TNT inhibitors for the treatment of neurological disorders

A method is disclosed for inhibiting the action of TNF for treating neurological conditions in a human by administering a TNF antagonist for reducing the inflammation of neuronal tissue or the neuromuscular junction of a human, or for modulating the immune response affecting neuronal tissue or the neuromuscular junction of a human by administering to the human a therapeutically effective dosage level of a TNF antagonist. The TNF antagonist is selected from the group consisting of etanercept, infliximab, pegylated soluble TNF receptor Type I (PEGsTNF-R1), other agents containing soluble TNF receptors, CDP571 (a humanized monoclonal anti-TNF-alpha antibody), other monoclonal anti-TNF-alpha antibodies, TNF-alpha converting enzyme inhibitors and D2E7 (a human anti-TNF mAb) for reducing the inflammation of neuronal tissue or the neuromuscular junction of a human, or for modulating the immune response affecting neuronal tissue or the neuromuscular junction of a human.

FIELD OF THE INVENTION
 The present invention relates to tumor necrosis factor (TNF) antagonists or
 TNF blockers for the treatment of neurological disorders, trauma, injuries
 or compression; demyelinating neurological disorders, including multiple
 sclerosis; neurodegenerative diseases, including Alzheimer's disease;
 muscular disorders; and disorders of the optic nerve and retina
 (hereinafter "Neurologic and Related TNF Disorders"). More particularly,
 the TNF antagonists, TNF inhibitors or TNF blockers, are used for the
 treatment, prevention or amelioration of these "Neurologic and Related TNF
 Disorders" by modulating the action of TNF in the human body. The use of
 these TNF antagonists or TNF blockers results in the amelioration of these
 disorders and diseases and represents a novel use for this class of drugs.
 BACKGROUND OF THE INVENTION
 Neurological disorders due to demyelinating disease (e.g. multiple
 sclerosis), immune disease, inflammation, trauma, or compression, occur in
 different clinical forms depending upon the anatomic site and the cause
 and natural history of the physiological problem. For example, in
 Alzheimer's disease the brain undergoes a serious form of
 neurodegeneration of unknown etiology. Common to all of these disorders is
 the fact that they can cause permanent neurological damage, that damage
 can occur rapidly and be irreversible, and that current treatment of these
 conditions is unsatisfactory, often requiring surgery and/or the use of
 pharmacologic agents, which are often not completely successful.
 These neurological conditions include acute spinal cord trauma, spinal cord
 compression, spinal cord hematoma, cord contusion (these cases are usually
 traumatic, such as motorcycle accidents or sports injuries); nerve
 compression, the most common condition being a herniated disc causing
 sciatic nerve compression, neuropathy, and pain; but also including
 cervical disc herniation, causing nerve compression in the neck; acute or
 chronic spinal cord compression from cancer (this is usually due to
 metastases to the spine, such as from prostate, breast or lung cancer);
 autoimmune disease of the nervous system; and demyelinating diseases, the
 most common condition being multiple sclerosis.
 Steroid drugs such as cortisone that are used to treat many of the
 aforementioned neurological problems and conditions are particularly
 hazardous because they are used either at high dosage, with a
 corresponding increasing risk of side effects, or because they are used
 chronically, also increasing their adverse effects. Lastly, steroids are
 only partially effective or completely ineffective.
 Tumor necrosis factor (TNF), a naturally occurring cytokine, plays a
 central role in the inflammatory response and in immune injury. TNF is
 formed by the cleavage of a precursor transmembrane protein, forming
 soluble molecules which aggregate to form trimolecular complexes. These
 complexes then bind to receptors found on a variety of cells. Binding
 produces an array of pro-inflammatory effects, including release of other
 pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1;
 release of matrix metalloproteinases; and up regulation of the expression
 of endothelial adhesion molecules, further amplifying the inflammatory and
 immune cascade by attracting leukocytes into extravascular tissues. TNF is
 now well established as key in the pathogenesis of rheumatoid arthritis
 (RA) and Crohn's Disease.
 Specific inhibitors of TNF, only recently commercially available, now
 provide the possibility of therapeutic intervention in TNF mediated
 diseases. Dramatic therapeutic success has already been demonstrated with
 infliximab, a chimeric anti-TNF monoclonal antibody (mAb), in treating
 Crohn's Disease and RA; and with etanercept, a recombinant fusion protein
 consisting of two soluble TNF receptors joined by the Fc fragment of a
 human IgG1 molecule, in treating RA and Psoriatic Arthritis. Other
 specific anti-TNF agents are under development, including D2E7 (a human
 anti-TNF mAb), CDP 571 (a chimeric, but 95% humanized, anti-TNF mAb), and
 a pegylated soluble TNF type 1 receptor. Additionally, thalidomide has
 been demonstrated to be a potent anti-TNF agent. Further, anti-TNF
 therapies may include gene therapy and the development of selective
 inhibitors of the TNF-alpha converting enzyme.
 As with other organ systems, TNF has been shown to have a key role in the
 central nervous system. There is a need for TNF inhibitors that will open
 a new realm of therapeutic possibilities for a wide variety of
 neurological and related disorders. These disorders are diverse and
 include inflammatory and autoimmune disorders of the nervous system,
 including multiple sclerosis, Guillain Barre syndrome, and myasthenia
 gravis; degenerative disorders of the nervous system, including
 Alzheimer's disease, Parkinson's disease and Huntington's disease;
 disorders of related systems of the retina and of muscle, including optic
 neuritis, macular degeneration, diabetic retinopathy, dermatomyositis,
 amyotrophic lateral sclerosis, and muscular dystrophy; and injuries to the
 nervous system, including traumatic brain injury, acute spinal cord
 injury, and stroke.
 The limited ability of the body to effect repair after injury to the
 nervous system, the devastating nature of these diseases and the lack of
 effective therapy all highlight the importance of early therapy aimed at
 preventing or limiting neuronal destruction. Anti-TNF therapies are
 ideally suited to this task because they have been demonstrated to
 dramatically limit inflammation by interrupting the inflammatory cascade
 at a fundamental level.
 There remains a need for a new pharmacologic treatment of these
 aforementioned physiological problems of the nervous system associated
 with autoimmune disease, demyelinating diseases, neurodegenerative
 diseases, trauma, injuries and compression with the pharmacological use of
 TNF antagonists or TNF blockers, which are greatly beneficial for the
 large number of patients whom these conditions affect. Drugs which are
 powerful TNF blockers are etanercept, infliximab, pegylated soluble TNF
 Receptor Type I (PEGs TNF-R1), other agents containing soluble TNF
 receptors, CDP571 (a humanized monoclonal anti-TNF-alpha antibodies),
 thalidomide, phosphodiesterase 4 (IV) inhibitor thalidomide analogues and
 other phosphodiesterase IV inhibitors. Etanercept or infliximab may be
 used for the immediate, short term and long term (acute and chronic)
 blockade of TNF in order to minimize neurological damage mediated by TNF
 dependent processes occurring in the aforementioned neurological
 disorders. The use of these TNF antagonists or TNF blockers would result
 in the amelioration of these physiological neurological problems.
 Additionally, several of these TNF agents will not cross the blood-brain
 barrier. Accordingly, there is also a need for these TNF agents to be
 introduced directly into the cerebrospinal fluid to be effective. This can
 be accomplished either at the level of the spinal cord, or by introduction
 into the ventricular system of the brain, usually via an indwelling,
 subcutaneous reservoir which is connected by catheter into the ventricular
 system. This will allow the chronic use of these agents for the treatment
 of neurological disorders which require chronic TNF modulation.
 DESCRIPTION OF THE PRIOR ART
 Pharmacologic chemical substances, compounds and agents which are used for
 the treatment of neurological disorders, trauma, injuries and compression
 having various organic structures and metabolic functions have been
 disclosed in the prior art. For example, U.S. Pat. Nos. 5,756,482 and
 5,574,022 to ROBERTS et al disclose methods of attenuating physical damage
 to the nervous system and to the spinal cord after injury using steroid
 hormones or steroid precursors such as pregnenolone, and pregnenolone
 sulfate in conjunction with a non-steroidal anti-inflammatory substance
 such as indomethacin. These prior art patents do not teach the use of a
 TNF antagonist or TNF blocker for the suppression and inhibition of the
 action of TNF in the human body to treat "Neurologic and Related TNF
 Disorders", as in the present invention.
 U.S. Pat. No. 5,605,690 to JACOBS discloses a method for treating
 TNF-dependent inflammatory diseases such as arthritis by administering a
 TNF antagonist, such as soluble human TNFR (a sequence of amino acids), to
 a human. This prior art patent does not teach the use of a TNF antagonist
 or TNF blocker for the suppression and inhibition of the action of TNF in
 the human body to treat "Neurologic and Related TNF Disorders", as in the
 present invention.
 U.S. Pat. No. 5,656,272 to LE et al discloses methods of treating
 TNF-alphamediated Crohn's disease using chimeric anti-TNF antibodies. This
 prior art patent does not teach the use of a TNF antagonist or TNF blocker
 for the suppression and inhibition of the action of TNF in the human body
 to treat "Neurologic and Related TNF Disorders", as in the present
 invention.
 U.S. Pat. No. 5,650,396 discloses a method of treating multiple sclerosis
 (MS) by blocking and inhibiting the action of TNF in a patient. This prior
 art patent does not teach the use of TNF antagonists as in the present
 invention.
 None of the prior art patents disclose or teach the use of the TNF
 antagonists or TNF blockers of the present invention for suppression and
 inhibition of the action of TNF in a human to treat "Neurologic and
 Related TNF Disorders", in which the TNF antagonist gives the patient a
 better opportunity to heal, slows disease progression, prevents
 neurological damage, or otherwise improves the patient's health.
 Accordingly, it is an object of the present invention to provide TNF
 antagonists for a new pharmacologic treatment of "Neurologic and Related
 TNF Disorders", such that the use of these TNF antagonists will result in
 the amelioration of these conditions.
 Another object of the present invention is to provide a TNF antagonist for
 providing suppression and inhibition of the action of TNF in a human to
 treat "Neurologic and Related TNF Disorders".
 Another object of the present invention is to provide a TNF antagonist that
 reduces inflammation to the patient by inhibiting the action of TNF in the
 human body for the immediate, short term (acute conditions) and long term
 (chronic conditions), such that this reduction in inflammation will
 produce clinical improvement in the patient and will give the patient a
 better opportunity to heal, slows disease progression, prevents
 neurological damage, or otherwise improves the patient's health.
 Another object of the present invention is to provide TNF antagonists that
 can offer acute and chronic treatment regimens for neurological conditions
 caused by neurological trauma, compression, injury and/or disease; such
 conditions including acute spinal cord or brain injury, herniated nucleus
 pulposus (herniated disc), spinal cord compression due to metastatic
 cancer, primary or metastatic brain tumors, chronic pain syndromes due to
 metastatic tumor, increased intracranial pressure, demyelinating diseases
 such as multiple sclerosis, neurodegenerative diseases such as Alzheimer's
 disease, inflammatory CNS disease, such as subacute sclerosing
 panencephalitis, and other related neurological disorders and diseases.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment regimens for neurological and
 related diseases. Examples of diseases in these categories include but are
 not limited to diseases of the central and peripheral nervous system such
 as Parkinson's disease, Bell's palsy, Guillain-Barre syndrome.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment for retinal and neuro-ophthalmic
 diseases. Examples of diseases in these categories include but are not
 limited to optic neuritis, macular degeneration and diabetic retinopathy.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment for muscular diseases and diseases
 of the neuromuscular junction. Examples of diseases in these categories
 include but are not limited to dermatomyositis, amyotrophic lateral
 sclerosis and muscular dystrophy.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment regimens for degenerative
 neurological disorders and neurologic disorders of uncertain etiology.
 Examples of diseases in these categories include but are not limited to
 Alzheimer's disease, Huntington's disease, and Creutzfeld-Jakob disease.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment regimens for neurologic injuries.
 Examples of diseases in these categories include but are not limited to
 acute spinal cord injury, acute brain injury, and stroke.
 Another object of the present invention is to provide a TNF antagonist that
 can offer acute and chronic treatment regimens for inflammatory and
 autoimmune disorders of the nervous system, examples being subacute
 sclerosing panencephalitis and myasthenia gravis.
 SUMMARY OF THE INVENTION
 The present invention provides a method for inhibiting the action of TNF
 for treating neurological conditions in a human by administering a TNF
 antagonist for reducing the inflammation of neuronal tissue or the
 neuromuscular junction of a human, or for modulating the immune response
 affecting neuronal tissue or the neuromuscular junction of a human by
 administering to the human a therapeutically effective dosage level of a
 TNF antagonist. The TNF antagonist is selected from the group consisting
 of etanercept, infliximab, pegylated soluble TNF receptor Type I
 (PEGsTNF-R1), other agents containing soluble TNF receptors, CDP571 (a
 humanized monoclonal anti-TNF-alpha antibody), other monoclonal
 anti-TNF-alpha antibodies, TNF-alpha converting enzyme inhibitors and D2E7
 (a human anti-TNF mAb) for reducing the inflammation of neuronal tissue or
 the neuromuscular junction of a human, or for modulating the immune
 response affecting neuronal tissue or the neuromuscular junction of a
 human. Additionally, other TNF antagonists are used for administering a
 therapeutically effective dosage level to a human wherein the TNF
 antagonist is selected from the group consisting of thalidomide,
 phosphodiesterase 4 (IV) inhibitor thalidomide analogues and other
 phosphodiesterase IV inhibitors for reducing the inflammation of neuronal
 tissue or the neuromuscular junction of a human, or for modulating the
 immune response affecting neuronal tissue or the neuromuscular junction of
 a human.
 The present invention further provides a method for inhibiting the action
 of TNF for treating conditions of the optic nerve or retina in a human by
 administering a TNF antagonist for reducing the inflammation of the optic
 nerve or retina of a human, or for modulating the immune response
 affecting the optic nerve or retina of a human by administering a
 therapeutically effective dosage level to the human of a TNF antagonist.
 The TNF antagonist is selected from the aforementioned pharmacological
 products listed above.
 The present invention also provides a method for inhibiting the action of
 TNF for treating muscular diseases in a human by administering a TNF
 antagonist for reducing the inflammation of muscle of a human, or for
 modulating the immune response affecting the muscle of a human by
 administering a therapeutically effective dosage level to the human of a
 TNF antagonist. The TNF antagonist is selected from the aforementioned
 pharmacological products listed above.
 In the step of administering the TNF antagonist to a human, the TNF
 antagonist is performed through any of the following routes including
 subcutaneous, intravenous, intrathecal, intramuscular, intranasal, oral,
 transepidermal, parenteral, by inhalation, or intracerebroventricular.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
 TNF antagonist regimens to be used for treating disorders are designed in
 two general ways: acute regimens, designed to achieve rapid blood levels
 and rapid action, wherein the TNF blockade is desired for hours to days;
 and chronic regimens, wherein the TNF blockade is desired for days, weeks,
 or months. TNF antagonists which are suitable for these regimens are
 etanercept (ENBREL.TM.) from Immunex Corporation; infliximab
 (REMICADE.TM.) from Centocor, Inc.; pegylated soluble TNF Receptor Type I
 (PEGs TNF-R1); other agents containing soluble TNF receptors; CDP571 (a
 humanized monoclonal anti-TNF-alpha antibodies); other monoclonal
 anti-TNF-alpha antibodies; D2E7 (a human anti-TNF mAb); thalidomide;
 phosphodiesterase 4 (IV) inhibitor thalidomide analogues; other
 phosphodiesterase IV inhibitors; and TNF alpha converting enzyme
 inhibitors. Etanercept or infliximab may be used for the immediate, short
 term and long term (acute and chronic) blockade of TNF in order to
 minimize neurological damage mediated by TNF dependent processes occurring
 in the aforementioned "Neurologic and Related TNF Disorders". The use of
 these TNF antagonists or TNF blockers results in the amelioration of these
 physiological problems.
 Trauma, injury, compression and other neurological disorders can affect
 individual nerves, nerve roots, the spinal cord, or the brain. The
 conditions which are of most concern in the present invention are the
 following:
 1) acute spinal cord and brain injury,
 2) demyelinating diseases, such as multiple sclerosis,
 3) spinal cord compression due to metastatic cancer,
 4) primary or metastatic brain tumors,
 5) chronic pain syndromes due to metastatic tumor,
 6) inflammatory CNS diseases, such as subacute sclerosing panencephalitis,
 7) Alzheimer's disease,
 8) Huntington's disease,
 9) Creutzfeld-Jakob disease,
 10) Parkinson's disease,
 11) myasthenia gravis,
 12) Guillain-Barre syndrome,
 13) Bell's palsy,
 14) diabetic neuropathy,
 15) amyotrophic lateral sclerosis,
 16) optic neuritis,
 17) macular degeneration,
 18) retinitis pigmentosa,
 19) diabetic retinopathy,
 20) muscular dystrophy, and
 21) polymyositis-dermatomyositis.
 TNF antagonists are a novel way to treat the above-listed disorders in
 comparison with steroids. Experimental evidence has shown that excessive
 levels of TNF are released by injury to neuronal tissue. Accordingly, the
 use of TNF antagonists will result in amelioration of these disorders and
 diseases. Because of the profoundly powerful action of the new TNF
 antagonists that have recently become available, these agents can provide
 treatment in a unique way, filling an urgent clinical need for more
 effective therapy. Also, because of the extremely safe side effect profile
 of these agents, they can be used either singly or in combination with
 other pharmacologic agents. TNF antagonists can also safely be used with
 steroids, which are the only other class of agents which have been shown
 to be beneficial for certain of these conditions. Importantly, the TNF
 antagonists lack the adverse effects of steroids as previously described.
 Lastly, steroids are only partially effective or completely ineffective.
 The TNF antagonists may be administered by any of the following methods to
 treat the above-identified disorders: subcutaneous, intravenous,
 intrathecal, intramuscular, intranasal, oral, transepidermal, parenteral,
 by inhalation, or intracerebroventricular. Also, the dosage regimens for
 treatment are of 3 types:
 Regimen 1: Acute Regimen
 This regimen can be used to treat all of the disorders listed above, with
 any of the TNF antagonists listed above, and with any of the routes of
 administration listed above. This regimen may include just a single dose,
 or repeated doses up to and including 30 continuous days.
 Regimen 2: Chronic Regimen
 This regimen can be used to treat all of the disorders listed above, except
 for: acute spinal cord and brain injury, spinal cord compression, and
 Bell's palsy. Any of the TNF antagonists listed above may be used, and any
 of the routes of administration listed above may be used. This regimen
 includes repeated doses of 31 days or longer.
 Regimen 3: Directly Into The CSF
 This regimen may be used for acute, chronic or both regimens. There are two
 variations: either through the intrathecal route at the level of the
 spinal cord; or directly into the cerebroventricular system at the level
 of the brain. This regimen can be used to treat all of the disorders
 listed above, except for: myasthenia gravis, Bell's palsy, diabetic
 neuropathy, and amyotrophic lateral sclerosis.
 More detailed discussion of each of these clinical conditions is as
 follows:
 1) Acute Spinal Cord and Brain Injury
 About 10,000 cases occur per year in the U.S., with a current population of
 over 200,000 patients with residual neurologic damage, many of whom are
 paralyzed (quadriplegia or paraplegia). Current treatment for the acute
 injury is inadequate. In the early 1990's it was shown that early (within
 8 hours of injury) treatment with high doses of steroids (methyl
 prednisolone) was beneficial for some of these patients. Surgical
 stabilization and spinal decompression is often necessary because of
 excessive swelling (edema) which can itself cause further severe injury to
 the cord due to further compression of the cord against its bony spinal
 canal. The etiology of most of these cases are motor vehicle accidents,
 with the remainder being sports injuries, falls, and other accidents. The
 window of opportunity for treatment is small, since massive swelling can
 occur within minutes.
 The treatment regimen used here would be the acute regimen. This could
 involve any of the TNF antagonists, but currently etanercept would be the
 leading candidate. Etanercept is currently approved only for rheumatoid
 arthritis, and is used as a subcutaneous injection of 25 mg given twice a
 week. This regimen produces peak blood levels in an average of 72 hours.
 Preferred methods for acute spinal cord or brain injury involve either
 administration directly into the CSF or through intravenous infusion
 producing a therapeutic effect more rapidly than can be produced by
 subcutaneous injection. These are new methods of dosing that are not being
 used for arthritis. These acute regimens are unique delivery methods for
 etanercept and are uniquely necessary for clinical neurologic conditions
 requiring rapid blockade of TNF.
 Regimens 1 and 3, as outlined above, may be used to treat these disorders.
 2) Demyelinating Disease, Such As Multiple Sclerosis
 Demyelinating neurological diseases, the most important being multiple
 sclerosis, are inadequately treated by currently available therapies, and
 continue to produce progressive, severe, neurologic impairment in a large
 population of patients in the United States and worldwide. There is
 experimental evidence which documents the role of TNF in multiple
 sclerosis. There is a wide body of work which documents the role of both
 cellular and humoral immunity in multiple sclerosis. Using the
 above-listed TNF antagonists represents a novel approach to the treatment
 of these important disorders.
 Several novel approaches are suggested. For acute demyelinating disease, it
 is paramount to use therapy which is rapidly effective to prevent
 permanent neurological damage. In this case, novel routes of
 administration of the TNF antagonists may be used. These novel routes
 include administration of etanercept or infliximab directly into the CSF;
 or intravenous administration of etanercept. For chronic forms of
 demyelinating disease, the more familiar routes of administration of
 etanercept (subcutaneous) or infliximab (intravenous) may be elected.
 These novel regimens are designed as such because of the complementary
 mechanisms of action and low toxicity of these biopharmaceutical agents.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 3) Spinal Cord Compression Due to Metastatic Cancer
 Cord compression due to metastatic cancer is a catastrophic event leading
 to rapid paralysis if not quickly diagnosed and treated. It is most common
 with cancers of the breast, colon, lung and prostate, but can be a
 complication of metastatic disease from a wide variety of malignancies,
 including melanoma and multiple myeloma. Current treatment regimens
 include high dose steroids, emergency radiation treatment, and/or emergent
 surgical decompression. Paralysis can occur within hours, so treatment
 must be initiated within this time period to avoid permanent sequelae. The
 mechanism of action of TNF blockage here would be similar to that above.
 In addition, it is possible that TNF blockade could be directly
 tumoricidal or tumoristatic with certain malignancies. Impending cord
 compression could be treated with the chronic regimen. However, as
 explained above, most patients would need to be emergently treated with
 the acute regimen, as outlined above.
 Regimens 1 and 3, as outlined above, may be used to treat these disorders.
 4) Primary or Metastatic Brain Tumors
 Primary brain tumors can be either benign (most commonly meningioma) or
 malignant (usually gliomas). Metastatic brain tumors can be from any
 source, most commonly lung cancer, breast cancer, or other malignancies
 such as melanoma. Treatment for these tumors is primarily surgery or
 radiation, with generally poor response to chemotherapy. Many of these
 tumors cause surrounding edema which can cause further neurologic
 deterioration. TNF blockade, either the acute or chronic treatment
 regimen, would be beneficial while these patients are awaiting surgery.
 Additionally, TNF blockade, as discussed above, would have direct tumor
 inhibiting properties.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 5) Chronic Pain Syndromes Due to Metastatic Tumor
 Pain due to metastatic cancer is inadequately treated by currently used
 agents. It is probable that the mechanism of action of this pain is
 mediated in part by the overproduction of TNF. TNF blockade would be
 beneficial for selected tumors, particularly bone metastases where
 compression is involved. The chronic treatment regimens would be used. One
 general note of caution when treating malignancies is necessary: While TNF
 blockade is likely to have an antitumor effect with certain malignancies,
 it is also possible that TNF blockade could increase growth rates with
 certain malignancies.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 6) Inflammatory CNS Diseases, Such As Subacute Sclerosing Panencephalitis
 Subacute sclerosing panencephalitis is a rare inflammatory disease of the
 brain, secondary to infection with a measles virus.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 7) Alzheimer's Disease
 Alzheimer's disease is a common form of progressive dementia, of unknown
 cause and without an effective cure. It is characterized by
 neurofibrillary tangles and plaques on pathologic examination of brain
 tissue.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 8) Huntington's Disease
 Huntington's disease (Huntington's chorea) is a rare, progressive, fatal
 neurological disorder for which there is currently no effective treatment.
 It is often hereditary, and is characterized by a movement disorder
 (chorea), as well as progressive dementia.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 9) Creutzfeld-Jakob Disease
 Creutzfeld-Jakob disease, as well as New Variant Creuzfeld-Jakob disease,
 is one of the transmissible spongioform encephalopathies, along with Kuru
 and Scrapie and "Mad Cow Disease (Bovine spongioform encephalopathy)".
 These diseases are caused by infection with a new class of biologic agent
 called prions. These diseases are progressive, fatal, and can be
 contracted by ingesting tissue of an infected animal. There is no known
 treatment.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 10) Parkinson's Disease
 Parkinson's disease is a common neurologic disorder characterized by
 tremor, gait disorder, and dementia, for which there is no known cure.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 11) Myasthenia Gravis
 Myasthenia gravis is an autoimmune disorder of the neuromuscular junction,
 characterized by muscle weakness and easy fatiguability. There is no known
 cure. Corticosteroids are one of the mainstays of treatment.
 Regimens 1 and 2, as outlined above, may be used to treat these disorders.
 12) Guillain-Barre Syndrome
 Guillain-Barre syndrome is characterized by the rapid onset of weakness,
 usually in an ascending distribution, and often culminating in difficulty
 breathing. It often follows a preceding viral infection.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 13) Bell's Palsy
 Bell's palsy is characterized by the sudden onset of hemifacial paralysis,
 caused by acute mononeuropathy of the seventh cranial nerve, the facial
 nerve. It can follow viral infection, vaccination, or may be idiopathic.
 The mainstay of treatment is large doses of corticosteroids.
 Regimen 1, as outlined above, may be used to treat this disorder.
 14) Diabetic Neuropathy
 Diabetic neuropathy consists of a variety of clinical syndromes of
 neurologic damage occurring in patients with either juvenile onset or
 adult onset diabetes mellitus. Diabetic peripheral neuropathy causes
 sensory deficits, numbness, tingling, and painful paresthesias in the
 extremities. Diabetic autonomic neuropathy causes disorders of the
 autonomic nervous system, including diabetic gastropathy.
 Regimens 1 and 2, as outlined above, may be used to treat these disorders.
 15) Amyotrophic Lateral Sclerosis
 Amyotrophic lateral sclerosis is a progressive fatal, neurologic disease
 causing progressive weakness and cranial nerve palsies, causing difficulty
 with speech, eye movements, and such. There is no known cure.
 Regimens 1 and 2, as outlined above, may be used to treat these disorders.
 16) Optic Neuritis
 Optic neuritis is characterized by acute inflammation affecting the optic
 nerve, causing visual field defects. It is often part of Multiple
 Sclerosis, for which it may be the presenting symptom. Attacks can be
 intermittent and repeated.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 17) Macular Degeneration
 Macular degeneration is a leading cause of blindness, affecting
 predominantly the older population, for which there is no known cure.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 18) Retinitis Pigmentosa
 Retinitis pigmentosa is a hereditary retinal disease, resulting in
 blindness, for which there is no known cure.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 19) Diabetic Retinopathy
 Diabetic Retinopathy includes a spectrum of retinal disorders, including
 hemorrhage and exudates, which occur in patients with diabetes mellitus.
 Part of the retinopathy is due to a vascular damage caused by diabetes.
 Regimens 1, 2 and 3, as outlined above, may be used to treat these
 disorders.
 20) Muscular Dystrophy
 Muscular dystrophy is a group of related diseases of muscle, many of which
 are hereditary, characterized by progressive muscular weakness. The cause
 and cure are unknown.
 Regimens 1 and 2, as outlined above, may be used to treat these disorders.
 21) Polymyositis--Dermatomyositis
 Polymyositis is an autoimmune inflammatory disease of muscle, characterized
 by progressive proximal muscle weakness and muscle wasting. Pathology
 shows an intense inflammatory infiltrate in the muscle. Treatment includes
 immunosuppressive drugs, corticosteroids, and respiratory support for more
 advanced cases. Dermatomyositis is polymyositis with a characteristic
 accompanying skin rash.
 Regimens 1 and 2, as outlined above, may be used to treat these disorders.
 Methods of Administration and Dosage Levels
 For treating the above diseases with the above mentioned TNF antagonists,
 these TNF antagonists may be administered by the following routes:
 The above TNF antagonists may be administered subcutaneously in the human
 and the dosage level is in the range of 5 mg to 50 mg for acute or chronic
 regimens.
 The above TNF antagonists may be administered intranasally in the human and
 the dosage level is in the range of 0.1 mg to 10 mg for acute or chronic
 regimens.
 The above TNF antagonists may be administered intramuscularly in the human
 and the dosage level is in the range of 25 mg to 100 mg.
 The above TNF antagonists may be administered intravenously in the human
 and the dosage level is in the range of 2.5 mg/kg to 20 mg/kg.
 The above TNF antagonists may be administered intrathecally in the human
 and the dosage level is in the range of 0.1 mg to 25 mg administered from
 once a day to every three months.
 The above TNF antagonists may be administered transepidermally in the human
 and the dosage level is in the range of 10 mg to 100 mg.
 The above TNF antagonists may be administered by inhaling by the human and
 the dosage level is in the range of 0.2 mg to 40 mg.
 The above TNF antagonists may be administered intracerebroventricularly in
 the human and the dosage level is in the range of 0.1 mg to 25 mg
 administered once a day to once every 3 month.
 The above TNF antagonists may be administered orally by the human and the
 dosage level is in the range of 10 mg to 300 mg.
 Etanercept is administered intramuscularly in a human wherein the dosage
 level is in the range of 25 mg to 100 mg.
 Infliximab is administered intravenously in a human wherein the dosage
 level is in the range of 2.5 mg/kg to 20 mg/kg.
 Etanercept is administered subcutaneously in a human wherein the dosage
 level is in the range of 5 mg to 50 mg.
 Etanercept is administered intrathecally in a human wherein the dosage
 level is in the range of 0.1 mg to 25 mg administered from once a day to
 once a month.
 Infliximab is administered intrathecally in a human wherein the dosage
 level is in the range of 0.1 mg/kg to 5 mg/kg administered from once a
 week to once every three months.
 Etanercept is administered intracerebroventricularly in a human wherein the
 dosage level is in the range of 0.1 mg to 25 mg administered once a day to
 once a month.
 Infliximab is administered intracerebroventricularly in a human wherein the
 dosage level is in the range of 0.1 mg/kg to 5 mg/kg administered once a
 week to once every 3 months.
 The thalidomide group is administered orally by a human wherein the dosage
 level is in the range of 10 mg to 300 mg.
 All antagonists and all routes of administration can be used for all of the
 above diseases with the following exceptions:
 a) Etanercept and infliximab will only be used subcutaneously,
 intramuscularly, intraventricularly, or intrathecally, or intravenously.
 b) Intracerebroventricular and intrathecal routes are more invasive, and
 will only be used with severe disorders, usually only with those that are
 fatal or devastating. As to the diseases and disorders discussed above,
 these routes are most suitable for acute brain and spinal cord injury;
 Alzheimer's disease; subacute sclerosing panencephalitis; Parkinson's
 disease; Huntington's disease; Creutzfeld-Jakob disease; amyotrophic
 lateral sclerosis; myasthenia gravis; optic neuritis; multiple sclerosis;
 macular degeneration, and retinitis pigmentosa. Excluded are diseases
 outside of the CNS, i.e. those involving muscle or peripheral nerves.
 These excluded diseases include diabetic neuropathy; Bell's palsy (too
 mild to justify this route), muscular dystrophies; and polymyositis.
 c) All other routes should be specified for all of the diseases, except
 that the thalidomide group will not be used for diabetic neuropathy or for
 peripheral neuropathy.
 Advantages of the Present Invention
 Accordingly, an advantage of the present invention is that it provides TNF
 antagonists for a new pharmacologic treatment of "Neurologic and Related
 TNF Disorders", such that the use of these TNF antagonists will result in
 the amelioration of these conditions.
 Another advantage of the present invention is that it provides for a TNF
 antagonist, for providing suppression and inhibition of the action of TNF
 in a human to treat "Neurologic and Related TNF Disorders".
 Another advantage of the present invention is that it provides for a TNF
 antagonist that reduces inflammation to the patient by inhibiting the
 action of TNF in the human body for the immediate, short term (acute
 conditions) and long term (chronic conditions), such that this reduction
 in inflammation will produce clinical improvement in the patient and will
 give the patient a better opportunity to heal, slows disease progression,
 prevents neurological damage, or otherwise improves the patient's health.
 Another advantage of the present invention is that it provides TNF
 antagonists that can offer acute and chronic treatment regimens for
 neurological conditions caused by neurological trauma, compression, injury
 and/or disease; such conditions including acute spinal cord injury, spinal
 cord compression due to metastatic cancer, primary or metastatic brain
 tumors, chronic pain syndromes due to metastatic tumor, increased
 intracranial pressure, demyelinating diseases such as multiple sclerosis,
 neurodegenerative diseases such as Alzheimer's disease, inflammatory CNS
 disease, such as subacute sclerosing panencephalitis, and other related
 neurological disorders and diseases.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment regimens for
 neurologic and related diseases. Examples of diseases in these categories
 include but are not limited to diseases of the central and peripheral
 nervous system such as Parkinson's disease, Bell's palsy, Guillain-Barre
 Syndrome.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment for retinal and
 neuro-ophthalmic diseases. Examples of diseases in these categories
 include but are not limited to optic neuritis, macular degeneration and
 diabetic retinopathy.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment for muscular
 diseases and diseases of the neuromuscular junction. Examples of diseases
 in these categories include but are not limited to dermatomyositis,
 amyotrophic lateral sclerosis and muscular dystrophy.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment regimens for
 degenerative neurologic disorders and neurologic disorders of uncertain
 etiology. Examples of diseases in these categories include but are not
 limited to Alzheimer's disease, Huntington's disease, and Creutzfeld-Jakob
 disease.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment regimens for
 neurologic injuries. Examples of diseases in these categories include but
 are not limited to acute spinal cord injury, acute brain injury, and
 stroke.
 Another advantage of the present invention is that it provides for a TNF
 antagonist that can offer acute and chronic treatment regimens for
 inflammatory and autoimmune disorders of the nervous system, examples
 being subacute sclerosing panencephalitis and myasthenia gravis.
 A latitude of modification, change, and substitution is intended in the
 foregoing disclosure, and in some instances, some features of the
 invention will be employed without a corresponding use of other features.
 Accordingly, it is appropriate that the appended claims be construed
 broadly and in a manner consistent with the spirit and scope of the
 invention herein.