Cytokine antagonists for the treatment of localized disorders

Details Cytokine antagonists for the treatment of localized disorders Cytokine antagonists for the treatment of localized disorders

2001-04-05

2002-07-16

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S427000, C424S434000, C424S130100, C424S134100, C424S141100, C424S142100, C424S145100, C435S007100, C435S007800, C514S885000, C514S913000, C514S914000

Reexamination Certificate

active

06419944

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to specific cytokine antagonists which are provided for the treatment and prevention of damage to the optic nerve, other cranial nerves, brain, spinal cord, nerve roots, peripheral nerves or muscles caused by any one of the following: a herniated nucleus pulposus, osteoarthritis, other forms of arthritis, disorders of bone, disease, or trauma. More particularly, the cytokine antagonists are used in a new treatment of these disorders utilizing localized anatomic administration which causes inhibition of the action of the corresponding pro-inflammatory cytokine in a localized anatomic area of the human body. The administration of these cytokine antagonists is performed by anatomically localized administration which includes, but is not limited to the following routes: perilesional; intralesional; and transconjunctival (for disorders of the optic nerve). Perilesional routes as mentioned above include, but are not limited to, subcutaneous, intramuscular, and epidural routes of administration.
BACKGROUND OF THE INVENTION
Localized administration for the treatment of localized clinical disorders has many clinical advantages over the use of conventional systemic treatment. Locally administered medication after delivery diffuses through local capillary, venous, arterial, and lymphatic action to reach the anatomic site of neurologic or muscular dysfunction; or in the case of the eye through the conjunctiva, then through the aqueous and vitreous humor to reach the optic nerve and retina.
All of the cytokine antagonists which are currently available have been developed for systemic administration. This is because all were developed to treat systemic illnesses, including rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and Crohn's Disease. Systemic illnesses by definition require systemic treatment.
The use of cytokine antagonists to treat localized disorders is discussed in U.S. Pat. Nos. 6,015,557 and 6,177,077 and other pending applications of the applicant. This invention includes further applications of these ideas.
Localized administration, including perilesional or intralesional administration, when compared to systemic administration, carries with it one or more of the following advantages:
1) greater efficacy due to the achievement of higher local concentration;
2) greater efficacy due to the ability of the administered therapeutic molecule to reach the target tissue without degradation caused by hepatic or systemic circulation;
3) more rapid onset of action;
4) longer duration of action; and
5) Potentially fewer side effects, due to lower required dosage.
Pilot studies conducted by the inventor for one of the disorders discussed herein, herniated nucleus pulposus, have demonstrated the dramatic efficacy, and the extraordinarily rapid onset of action of perilesional administration in this clinical disorder. Ongoing pilot studies for other clinical conditions also demonstrate positive results.
Neurological disorders due to a herniated nucleus pulposus, osteoarthritis, other forms of arthritis, disorders of bone, disease, or trauma causing damage to the optic nerve, other cranial nerves, spinal cord, nerve roots, or peripheral nerves are common and cause considerable morbidity in the general population. 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 by pharmacologic or other means is often unsatisfactory. Surgical treatment is therefore often required, and is not uniformly successful.
Of these neurological disorders, radiculopathy due to a herniated nucleus pulposus is among the most common. This condition occurs in both the lumbar and cervical regions. Lumbar radiculopathy due to the herniation of a lumbar intervertebral disc causes sciatica i.e. pain in the lower back with radiation to a leg. Neurologic symptoms and signs are often present, including numbness, paresthesia, and motor symptoms involving the leg or foot. Cervical radiculopathy caused by a herniated nucleus pulposus in the cervical region causes pain and neurologic symptoms in the neck and an upper extremity. Other localized 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); 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); and carpal tunnel syndrome. Localized disorders of the cranial nerves include Bell's Palsy; and glaucoma, caused by glaucomatous degeneration of the optic nerve.
Pharmacologic agents used in the past to treat these disorders have included corticosteroids. Corticosteroid administration, however, may cause multiple side effects, and is often ineffective.
Newer biopharmaceutical medications have been developed which have been shown to offer dramatic clinical benefit for systemic illnesses in humans, even for those disorders which have not responded to large and repeated doses of corticosteroids. These biopharmaceutical medications fall into the category of cytokine antagonists because they block, or antagonize, the biologic action of a specific cytokine which has adverse clinical effects. These cytokines include members of the interleukin class and tumor necrosis factor.
Tumor necrosis factor (TNF) is intimately involved in the nervous system and in inflammatory disorders of muscle. It is central to the response to injury, either virally induced, disease induced, or occurring as a result of mechanical trauma. TNF is also central to neuronal apoptosis, a process important in many neurological disorders.
Specific inhibitors of TNF, only recently commercially available, now provide the possibility of therapeutic intervention in TNF mediated disorders. These agents have been developed to treat systemic illnesses, and therefore have been developed for systemic administration. Various biopharmaceutical companies have developed TNF antagonists to treat systemic illnesses: Immunex Corporation developed etanercept (Enbrel®) to treat rheumatoid arthritis; Johnson and Johnson developed infliximab (Remicade®) to treat Crohn's Disease and rheumatoid arthritis; D2E7, a human anti-TNF monoclonal antibody (Knoll Pharmaceuticals) is being developed to treat rheumatoid arthritis and Crohn's Disease; and Celltech is developing CDP 571 to treat Crohn's Disease and CDP 870 to treat rheumatoid arthritis.
Members of the interleukin family, including interleukin 1(IL-1), have been demonstrated to be key components of inflammation. Antagonists of these cytokines which are in development include interleukin 1 receptor antagonist (IL-1 RA) (Amgen) and interleukin 1 receptor type II (IL-1R type II) (Immunex). Other interleukin antagonists which are the subject of this patent include antagonists to IL-6 (including monoclonal antibodies directed to IL-6) and antagonists to IL-8 (including monoclonal antibodies directed to IL-8). Use of these interleukin antagonists can suppress inflammation, which is important to the pathogenesis of a variety of clinical disorders. Localized administration of these cytokine antagonists, either directed against TNF or interleukin, can ameliorate the localized neurologic disorders and inflammatory disorders of muscle which are of consideration in this invention.


REFERENCES:
patent: 6105557 (2000-01-01), Tobinick et al.
patent: 6177077 (2001-01-01), Tobnick
patent: 6180355 (2001-01-01), Alexander et al.

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