical or chemical signal transmission from the neurons. Examples of GABA.sub.A receptor modulators include benzodiazepines, such as diazepam, oxaxepam, lorazepam, prazepam, alprazolam, halazeapam, chordiazepoxide, and chlorazepate. Compositions may also contain glutamate receptor modulators that decrease the excitatory effects mediated by glutamate receptors. Examples of glutamate receptor modulators include agents that inhibit current flux through AMPA, NMDA, and/or kainate types of glutamate receptors. The compositions may also include agents that modulate dopamine receptors, such as antipsychotics, norepinephrine receptors, and/or serotonin receptors. The compositions may also include agents that affect ion flux through voltage gated calcium channels, potassium channels, and/or sodium channels. Thus, the compositions used to treat neuropsychiatric disorders may include one or more neurotoxins, such as botulinum toxins, in addition to ion channel receptor modulators that may reduce neurotransmission.

The neurotoxin may be intracranially administered by any suitable method as determined by the attending physician. The methods of administration permit the neurotoxin to be administered locally to a selected target tissue. Methods of administration include injection of a solution or composition containing the neurotoxin, as described above, and include implantation of a controlled release system that controllably releases the neurotoxin to the target tissue. Such controlled release systems reduce the need for repeat injections. Diffusion of biological activity of a botulinum toxin within a tissue appears to be a function of dose and can be graduated. Jankovic J., et al Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusion of botulinum toxin can be controlled to reduce potentially undesirable side effects that may affect the patient's cognitive abilities. For example, the neurotoxin may be administered so that the neurotoxin primarily effects neural systems believed to be involved in the neuropsychiatric disorder, and does not have negatively adverse effects on other neural systems, such as primary sensory systems.

In addition, the neurotoxin may be administered to the patient in conjunction with a solution or composition that locally decreases the pH of the target tissue environment. For example, a solution containing hydrochloric acid may be used to locally and temporarily reduce the pH of the target tissue environment to facilitate translocation of the neurotoxin across cell membranes. The reduction in local pH may be desirable when the composition contains fragments of neurotoxins that may not have a functional targeting moiety (e.g., a portion of the toxin that binds to a neurotoxin receptor), and/or a translocation domain). By way of example, and not by way of limitation, a fragment of a botulinum toxin that comprises the proteolytic domain of the toxin may be administered to the patient in conjunction with an agent that decreases the local pH of the target tissue. Without wishing to be bound by any particular theory, it is believed that the lower pH may facilitate the translocation of the proteolytic domain across the cell membrane so that the neurotoxin fragment can exert its toxic effects within the cell. The pH of the target tissue is only temporarily lowered so that neuronal and/or glial injury is reduced.

Similarly, the neurotoxin may be administered intracranially, and a composition containing other pharmaceutical agents, such as antipsychotics, that can cross the blood brain barrier may be administered systemically, such as by intravenous administration, to achieve the desired therapeutic effects.

The neurotoxin may also be administered intracranially using intracranial implants. Intracranial implants have been used for various conditions. For example, stereotactically implanted, temporary, iodine-125 interstitial catheters can be used to treat malignant gliomas. Scharfen, C.O., et al., High Activity Iodine-125 Interstitial Implant For Gliomas, Int. J. Radiation Oncology Biol Phys 24(4);583 591:1992. Additionally, permanent, intracranial, low dose .sup.125I seeded catheter implants have been used to treat brain tumors. Gaspar, et al., Permanent .sup.125I Implants for Recurrent Malignant Gliomas, Int J Radiation Oncology Biol Phys 43(5);977 982:1999. See also chapter 66, pages 577 580, Bellezza D., et al., Stereotactic Interstitial Brachytherapy, in Gildenberg P. L. et al., Textbook of Stereotactic and Functional Neurosurgery, McGraw-Hill (1998).

Surgically implanted biodegradable implants have been utilized to locally administer anti-cancer drugs to treat malignant gliomas. For example, polyanhydride wafers containing 3-bis(chloro-ethyl)-1-nitrosourea (BCNU) (Carmustine) have been used as intracranial implants. Brem, H. et al., The Safety of Interstitial Chemotherapy with BCNU-Loaded Polymer Followed by Radiation Therapy in the Treatment of Newly Diagnosed Malignant Gliomas: Phase I Trial, J Neuro-Oncology 26:111 123:1995.

A polyanhydride polymer, Gliadel.RTM. (Stolle R & D, Inc., Cincinnati, Ohio) a copolymer of poly-carboxyphenoxypropane and sebacic acid in a ratio of 20:80 has been used to make implants, and has been intracranially implanted to treat malignant gliomas. Polymer and BCNU can be co-dissolved in methylene chloride and spray-dried into microspheres. The microspheres can then be pressed into discs 1.4 cm in diameter and 1.0 mm thick by compression molding, packaged in aluminum foil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads of gamma irradiation. The polymer permits release of carmustine over a 2 3 week period, although it can take more than a year for the polymer to be largely degraded. Brem, H., et al, Placebo-Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas, Lancet 345; 1008 1012:1995.

Implants useful in practicing the methods disclosed herein may be prepared by mixing a desired amount of a stabilized neurotoxin (such as non-reconstituted BOTOX.RTM.) into a solution of a suitable polymer dissolved in methylene chloride. The solution may be prepared at room temperature. The solution can then be transferred to a Petri dish and the methylene chloride evaporated in a vacuum desiccator. Depending upon the implant size desired and hence the amount of incorporated neurotoxin, a suitable amount of the dried neurotoxin incorporating implant is compressed at about 8000 p.s.i. for 5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implant discs encapsulating the neurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of Interstitial Delivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel From a Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58;672 684:1998.

Local, intracranial delivery of a neurotoxin, such as a botulinumtoxin, can provide a high, local therapeutic level of the toxin and can significantly prevent the occurrence of any systemic toxicity since many neurotoxins, such as the botulinum toxins, are too large to cross the blood brain barrier. A controlled release polymer capable of long term, local delivery of a neurotoxin to an intracranial site can circumvent the restrictions imposed by systemic toxicity and the blood brain barrier, and permit effective dosing of an intracranial target tissue. A suitable implant, as set forth in U.S. Pat. No. 6,306,423 entitled "Neurotoxin Implant", allows the direct introduction of a chemotherapeutic agent to a brain target tissue via a controlled release polymer. The implant polymers used are preferably hydrophobic so as to protect the polymer incorporated neurotoxin from water induced decomposition until the toxin is released into the target tissue environment.

Local intracranial administration of a botulinum toxin, according to the present invention, by injection or implant to a nucleus of the brain having neurons believed to be involved in symptoms associated with neuropsychiatric disorder provides a superior alternative to systemic administration of pharmaceuticals to patients to alleviate the symptoms associated with neuropsychiatric disorders.

The target sites for administration of the neurotoxin to the patient may be targeted by using a stereotactic placement apparatus. For example, a neurotoxin containing implant, or a needle containing a neurotoxin, may be stereotactically placed at a desired target site using the Riechert-Mundinger unit and the ZD (Zamorano-Dujovny) multipurpose localizing unit. A contrast-enhanced computerized tomography (CT) scan, injecting 120 ml of omnipaque, 350 mg iodine/ml, with 2 mm slice thickness can allow three dimensional multiplanar treatment planning (STP, Fischer, Freiburg, Germany). This equipment permits planning on the basis of magnetic resonance imaging studies, merging the CT and MRI target information for clear target confirmation.

Other stereotactic systems may also be used, including for example, the Leksell stereotactic system (Downs Surgical, Inc., Decatur, Ga.) modified for use with a GE CT scanner (General Electric Company, Milwaukee, Wis.) as well as the Brown-Roberts-Wells (BRW) stereotactic system (Radionics, Burlington, Mass.). The annular base ring of the BRW stereotactic frame can be attached to the patient's skull. Serial CT sections can be obtained at 3 mm intervals though the (target tissue) region with a graphite rod localizer frame clamped to the base plate. A computerized treatment planning program can be run on a VAX 11/780 computer (Digital Equipment Corporation, Maynard, MA) using CT coordinates of the graphite rod images to map between CT space and BRW space.

Without wishing to be bound by any particular theory, a mechanism can be proposed for the therapeutic effects of a method practiced according to the present invention. Thus, a neurotoxin, such as a botulinum toxin, can inhibit neuronal exocytosis of several different CNS neurotransmitters, for example acetylcholine. It is known that cholinergic neurons are present throughout the brain. Additionally, cholinergic nuclei exist in the basal ganglia or in the basal forebrain, with projections to cerebral regions involved in emotion, behavior, and other cognitive functions. Thus, target tissues for a method within the scope of the present invention can include neurotoxin induced reversible denervation of brain cholinergic systems, such as basal nuclei or pedunculopontine nucleis. For example, injection or implantation of a neurotoxin to a cholinergic nucleus can result in (1) downregulation of dopaminergic release from target sites of cholinergic neurons due to the action of the toxin upon cholinergic terminals projecting into the ventral tegmental area from pedunculopontine nucleus; and (2) attenuation of ventral tegmental area output due to the action of the toxin upon cholinergic neurons projecting to the ventral tegmental area.

Another mechanism proposed for the present invention includes inhibition of exocytosis of nonacetylcholine neurotransmitters. For example, it is believed that once the proteolytic domain of a neurotoxin, such as a botulinum toxin, is incorporated into a neuron, the toxin inhibits release of any neurotransmitter from that neuron. Thus, the neurotoxin may be administered to nuclei containing a substantial number of dopaminergic neurons so that the neurotoxin effectively inhibits the release of dopamine from those neurons. Similarly, the neurotoxin may be administered to other nuclei such as the Raphe nuclei to inhibit serotonin exocytosis, the locus ceruleus nuclei to inhibit norepinephrine exocytosis.

The amount of a neurotoxin selected for intracranial administration to a target tissue according to the present disclosed invention can be varied based upon criteria such as the neuropsychiatric disorder being treated, its severity, the extent of brain tissue involvement or to be treated, solubility characteristics of the neurotoxin toxin chosen as well as the age, sex, weight and health of the patient. For example, the extent of the area of brain tissue influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the suppressant effect is, for most dose ranges, believed to be proportional to the concentration of neurotoxin injected. Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14.sup.th edition, published by McGraw Hill).

A neurotoxin, such as a botulinum toxin, can be intracranially administered according to the present disclosed methods in amounts of between about 10.sup.-4 U/kg to about 1 U/kg. A dose of about 10.sup.-4 U/kg can result in a suppressant effect if delivered to a small nuclei. Intracranial administration of less than about 10.sup.-4 U/kg does not result in a significant or lasting therapeutic result. An intracranial dose of more than 1 U/kg of a neurotoxin, such as a botulinum toxin, can pose a significant risk of denervating other afferent or efferent neuronal systems adjacent to such nuclei. However, it is also believed that the neurons within these nuclei are not as sensitive to the neurotoxin as are neurons at the neuromuscular junction. Accordingly, administration of a neurotoxin, such as botulinum toxin, to an intracranial target tissue involved in neuropsychiatric disorders effectively reduces symptoms associated with the disorders without causing significant cognitive dysfunction. Thus, the methods of the present invention provide more selective treatment with fewer undesirable side effects than current systemic therapeutic regimes.

A preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve an tremor suppressant effect in the patient treated is from about 10.sup.-4 U/kg to about 1 U/kg. Less than about 104.sup.2 U/kg can result in a relatively minor, though still observable, neuropsychiatric symptom suppressant effect. A more preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve the desired effect in the patient treated is from about 10.sup.-3 U/kg to about 1 U/kg. Less than about 10.sup.-3 U/kg can result in the desired therapeutic effect being of less than the optimal or longest possible duration. A most preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a desired tremor suppressant effect in the patient treated is from about 0.1 units to about 20 units. Intracranial administration of a botulinum toxin, such as botulinum toxin type A, in this preferred range can provide dramatic therapeutic success.

Significantly, a method within the scope of the present invention can provide improved patient function. "Improved patient function" can be defined as an improvement measured by factors such as a reduced pain, reduced time spent in bed, increased ambulation, healthier attitude, more varied lifestyle and/or healing permitted by normal muscle tone. Improved patient function is synonymous with an improved quality of life (QOL). QOL can be assessed using, for example, the known SF-12 or SF-36 health survey scoring procedures. SF-36 assesses a patient's physical and mental health in the eight domains of physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health perceptions. Scores obtained can be compared to published values available for various general and patient populations.

As set forth above, I have discovered that administration of a neurotoxin to a patient suffering from a neuropsychiatric disorder surprisingly provides effective and long lasting treatment of the neuropsychiatric disorder, and reduces the symptoms associated with the disorder. In its most preferred embodiment, the present invention is practiced by intracranial injection or implantation of botulinum toxin type A.
 


Claim 1 of 7 Claims

1. A method for treating schizophrenia, the method comprising a step of administering to a patient with schizophrenia a therapeutically effective, non-lethal amount of a botulinum toxin, wherein the botulinum toxin is locally administered to a brain region selected from the group consisting of a lower brain region and pontine region, thereby treating schizophrenia.
 

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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