The present invention relates to a method for treating nerve disorders in a mammal or a vertebrate by administering a TNF-alpha inhibitor. The invention also relates to the use of a TNF-alpha inhibitor in the preparation of pharmaceutical compositions for the treatment of nerve root injury and other nerve disorders.

Description of the Invention

SUMMARY OF THE INVENTION

It has been found that the use of a TNF-alpha inhibitor, such as a substance selected from the group consisting of metalloproteinase inhibitors excluding methylprednisolone, tetracyclines including chemically modified tetracyclines, quinolones, corticosteroids, thalidomide, lazaroids, pentoxifylline, hydroxamic acid derivatives, carbocyclic acids, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogs, and melatonin are suitable for treatment of spinal disorders and nerve root injury caused by the liberation of TNF-alpha and compounds triggered by the liberation of or presence of TNF-alpha by inhibiting spinal disc TNF-alpha.

These substances are thus suitable for treatment of nerve root injury, and for treatment of sciatica, low back pain (LBP), and whiplash associated disorder (WAD). The substances can be used to treat nerve and spinal disorders such as nerve root injuries, a nerve disorder caused by or associated with a herniated disc(s), a nerve disorder involving pain, a nucleus pulposus-induced nerve injury, a spinal cord compression and sciatica.

TNF is one of many pro-inflammatory substances with similar action, and it is considered as a "major player" in inflammatory events. However, TNF may also in part acts through other pro-inflammatory cytokines such as for instance IL-1, IL-6, FAS, and IFN-gamma.

It is an object of the invention to provide novel and improved methods for inhibiting the action of TNF-alpha for treating disorders in a subject by administering a TNF-alpha inhibitor comprising the step of administering to said subject a therapeutically effective dosage of said TNF-alpha inhibitor, wherein said TNF-alpha inhibitor is a monoclonal antibody selected from CDP-571 (HUMICADE.TM.) D2E7, and CDP-870.

It is an object of the invention to provide novel and improved methods for inhibiting the action of TNF-alpha for treating disorders in a subject by administering a TNF-alpha inhibitor comprising the step of administering to said subject a therapeutically effective dosage of a soluble cytokine receptor, such as etanercept.

Alternatively the TNF-alpha inhibitor used in the above method can be lactoferrin, CT3, ITF-2357, PD-168787, CLX-1100, M-PGA, NCS-700, PMS-601, RDP-58, TNF-484A, PCM-4, CBP-1011, SR-31747, AGT-1, Solimastat, CH-3697, NR58-3.14.3, RIP-3, Sch-23863 and SH-636.

The subject which can be treated by these methods include any vertebrate, preferably mammals, and of those, most preferably humans.

It is a more specific object of the invention to provide a novel pharmaceutical composition for treating nerve disorders in a subject comprising a therapeutically effective amount of a TNF-alpha inhibitor that is a monoclonal antibody selected from the group consisting of CDP-571 (HUMICADE.TM.), D2E7, and CDP-870, and a pharmaceutically acceptable carrier, wherein said pharmaceutical composition inhibits nerve injury when administered to said subject. The pharmaceutical composition may comprise a therapeutically effective amount of a TNF-alpha inhibitor that is a soluble cytokine receptor, such as etanercept. The pharmaceutical composition alternatively can comprise one or more of these agents, or can comprise, alone or in combination, any of the agents discussed herein.

In another embodiment, the methods and pharmaceutical compositions described herein can be used to treat such nerve disorders as spinal disorders, nerve root injuries, a nerve disorder caused by or associated with a herniated disc(s), a nerve disorder involving pain, a nucleus pulposus-induced nerve injury, a spinal cord compression and sciatica.

Nerve disorders treatable with the method and the pharmaceutical composition according to the invention are, for example, nerve disorders due to a reduced nerve reduction velocity, spinal disorders, nerve root injuries, nerve disorders caused by disc herniation, sciatica, cervical rhizopathy, low back pain, whiplash associated disorder, nerve disorders involving pain, nucleus pulposus-induced nerve injuries, and spinal cord compressions.

The subject which can be treated by these methods include any vertebrate, preferably mammals, and of those, most preferably humans.

With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

It has now surprisingly been shown possible to be able to treat nerve root injuries, or at least alleviate the symptoms of nerve root injuries by using a pharmaceutical composition comprising a therapeutically active amount of a TNF-alpha inhibitor. TNF-alpha inhibitors, include but are not limited to, metalloproteinase (MMP) inhibitors (excluding methylprednisolone), tetracyclines, chemically modified tetracyclines, quinolones, corticosteroids, thalidomide, lazaroids, pentoxifylline, hydroxamic acid derivatives, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards TNF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogous, and melatonin in the form of bases or addition salts together with a pharmaceutically acceptable carrier.

By "therapeutically active amount" and "therapeutically effective dosage" are intended to be an amount that will lead to a desired therapeutic effect, i.e., an amount that will lead to an improvement of the patient's condition. In one preferred example, an amount sufficient to ameliorate or treat a condition associated with a nerve disorder. In some embodiments, the therapeutically effective amount is a dosage normally used when using such compounds for other therapeutic uses. Many of these drugs are commercially known registered drugs.

By "mammal" is meant to include but is not limited to primate, human, canine, porcine, equine, murine, feline, caprine, ovine, bovine, lupine, camelid, cervidae, rodent, avian and ichthyes. By animal is meant to include any vertebrate animal wherein there is a potential for nerve root injury.

As used herein, the term "antibody" is meant to refer to complete, intact antibodies, and Fab fragments, scFv, and F(ab).sub.2 fragments thereof. Complete, intact antibodies include monoclonal antibodies such as murine monoclonal antibodies (mAb), chimeric antibodies, humanized antibodies and human antibodies. The production of antibodies and the protein structures of complete, intact antibodies, Fab fragments, scFv fragments and F(ab).sub.2 fragments and the organization of the genetic sequences that encode such molecules, are well known and are described, for example, in Harlow et al., ANTIBODIES: A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1988) and Harlow et al., USING ANTIBODIES: A LABORATORY MANUAL, Cold Spring Harbor Press, 1999, which are herein incorporated by reference in their entirety.

By "epitope" is meant a region on an antigen molecule to which an antibody or an immunogenic fragment thereof binds specifically. The epitope can be a three dimensional epitope formed from residues on different regions of a protein antigen molecule, which, in a naive state, are closely apposed due to protein folding. "Epitope" as used herein can also mean an epitope created by a peptide or hapten portion of TNF-alpha and not a three dimensional epitope. Preferred epitopes are those wherein when bound to an immunogen (antibody, antibody fragment, or immunogenic fusion protein) results in inhibited or blocked TNF-alpha activity.

By "TNF-alpha blocking" is meant a compound or composition that blocks, inhibits or prevents the activity of TNF or TNF-alpha.

Compounds that possess TNF-alpha inhibitory activity are for example tetracyclines, (e.g., tetracycline, doxycycline, lymecycline, oxytetracycline, minocycline), and chemically modified tetracyclines (e.g., dedimethylamino-tetracycline), hydroxamic acid compounds, carbocyclic acids and derivatives, thalidomide, lazaroids, pentoxifylline, napthopyrans, soluble cytokine receptors, monoclonal antibodies towards INF-alpha, amrinone, pimobendan, vesnarinone, phosphodiesterase inhibitors, lactoferrin and lactoferrin derived analogs, melatonin, norfloxacine, ofloxacine, ciprofloxacine, gatifloxacine, pefloxacine, lomefloxacine, temafloxacine, TTP and p38 kinase inhibitors. These compounds can be present as bases or in the form of addition salts, whichever possesses the best or preferred pharmaceutical effect, and best property to be brought into a suitable pharmaceutical composition. A more complete list is given below.

Further, the active component can comprise a substance inhibiting a compound triggered by the release of TNF-alpha, such as interferon-gamma, interleukin-1, and nitrogen oxide (NO).

Aminoguanidine has been shown to inhibit the release of nitrogen oxide (NO) at nerve root injuries by inhibiting inducible nitrogen oxide synthetase, and aminoguanidine is thus one compound that inhibits a compound trigged by the release of TNF-alpha.

As stated above, there are several different types of cytokine blocking substances and pharmacological preparations that may be used according to the invention, and examples of those substances may be grouped in different subclasses -- see Original Patent.

TNF Inhibitors Specific TNF Inhibitors

Monoclonal antibodies such as: infliximab, CDP-571 (HUMICADE.TM.), D2E7 (Adalimumab), and the antibody fragment CDP-870; Polyclonal antibodies; Soluble cytokine receptors such as: etanercept, lenercept, pegylated TNF receptor type I, and TBP-1; TNF receptor antagonists; Antisense oligonucleotides such as: ISIS-104838

Non-Specific TNF Inhibitors

5,6-dimethylxanthenone-4-acetic acid (acemannan); AGT-1; ANA 245; AWD 12281; BN 58705; Caspase inhibitors; CBP-1011; CC 1069; CC 1080; CDC 801; CDDO; CH-3697; CLX 1100; CM 101; CT3; CT 2576; CPH 82; CV 1013; Cyclosporin; Compounds used in anti-cancer treatment such as: the binuclear DNA threading transition metal complexes and pharmaceutical compositions comprising them described in WO 99/15535, and methotrexate; Declopramide; DPC 333; DWP 205297; DY 9973; Edodekin alfa; Flt ligand (available from Immunex); Gallium nitrate; HP 228; Hydroxamic acid derivates; IL-12; IL-18; Ilodekacin; Ilomastat; ITF-2357; JTE 607; Lactoferrin; Lactoferrin derived or derivable peptides such as: the peptides described in WO 00/01730; Lazaroids; nonglucocorticoid 21-aminosteroids such as: U-74389G (16-desmethyl tirilazad), and U-74500; LPS agonist Esai; Melancortin agonists such as: HP-228; Mercaptoethylguanidine; Metoclopramide; MMP inhibitors (i.e. matrix metalloproteinase inhibitors or TACE inhibitors, i.e. TNF Alpha Converting Enzyme-inhibitors) such as: Tetracyclines such as: Doxycycline, Lymecycline, Oxitetracycline, Tetracycline, and Minocycline; Synthetic tetracycline derivates (CMT=Chemically Modified Tetracyclines); KB-R7785; TIMP1 and TIMP2; adTIMP2 and adTIMP2; M-PGA; Napthopyrans; NCS-700; Nimesulide; NR58-3.14.3; p38 kinase inhibitors such as: VX-702, VX-740, VX-745 (Pralnacasan), VX-765, VX-850, SB-202190, SB-203580, and Pyridinyl imidazoles; PCM-4; PD-168787; Pentoxifyllin derivates; Pharma projects no. 6181, 6019 and 4657; Phosphodiesterase I, II, III, IV, and V-inhibitors such as: CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, and SB 207499; Piclamastat; PMS-601; Prostaglandins such as: Iloprost (prostacyclin); Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, and Temafloxacin; RDP-58; RIP-3; Sch-23863; SH-636; Solimastat; SR-31747; Tasonermin; Thalidomide derivates (or SelCID=Selective Cytokin inhibitors, e.g. thalidomide derivate) such as: CC-1088 CDC-501, and CDC-801; TNF alpha proteinase inhibitor available from Immunex; TNF-484A; Tristetraproline (TTP) (available from AstraZeneca); VRCTC 310; Yissum project no. 11649; Zanamivir

Inhibitors of Interleukin-1 Alpha and Beta (IL-1.alpha. and IL-1.beta.)

Specific Inhibitors of IL-1 Alpha and IL-1 Beta

Monoclonal antibodies such as: CDP-484; Soluble cytokine receptors; IL-1 type II receptor (decoy RII); Receptor antagonists such as: IL-1ra, anakinra (KINERET.RTM.), and ORTHOKIN.RTM.; Antisense oligonucleotides

Non-Specific Inhibitors of IL-1 Alpha and IL-1 Beta

MMP inhibitors (i.e. matrix metalloproteinase inhibitors) such as: Tetracyclines such as: Doxycycline, Trovafloxacin, Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; Prinomastat (AG3340); Batimastat; Marimastat; BB-3644; KB-R7785; TIMP-1, and TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), and adTIMP-2 (adenoviral delivery of TIMP-2);

Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin; Prostaglandins; Iloprost (prostacyclin); Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499

Inhibitors of Interleukin-6 (IL-6)

Specific Inhibitors of IL-6

Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides

Non-Specific Inhibitors of IL-6

MMP inhibitors (i.e. matrix metalloproteinase inhibitors) such as: Tetracyclines such as: Doxycycline, Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; Prinomastat (AG3340); Batimastat; Marimastat; BB-3644; KB-R7785; TIMP-1, and TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), and adTIMP-2 (adenoviral delivery of TIMP-2);

Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin; Prostaglandins; Iloprost (prostacyclin); Cyclosporin Pentoxifyllin derivates; Hydroxamic acid derivates; Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499; Melanin and melancortin agonists; HP-228

Inhibitors of Interleukin-8 (IL-8)

Specific Inhibitors of IL-8

Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides

Non-Specific Inhibitors of IL-8

Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin; Thalidomide derivates such as: SelCID, i.e. Selective Cytokine inhibitors such as: CC-1088, CDC-501, CDC-801 and Linomide (Roquininex.RTM.); Lazaroids; Cyclosporin; Pentoxifyllin derivates

FAS Inhibitors

Specific FAS Inhibitors

Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides

Non-Specific FAS Inhibitors

Inhibitors of FAS Ligands

Specific Inhibitors of FAS Ligands

Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides

Non-Specific Inhibitors of FAS Ligands

Inhibitors of Interferon-Gamma (IFN-Gamma)

Specific IFN-Gamma Inhibitors

Monoclonal antibodies; Soluble cytokine receptors; Receptor antagonists; Antisense oligonucleotides;

Non-Specific IFN-Gamma Inhibitors

MMP inhibitors (i.e. matrix metalloproteinase inhibitors) such as: Tetracyclines such as: Doxycycline, Trovafloxacin, Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; Prinomastat (AG3340); Batimastat; Marimastat; BB-3644; KB-R7785; TIMP-1, and TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), and adTIMP-2 (adenoviral delivery of TIMP-2); Quinolones (chinolones) such as: Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin, Rebamipide, and Nalidixic acid; Lazaroids; Pentoxifyllin derivates; Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499.

Also contemplated are the pharmaceutically acceptable bases and salts of the substances listed above.

Preferred groups of TNF-alpha blocking substances for use according to the present invention are soluble cytokine receptors, monoclonal antibodies, and tetracyclines or chemically modified tetracyclines.

Two preferred substances for use according to the present invention are the monoclonal antibodies, D2E7 and CDP-870.

D2E7 is a fully humanized monoclonal antibody directed against human TNF-alpha, which has been developed by Knoll and Cambridge Antibody Technology. A transgenic recombinant version of this antibody is under development by Genzyme Transgenic. The invention contemplates any antibody that binds to the same epitope as D2E7 or that has the same TNF-alpha inhibitory effect as D2E7. Preferably the antibody is primatized.RTM., humanized or human.

CDP-870 (or CDP 870) is a humanized antibody fragment with high affinity to TNF-alpha. It has been developed by Celltech Group plc, and was co-developed with Pharmacia Corporation. The invention contemplates any antibody, antibody fragment or immunogen that binds to the same epitope as CDP-870 or that has the same TNF-alpha inhibitory activity as CDP-870. Preferably the antibody, antibody fragment or immunogen has the same or similar TNF-alpha inhibitory activity. Preferably the antibody, antibody fragment or immunogen is primatized, humanized or human.

Further, the active component may be a substance inhibiting a compound triggered by the release of TNF-alpha or part of a TNF-alpha cascade that is associated with nerve root injury, such as interferon-gamma (INF-.gamma.), interleukin-1 (IL-1), and nitrogen oxide (NO).

It is possible to use either one or two or more substances according to the invention in the treatment, for example, of low back pain (LBP). When two or more substances are used they may be administered either simultaneously or separately.

Doxycycline inhibits the action of TNF in a non-specific manner. TNF and other similar bioactive substances are first produced in an inactive form and transported to the cell membrane. Upon activation, the active part of the pro-TNF is cleaved and released. This process is called shedding and may be initiated by one or more enzymes. These enzymes have in common that they are metalloproteinases, i.e. dependent of a metal-ion for their function. Doxycycline and other tetracyclines are known to bind to metal-ions and will thereby inhibit the action of metalloproteinases and subsequently the release of TNF and other pro-inflammatory cytokines in a non-specific manner. A monoclonal anti-TNF antibody, on the other hand, will bind directly to TNF and thereby inhibit TNF in a more specific way than doxycycline. The inhibition may thus be assumed to be more efficient but will be restricted to TNF. However, in the work leading to the present invention, it was found that anti-TNF treatment was more efficient than doxycycline treatment.

The substances according to the invention may also be administered in combination with other drugs or compounds, provided that these other drugs or compounds do not eliminate the desired effects according to the present invention, i.e., the effect on TNF-alpha.

The invention further relates to a method for inhibiting the symptoms of nerve root injury.

The effects of doxycycline, soluble cytokine-receptors, and monoclonal cytokine-antibodies have been studied and representative methods used and results obtained are disclosed below. Although the present invention has been described in detail with reference to examples herein, it is understood that various modifications can be made without departing from the spirit of the invention, and would be readily known to the skilled artisan.

The compounds of the invention can be administered in a variety of dosage forms, e.g., orally (per os), in the form of tablets, capsules, sugar or film coated tablets, liquid solutions; rectally, in the form of suppositories; parenterally, e.g., intramuscularly (i.m.), subcutaneous (s.c.), intracerebroventricular (i.c.v.), intrathecal (i.t.), epidurally, transepidermally or by intravenous (i.v.) injection or infusion; by inhalation; or intranasally.

The therapeutic regimen for the different clinical syndromes may be adapted to the disease or condition, medical history of the subject as would be know to the skilled artisan or clinician. Factors to be considered but not limiting to the route of administration, the form in which the compound is administered, the age, weight, sex, and condition of the subject involved.

For example, the oral route is employed, in general, for all conditions, requiring such compounds. In emergency cases, preference is sometimes given to intravenous injection. For these purposes, the compounds of the invention can be administered, for example, orally at doses ranging from about 20 to about 1500 mg/day. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response depending on the subject's condition.

The nature of the pharmaceutical composition containing the compounds of the invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration. The composition may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules (hard or soft ones), syrups, drops or suppositories.

For oral administration, the pharmaceutical compositions containing the compounds of the invention are preferably tablets, pills or gelatine capsules, which contain the active substance or substances together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methyl cellulose, carboxymethylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents such as starches, alginic acid, alginates, sodium starch glycolate, microcrystalline cellulose; effervescing agents, such a carbonates and acids; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and in general non-toxic and pharmaceutically inert substances used in the formulation of pharmaceutical compositions. Said pharmaceutical compositions may be manufactured in known manners, e.g., by means of mixing, granulating, tableting, sugar-coating or film-coating processes. Film providing compounds can be selected to provide release in the right place or at the appropriate time in the intestinal tract with regard to absorption and maximum effect. Thus pH-dependent film formers can be used to allow absorption in the intestines as such, whereby different phthalates are normally used or acrylic acid/methacrylic acid derivatives and polymers.

The liquid dispersions for oral administration may be, e.g., syrups, emulsions, and suspensions.

The syrups may contain as carrier, e.g., saccharose, or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as Garner, e.g., a natural gum, such as gum arabic, xanthan gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethylcellulose, polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain together with the active compound, a pharmaceutically acceptable carrier, such as e.g., sterile water, olive oil (or other vegetable or nut derived oil), ethyl oleate, glycols, e.g., propylene glycol, and if so desired, a suitable amount of lidocaine hydrochloride. Adjuvants for triggering the injection effect can be added as well.

The solutions for intravenous injection or infusion may contain as carrier, e.g., sterile water, or preferably, a sterile isotonic saline solution, as well as adjuvants used in the field of injection of active compounds. Such solutions would also be suitable for i.m. and i.c.v. injection.

The suppositories may contain together with the active compounds, a pharmaceutically acceptable carrier, e.g., cocoa-butter polyethylene glycol, a polyethylene sorbitan fatty acid ester surfactant or lecithin.

Examples of suitable doses of the active agents contemplated for different administration routes are given below -- see Original Patent.

These ranges are approximate (e.g., about 1 to about 100) and may vary depending on the specific agent being administered and the nature of the disorder in the subject. Thus, it is further contemplated that any dosage in between for the cited ranges may also be used.

Examples of suitable doses for different TNF-alpha inhibitors are given in the table below -- see Original Patent.
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Claim 1 of 32 Claims

1. A method for treating or alleviating one or more symptoms of a spinal disorder mediated by nucleus pulposus, which spinal disorder is not arthritis or a related inflammatory disorder, the method comprising the step of administering a therapeutically effective amount of one or more specific TNF-.alpha. inhibitors to a patient in need of the treatment.

 

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