ES2358687T3 - TALIDOMIDE AND DEXAMETASONE FOR TUMOR TREATMENT. - Google Patents

Abstract

Thalidomide and dexamethasone for use in the treatment of a blood-borne tumor, where thalidomide and dexamethasone are administered to a human or animal together.

Description

The present invention relates to thalidomide and dexamethasone for use in the treatment of a solid tumor.

or transported by blood.

Background of the Invention

As used herein, the term "angiogenesis" means the generation of new blood vessels in a tissue or organ. Under normal physiological conditions, humans or animals suffer only angiogenesis in very specific restricted situations. For example, angiogenesis is usually observed in wound healing, fetal and embryonic development and in the formation of the corpus luteum, the endometrium and the placenta. Angiogenesis control is a rigorously regulated system of angiogenic stimulators and inhibitors.

It has been found that the control of angiogenesis is altered in certain disease states and, in many cases, the pathological deterioration associated with the disease is related to uncontrolled angiogenesis.

It is believed that both controlled and uncontrolled angiogenesis run similarly. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. Endothelial cells, which internally line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulators induce endothelial cell migration through the eroded basement membrane. Migrant cells form an "outbreak" that starts from the original blood vessel, where endothelial cells undergo mitosis and proliferate. The endothelial buds fuse with each other to form capillary loops creating the new blood vessel. In the disease state, prevention of angiogenesis could prevent damage caused by the invasion of the new microvascular system.

Persistent and unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastases and abnormal growth by endothelial cells, and supports the pathological deterioration observed in these conditions. The various disease states created due to unregulated angiogenesis have been grouped as angiogenesis-dependent diseases or associated with angiogenesis. Therapies aimed at controlling angiogenic processes could lead to the cancellation or mitigation of these diseases.

An example of an angiogenesis-mediated disease is ocular neovascular disease. This disease is characterized by the invasion of new blood vessels in the eye structures such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty ophthalmic diseases. In age-related macular degeneration, the associated visual problems are caused by internal growth of choroidal capillaries through Bruch's membrane defects with proliferation of fibrovascular tissue below the retinal pigmentary epithelium. Angiogenic deterioration is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Other diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, vitamin A deficiency, excessive use of contact lenses, atopic keratitis, upper limb keratitis, dry pterygium keratitis, Sjögren's syndrome, acne rosacea , filectenulosis, syphilis, Mycobacterial infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, marginal Terrien degeneration, marginal keratolysis , rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, pemphigoid and corneal graft rejection.

Diseases associated with retinal / choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, elastic pseudoxanthoma, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, uveitis / chronic vitritis , mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, Eales disease, Behcet disease, infections causing retinitis or choroiditis, supposed ocular histoplasmosis, Best's disease, myopia, optical wells, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications. Other diseases include, but are not limited to, diseases associated with rubeosis (neovascularization of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of proliferative vitreoretinopathy.

Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. The blood vessels in the synovial lining of the joints suffer angiogenesis. In addition to forming new vascular networks, endothelial cells release reactive oxygen chemical factors and species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis can actively contribute to the chronically inflamed state of rheumatoid arthritis, and favor its maintenance.

The factors associated with angiogenesis may also play a certain role in osteoarthritis. Chondrocyte activation by factors related to angiogenesis contributes to the destruction of the joint. At a later stage, angiogenic factors could promote new bone formation. The therapeutic intervention that prevents the destruction of the bone could stop the progress of the disease and provide relief for people suffering from arthritis.

Chronic inflammation may also involve pathological angiogenesis. Disease states such as ulcerative colitis and Crohn's disease exhibit histological changes with the internal growth of new blood vessels in inflamed tissues. Bartonellosis, a bacterial infection found in South America, can result in a chronic condition characterized by proliferation of endothelial vascular cells. Another pathological role associated with angiogenesis is found in atherosclerosis. Plaques formed within the lumen of blood vessels have been shown to have angiogenesis stimulating activity.

One of the most frequent angiogenic diseases of childhood is hemangioma. In most cases, the tumors are benign and return without intervention. In more severe cases, the tumors progress to large cavernous and infiltrating forms and create clinical complications. Systemic forms of hemangiomas, hemangiomatosis, have a high mortality rate. There are therapy-resistant hemangiomas that cannot be treated with the therapeutic means currently used.

Angiogenesis is also responsible for the deterioration found in hereditary diseases such as Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia. This is an inherited disease characterized by small angiomas, tumors of the blood vessels or multiple lymphatics. Angiomas are found in the skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatic arteriovenous fistula.

Angiogenesis is prominent in the formation of solid tumors and metastases. Angiogenic factors associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma have been found. A tumor cannot expand without a blood supply to provide nutrients and eliminate cellular debris. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas. The prevention of angiogenesis could stop the growth of these tumors and the resulting damage to the animal due to the presence of the tumor.

It should be noted that angiogenesis has been associated with blood-borne tumors such as leukemia, any of several acute or chronic bone marrow neoplastic diseases in which uncontrolled white blood cell proliferation occurs, usually accompanied by anemia, impaired blood clotting. blood, and thickening of the lymph nodes, liver, and spleen. Angiogenesis is believed to play a role in bone marrow abnormalities that lead to leukemia-like tumors.

Angiogenesis is important in two stages of tumor metastasis. The first stage in which angiogenesis stimulation is important is in the vascularization of the tumor that allows tumor cells to enter the bloodstream and circulate through the body. After the tumor cells have left the primary site, and have been deposited in the secondary site, site of metastasis, angiogenesis has to occur before the new tumor can grow and expand. Therefore, the prevention of angiogenesis could lead to the prevention of tumor metastasis and possibly restrain the neoplastic growth in the primary site.

Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer. The amount of neovascularization found in the primary tumor was determined by counting the density of microvessels in the area of the most intense neovascularization in invasive breast carcinoma. It was found that a high level of density of microvessels was correlated with tumor recurrence. The control of angiogenesis by therapeutic means could possibly lead to cessation of tumor recurrence.

Angiogenesis is also involved in normal physiological processes such as reproduction and wound healing. Angiogenesis is an important step in ovulation and also in the implantation of the blastula after fertilization. Angiogenesis prevention could be used to induce amenorrhea, to block ovulation or to prevent implantation by the blastula.

In wound healing, excessive repair or fibroplasia may be a detrimental side effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication in surgery and lead to problems such as obstruction of the small intestine.

Several classes of compounds have been used to prevent angiogenesis. Taylor et al. have used protamine to inhibit angiogenesis, see Taylor et al. Nature 297: 307 (1982). The toxicity of protamine limits its practical use as a therapeutic agent. Folkman et al. have exposed the use of heparin and steroids to control angiogenesis. See Folkman et al., Science 221: 719 (1983) and U.S. Pat. No. 5,001,116 and 4,994,443. It has been found that steroids, such as tetrahydrocortisol, which lack activity of glucocorticoids and mineral corticosteroids, are angiogenic inhibitors.

Other factors found endogenously in animals, such as a 4 kDa glycoprotein of bovine vitreous humor and a cartilage derived factor, have been used to inhibit angiogenesis. Cellular factors such as interferon inhibit angiogenesis. For example, it has been shown that human interferon a or interferon β inhibits tumor-induced angiogenesis in the mouse dermis stimulated by human neoplastic cells. Interferon β is also a potent inhibitor of angiogenesis induced by the allogeneic cells of the spleen. See Sidky et al., Cancer Research 47: 5155-5161 (1987). It has been reported that recombinant human interferon (alpha / A) has been used successfully in the treatment of pulmonary hemangiomatosis, an angiogenesis-induced disease. See White et al., New England J. Med. 320: 1197-1200 (1989).

Other agents that have been used to inhibit angiogenesis include ethers of ascorbic acid and related compounds. See Japanese Kokai Tokkyo Koho No. 58-131978. The sulfated polysaccharide DS 4152 also exhibits angiogenic inhibition. See Japanese Kokai Tokkyo Koho No. 63-119500. A fungal product, fumagillin, is a potent angiostatic agent in vitro. The compound is toxic in vivo, but a synthetic derivative, AGM 12470, has been used in vivo to treat arthritis caused by type II collagen. The fumagillin and O-substituted fumagillin derivatives are described in EPO Publications Nos. 0325199A2 and 0357061A1.

PCT Application No. WO 92/14455 granted to Kaplan et al. It is directed to a method to control the abnormal concentration of TNF-a by administration of thalidomide or thalidomide derivatives to a patient with toxic concentrations of TNF-a.

The above compounds are topical or injectable therapeutic products. For this reason, there are drawbacks in its use as a general angiogenic inhibitor and lack adequate potency. For example, in the prevention of excessive wound healing, surgery on the internal body organs involves incisions in various structures contained within the body cavities. These wounds are not accessible to local applications of angiogenic inhibitors. Local delivery systems also involve frequent bandages that are impracticable for internal wounds, and increase the risk of infection or deterioration of delicate granulation tissue for superficial wounds.

Thus, a method and a composition that are capable of inhibiting angiogenesis and that are easily administered are required. A simple and effective method of treatment would be by the oral route. If an angiogenic inhibitor could be administered by the oral route, the numerous classes of diseases described above, and other pathologies dependent on angiogenesis, could be easily treated. The optimal dosage could be distributed in a way that the patient could self-administer.

An objective of the present invention is to provide a treatment for solid tumors.

Another objective of the present invention is to provide a method and composition for the treatment of tumors transported by blood such as leukemia.

Another objective of the present invention is to provide a method and composition for the treatment of hemangioma.

Another objective of the present invention is to provide a method and composition for the treatment of Kaposi's sarcoma.

A further objective of the present invention is to provide a method and composition comprising thalidomide and steroidal anti-inflammatory drugs for the treatment of cancer.

These and other objectives, features and advantages of the present invention will become clear upon review of the following detailed description of the described embodiments and the appended claims.

In a first aspect of the invention, thalidomide and dexamethasone is provided for use in the treatment of a solid or blood transported tumor, where thalidomide and dexamethasone are administered to a human.

or to an animal together.

In a second aspect of the invention, thalidomide and dexamethasone is provided for use in the treatment of a solid or blood transported tumor, where thalidomide and dexamethasone are administered to a human or an animal sequentially.

The embodiments of the invention in any of its various aspects are as described below or as defined in the dependent claims.

Figures 1 to 3 are a list of representative compounds in the genus represented by the following general formulas:

image 1

Figure 4 is a list of representative compounds in the genus represented by the following general formula:

image 1

Figure 5 is a list of representative compounds in the genus represented by the following general formula:

image 1

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Figure 6 shows the effect of thalidomide and EM12 on angiogenesis in an angiogenesis model in a rabbit's cornea.

Figure 7 shows the effect of thalidomide on the vascularization area of the cornea in a model of angiogenesis in the cornea of a rabbit.

Figure 8 shows the effect of thalidomide, sulindac, or a combination of the two on the inhibition of tumor growth of V2 carcinoma in New Zealand White female rabbits.

Compositions and methods for the treatment of diseases that are mediated by angiogenesis are described. The use of thalidomide or thalidomide metabolites is described herein to inhibit the

5 undesirable angiogenesis. Compounds that cause dysmelia in the developing fetus and have antiangiogenic activity are also described. A method for treating undesirable angiogenesis in a human or animal is also described, which comprises the steps of administering to the human or animal with undesirable angiogenesis a composition comprising an effective amount of a teratogenic compound that is antiangiogenic.

Compounds that can be used include compounds included in the following general formulas. Examples of compounds that have antiangiogenic properties that have one of the following three formulas (A), (B), or (C):

image 1

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In the above formulas A), B), and C), R1, R2, R3 and R4 can be selected from: -H; -OH; = 0, alkanes, alkenes and alkynes of linear and branched chain; alkanes, alkenes and cyclic alkynes; combinations of alkanes, alkenes and cyclic and acyclic alkynes; alcohol, aldehyde, ketone, carboxylic acids, esters, or ethers in combination with acyclic, cyclic, or acyclic / cyclic combination moieties; aza; Not me; -XOn or O-XOn,

20 where X = N and n = 2; X = S and n = 2 or 3; or X = P and n = 1-3; yhalogens; R5, R6, R7 and R8 are each independently selected from:

image 1

or -OR-, where Y is optional and is the same as defined above for R1; and R10 is the same as defined above for R1, or when Y is absent, R10 is = O; and R9 is a residue having the formula D), E), F), G) or H):

image 1

where each of R11-R17 is independently the same as defined above for R5;

image 1

where R18, R19 and R20 are independently selected from

image 1

10 and n = 1 to 4.

Accordingly, the inhibition of angiogenesis in a mammal is described by administering a

therapeutic composition comprising one of the compounds described above in a sufficient dose

to inhibit angiogenesis.

The compound may have the formula B), where R5 and R6 are selected from the group consisting of:

image 1

and R9 has the formula F) or H); and R14 and R16 are selected from the group consisting of:

image 1

where R21 is -H, -CH3, or -OH. Specific preferred compounds include thalidomide, its precursors, metabolites and the like. Particular analogs include EM-12, N-phthaloyl-DL-glutamic acid (PGA) or N-phthaloyl-DL20 glutamine anhydride. Examples of compounds that are members of this genus are listed in Figures 1 to 3.

Compounds of the following formula that have antiangiogenic properties:

image2

The inhibition of angiogenesis in a mammal by administering a compound according to the

previous formula in a dosage sufficient to inhibit angiogenesis. Examples of specific compounds that

They are members of this genus are presented in Figure 4.

Thalidomide hydrolysis products of angiogenesis inhibitors having the following general formula may be used:

image 1

10 where X is R6 as defined above, or

image 1

and R25 and R26 are, independently, -OH, -H, or NH2, and n = 1 to 4. Examples of such compounds are shown in Figure 5.

Angiogenesis inhibitor compounds having the following general formula may be used:

image3

wherein R is selected from the group consisting of hydrogen, alkyl radicals of 1 to 6 carbon atoms, the phenyl radical, and the benzyl radical; wherein R 'is selected from the group consisting of the phthalimido radical and the radical is CH2 or C = O; and where R "is H, -CH2CH3, -C6H5, -CH2C6H5, -CH2CH = CH2, or

and hydrolysis products of the compounds in which R "is H and the piperidino ring or both piperidino and imido rings are hydrolyzed.

Another series of compounds are the thalidomide epoxides, EM-12 and EM-138. Representative epoxy compounds are shown below:

image4

image 1

It should be understood that the epoxide can be attached at the 6.1 site in the benzene ring, the 1.2 site, the site

2.3, site 3.4 or site 4.5. The epoxides of thalidomide, EM-12, and EM-138 can be hydrolyzed to the compounds

following:

image 1

image 1

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It should be understood that the hydroxyl group may be located at carbons 1, 2, 3, 4, 5 and 6 of the benzene ring. Dihydroxy compounds are also contemplated in which the two hydroxyl groups are located in a bis position with respect to each other at carbons 1, 2, 3, 5 and 6 of the above compounds. All epoxides, hydrolysis products of epoxides, and hydrolysis products of thalidomide are contemplated.

It is known that epoxides are hydrolyzed by a group of enzymes known as epoxy hydrolases. There is a class of compounds that are epoxy hydrolase inhibitors. Examples of these compounds are valpromide (2-propylpentanamide) and valproic acid (2-propylpentanoic acid). Since epoxides are important inhibitors of angiogenesis, compositions comprising any of the angiogenesis inhibitor compounds cited herein in combination with epoxyhydrolase inhibitors are contemplated. Epoxide hydrolase inhibitors can be administered to a human or animal together or sequentially. The epoxide group seems to be an important substituent common to several angiogenesis inhibitors. The use of epoxide hydrolase inhibitors to enhance the activity of any angiogenesis inhibitor containing an epoxide is contemplated as part of the present invention. For example, epoxy hydrolase inhibitors can be administered with the following epoxy-containing anti-angiogenesis compounds: AGM 1470, Eponimycin, microbial metabolites of Scolecobasidium arenarium designated f / 2015, fr / 111142 and fr / 18487. See Oikawa, Biochem. Biophys Res. Comm, Vol. 81: 1070 (1971) and Otsuka J. Microbial. Biotech., Vol. 1: 163 (1991).

The use of epoxy-containing angiogenesis inhibitors with or without epoxy hydrolase inhibitors is contemplated as a treatment of diseases mediated by elevated or toxic levels of TNF-a. TNF-a has been recognized as a manifestator of a dose-dependent toxicity. If present at low levels for a long period of time, TNF-a may result in cachexia. Cachexia is a general loss of weight and muscle mass that occurs in the course of some chronic diseases such as cancer, opportunistic AIDS infections, inflammatory diseases, parasitic diseases, tuberculosis, and high-dose therapy of IL-2. Epoxy-containing angiogenesis inhibitors, with or without epoxy hydrolase inhibitors, are also effective in the treatment of diseases such as septic shock, leprosy and reverse rejection disease.

For example, other compounds causing dysmelia can be used in accordance with the present invention, e.g. 4-methylphthalic acid, pyridoxine, vasopressin, acetazolamide, or a compound having the following formula (where R = H, -OH, or -CH3):

image 1

Other compounds that are teratogens, such as valproic acid (2-propylpentanoic acid), retinoids, such as cis-retinoic acid, and rifampin can also be used in accordance with the invention.

In summary, the preferred compounds are thalidomide, as well as analogs, hydrolysis products, metabolites and thalidomide precursors that are teratogenic, and, more specifically, that cause dysmelia. However, it should be understood that it is not necessary for a compound to have both teratogenic activity and angiogenesis inhibitory activity to be considered as part of the present invention. The compounds causing dysmelia can be identified by the general procedures of Helm, Arzneimittelforschung, 31 (i / 6): 941-949 (1981), in which rabbit pups are examined after exposure to the compound in the uterus. The compounds can generally be purchased, e.g., from Andrulis Pharmaceuticals, Beltsville, MD, or synthesized according to known procedures; It should be understood that the compounds of the present invention may exist as enantiomers and that they are considered the racemic mixture of enantiomers or isolated enantiomers. Many of the

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Four. Five

Compounds contemplated may be enriched in optically active enantiomers of the compounds specified above. Specifically, Blaschke has reported that S-enantiomers may be disproportionately responsible for the dysmelia-producing effect of these compounds. See generally Blaschke, Arzneimittelforschung, 29: 1640-1642 (1979). The articles cited above generally describe procedures for obtaining optically active preparations of the compounds of interest. See, e.g. Shealy et al., Chem. Indus. 1030 (1965); and Casini et al., Farmaco Ed. Sci. 19: 563 (1964).

The inhibition of angiogenesis and the treatment of angiogenesis-dependent diseases by administration of anti-inflammatory compounds, either alone or in combination with other angiogenesis inhibitor compounds, such as those described above, are also described. These anti-inflammatory compounds may be steroids or non-steroidal anti-inflammatory drugs (NSAIDs). Examples of steroids that can be used in the invention include, but are not limited to, cortisone, cortisol, corticosterone, hydrocortisone, hydrocortisol, prednisone, prednisolone, dexamethasone, beclomethasone, betamethasone, mometasone, mometasone-furoate, budesonide, triamcinolone, acetonidozone . Preferred steroids are prednisone, hydrocortisone, cortisol, dexamethasone, betamethasone, and beclomethasone. Especially preferred steroids are hydrocortisone, dexamethasone, and betamethasone.

Examples of NSAIDs that may be used include, but are not limited to, aspirin, acetaminophen, ibuprofen, esculetin, phenyidone, quercetin, ketoprofen, nordihydroguayretic acid (NDGA), sulindac, sulindacsulfone, sulindac-sulfide, indomethacin, NS-398 (an inhibitor of cyclooxygenase-2), inhibitors of cyclooxygenase-1, methylheptyl-imidazole, sodium furegrelate, SKF525AHCL, thromboxane inhibitors, toradol, ECASA, salsalate, diflunisal, mefenamic acid, naproxen, naproxen-sodium, floctafenone, meclofenabutane, meclofenabutane, meclofenabutane, phecliphenazone, meclofenabenone, meclofenabenone, meclofenabenone, meclofenabutane, phenylobutaone, meclofenabenone, meclofenabenone, meclofenabutane, phenylobutaone, meclofenabenone, meclofenabuone , diclofenac, etodolac, fenoprofen, flufenamic acid, flurbiprofen, pyrprofen, tolmetine, apazone, fenbufen, nabumetone, oxaprozin, piroxicam, salicylate, and tenoxicam. Preferred NSAIDs are sulindac, sulindac-sulfone, sulindac-sulfide, indomethacin, NS-398, methylheptyl-imidazole, sodium furegrelate, and SKF525AHCL. Especially preferred NSAIDs are indomethacin and sulindac.

Sulindac, which includes (Z) -5-fluoro-2-methyl-1 - [[4- (methyl-sulfinyl) phenyl] -methylene] -1H-indene-3-acetic acid, or cis-5-fluoro acid -2-methyl-1- [p- (methylsulfinyl) -benzylidene] -indene-3-acetic, has the following structure:

image 1

Such compounds can be used to treat diseases dependent on angiogenesis. Such compounds can be used alone or in combination with other angiogenesis inhibitor compounds to treat angiogenesis-dependent diseases, such as cancer.

The compounds described above can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art. These formulations can be administered by standard routes. In general, the combinations can be administered by the topical, transdermal, oral, rectal or parenteral route (e.g., intravenous, subcutaneous or intramuscular). Additionally, the combinations can be incorporated into biodegradable polymers that allow sustained release of the compound, the polymers being implanted in the vicinity of where drug delivery is desired, for example, at the site of a tumor. Biodegradable polymers and their use are described, for example, in detail in Brem et al., J. Neurosurg. 74: 441-446 (1991).

The dosage of the compound will depend on the condition in question, the particular compound, and other clinical factors such as the weight and condition of the human or animal and the route of administration of the compound. It should be understood that the present invention has application for both human and veterinary use. For oral administration to humans, a dosage between about 0.1 and 300 mg / kg / day, preferably between about 0.5 and 50 mg / kg / day, and most preferably between about 1 and 10 is generally sufficient. mg / kg / day

The formulations include those that are suitable for oral, rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including oral and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal, and epidural).

The formulations can be conveniently presented in unit dosage form and can be prepared by conventional pharmaceutical techniques. Such techniques include the step of associating the active ingredient and the pharmaceutical carrier or excipients. In general, the formulations are prepared by uniformly and intimately associating the active ingredient with liquid vehicles or finely divided solid vehicles or both, and then, if necessary, forming the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, seals or tablets containing in each case a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid oil-in-water emulsion or a water-in-oil emulsion and as a bolus, etc.

A tablet can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compression, in a suitable machine, of the active ingredient in a form that flows by itself such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded molded tablets can be produced in a suitable machine of a mixture of the powdered compound wetted with an inert liquid diluent. The tablets may be optionally coated or grooved and can be formulated so as to provide a slow or controlled release of the active ingredient contained therein.

Formulations suitable for topical administration in the mouth include kneecaps comprising the ingredients in a flavored base, usually sucrose and gum arabic or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic; and oral elixirs that comprise the ingredient to be administered in a suitable liquid vehicle.

Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in an acceptable pharmaceutical vehicle. A preferred topical delivery system is a transdermal patch that contains the ingredient to be administered.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for nasal administration, in which the vehicle is a solid, include a coarse-grained powder having a particle size comprised, for example, in the range of 20 to 500 micrometers that is administered in the manner in which it is administered. the snuff, that is, by rapid inhalation through the nasal passage from a container of the powder kept very close to the nose. Suitable formulations, in which the vehicle is a liquid, for administration, such as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for vaginal administration may be presented as pessaries, Tamports, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, vehicles such as those known in the art as appropriate.

Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostatic and solute agents that make the isotonic formulation with the blood of the proposed recipient; and sterile aqueous and non-aqueous suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in freeze-dried conditions (lyophilized) that require only the addition of the sterile liquid vehicle, for example, water for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the class described previously.

Preferred unit dosage formulations are those that contain a daily dose or unit, or daily sub-dose of the administered ingredient, as set forth herein, or an appropriate fraction thereof.

It should be understood that, in addition to the ingredients mentioned particularly above, the formulations of the present invention may include other conventional agents in the art that are related to the type of formulation in question, for example, those that are suitable for oral administration may include agents. flavorings

Diseases associated with neovascularization of the cornea that can be treated include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A deficiency, excessive use of lenses of contact, atopic keratitis, upper limbic keratitis, dry keratitis of the pterygium, Sjögren's syndrome, acne rosacea, filectenulosis, syphilis, Mycobacterial infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes symplex infections, Herpes simplex infections zoster, protozoal infections, Kaposi's sarcoma, Mooren's ulcer, marginal degeneration of Terrien, marginal keratolysis, trauma rheumatoid arthritis, systemic lupus, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, penfigoid and rejection of grafts of cornea

Diseases associated with retinal / choroidal neovascularization that can be treated include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, elastic pseudoxanthoma, Paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, uveitis / chronic vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, Eales disease, Behcet disease, infections causing retinitis or choroiditis, supposed ocular histoplasmosis, Best's disease, myopia, optical wells disease Stargardt, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications. Other diseases include, but are not limited to, diseases associated with rubeosis (neovascularization of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.

With the compositions and methods described, diseases associated with chronic inflammation can be treated. Diseases with symptoms of chronic inflammation include inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis and rheumatoid arthritis. Angiogenesis is a key element that these chronic inflammatory diseases have in common. Chronic inflammation depends on the continuous formation of hair buds to maintain the influx of inflammatory cells. The influx and presence of inflammatory cells produce granulomas and, thus, maintain the chronic inflammatory state. Inhibition of angiogenesis by the compositions and methods of the present invention could prevent granuloma formation and alleviate the disease.

The compositions and methods can be used to treat patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Both Crohn's disease and ulcerative colitis are characterized by chronic inflammation and angiogenesis at various sites of the gastrointestinal tract. Crohn's disease is characterized by chronic granulomatous inflammation throughout the gastrointestinal tract consisting of new hair buds surrounded by a cylinder of inflammatory cells. The prevention of angiogenesis by the compositions and methods of the present invention inhibits the formation of outbreaks and prevents the formation of granulomas.

Crohn's disease occurs as a transmural chronic inflammatory disease that in most cases affects the distal ileus and the colon, but can also occur anywhere in the gastrointestinal tract from the mouth to the anus and the perianal area. Patients with Crohn's disease generally have chronic diarrhea associated with abdominal pain, fever, anorexia, weight loss and abdominal swelling. Ulcerative colitis is also a chronic, nonspecific, inflammatory and ulcerative disease that originates in the mucosa of the colon and is characterized by the presence of bloody diarrhea.

Inflammatory bowel diseases also exhibit extraintestinal manifestations such as skin lesions. Such lesions are characterized by inflammation and angiogenesis and can occur in many different sites of the gastrointestinal tract. The compositions and methods of the present invention are also capable of treating these lesions by preventing angiogenesis, thereby reducing the influx of inflammatory cells and the formation of lesions.

Sarcoidosis is another chronic inflammatory disease that is characterized as a multisystemic granulomatous disorder. Granulomas of this disease can appear anywhere in the body and, therefore, the symptoms depend on the site of the granulomas and whether the disease is active. Granulomas are caused by angiogenic hair buds that provide a constant supply of inflammatory cells.

The compositions and methods described can also treat the chronic inflammatory conditions associated with psoriasis. Psoriasis, a skin disease, is another chronic and recurrent disease characterized by papules and plaques of various sizes. The prevention of the formation of the new blood vessels necessary to maintain the characteristic lesions leads to the relief of symptoms.

Another disease that can be treated is rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory disease characterized by nonspecific inflammation of the peripheral joints. It is believed that blood vessels in the synovial lining of the joints suffer angiogenesis. In addition to forming new vascular networks, endothelial cells release reactive oxygen chemical factors and species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis can actively contribute to, and help maintain the chronically inflamed state of rheumatoid arthritis.

Other diseases that can be treated are hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood-borne tumors, and acquired immunodeficiency syndrome.

The compositions and methods of the present invention include the use of angiogenesis inhibitor compounds and anti-inflammatory compounds, such as steroids or non-steroidal anti-inflammatory drugs (NSAIDs). The compositions and methods of the present invention include the combination of compounds

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angiogenesis inhibitors, such as thalidomide or thalidomide-like analogs or AMG-1470, EM-12 or EM138 with anti-inflammatory compounds, such as steroids or non-steroidal anti-inflammatory drugs (NSAIDs). The compositions and methods of the present invention also include the use of anti-inflammatory compounds alone. These compositions can be used to treat angiogenesis-dependent diseases.

For example, indomethacin (5 mg / kg) has been found to inhibit bFGF-induced angiogenesis in 59% and VEGF-induced angiogenesis in 61%. Similarly, sulindac (25 mg / kg) has been found to inhibit bFGF-induced angiogenesis by 50% and VEGF-induced angiogenesis by 55%. Sulindac is metabolized in vivo to give two metabolites: sulindac-sulfide and sulindac-sulfone. Sulindac-sulfide actively inhibits the synthesis of prostaglandins, while sulindac-sulfone does not; however, both have been found to be angiogenesis inhibitors. Sulindac-sulfide was found to inhibit bFGF-induced neovascularization by 34%, and sulindac-sulfone exhibited 31% inhibition.

It has also been found that other NSAIDs inhibit neovascularization associated with angiogenesis. For example, carbomethylheptyl-imidazole and sodium furegrelate, both thromboxane inhibitors, inhibit bFGF-induced neovascularization by 32% and 22%, respectively. It was found that another thromboxane inhibitor, SKF525AHCL, which promotes the production of prostaglandins, inhibits bFGF-induced neovascularization by 25%. The specific cyclooxygenase-2 inhibitor, NS-398, also inhibited bFGF-induced neovascularization by 25%.

When sulindac is combined with thalidomide, an additive effect is produced in the inhibition of angiogenesis. When sulindac is combined with other angiogenesis inhibitor compounds, such as AMG 1470, EM-12 or EM-138, there is an additive effect in the inhibition of angiogenesis. Angiogenesis in the eye, in the test described in Example 2, is produced by the presence of bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor). Inhibition of said angiogenesis was demonstrated with NSAIDs, steroids, thalidomide, or the combination of thalidomide and an NSAID, sulindac.

AGENT

 DOSE bFGF1 VEGF2

Aspirin

 100 mg / kg 8 -

Acetaminophen

 100 mg / kg 0 0

Ibuprofen

 20 mg / kg 7 eleven

Hydrocortisone

 20 mg / kg fifty 40

Sulindac

 25 mg / kg 52 54

Thalidomide

 200 mg / kg 42 44

Thalidomide + Sulindac

200 mg / kg (tal) + 25 mg / kg (sulindac) 65  74

AGM 1470

30 mg / kg qod 48

AGM 1470 + Sulindac

30 mg / kg qod (AGM) + 25 mg / kg (Sulindac) 70

1% inhibition of bFGF-induced angiogenesis

2% inhibition of VEGF-induced angiogenesis

VEGF inhibition in 74% demonstrates the additive effect when thalidomide and sulindac are combined. Data for hydrocortisone, sulindac, thalidomide and thalidomide + sulindac differ significantly from the controls (p <0.0001). Studies with the composition comprising thalidomide and sulindac on V2 carcinoma in rabbits have demonstrated a T / C value (treated to control ratio) of 0.32 after 18 days of oral treatment with 200 mg / kg of combined thalidomide with 25 mg / kg sulindac.

An additive effect is also observed in the combination of non-steroidal anti-inflammatory drugs and other angiogenesis inhibitor compounds such as the combination of sulindac and AGM-1470. AGM-1470 is a known angiogenesis inhibitor compound as set forth in Brem et al. Minimal drug resistance occurs after prolonged antiangiogenic therapy with AGM-1470, Surgical Forum 45 (0), 1994, pp 674-677, incorporated herein by reference. As shown in the table above, sulindac plus AGM-1470 exhibits an inhibitory effect on angiogenesis greater than any of the compounds separately.

Example I

The chicken embryo chorioallantoic membrane assay described by Crum et al., Science 230: 1375 et seq. (1985) is used to identify compounds that do not require further metabolic conversion. See also U.S. Patent 5,001,116, which describes the CAM test in col. 7 of the patent. Briefly, fertilized chicken embryos were removed from its shell on day 3 or 4, and a methylcellulose disk containing the compound was implanted in the chorioallantoic membrane. The embryos were examined 48 hours later and, if a clear area devoid of vessels around the methylcellulose disk appeared, the diameter of that area was measured.

Example II

Angiogenesis assay in rabbit cornea

Pellets for implantation in rabbit corneas were prepared by mixing 110 µl of saline solution containing 12 µg of recombinant bFGF (Takeda Pharmaceuticals-Japan) with 40 mg of sucralfate (Bukh Meditec-Denmark); this suspension was added to 80 µl of 12% Hydron (Interferon Sciences) in ethanol. 10 µl aliquots of this mixture were then pipetted onto Teflon chips and allowed to dry, yielding approximately 17 pellets. A pellet was implanted in the corneal microbags of each eye of an anesthetized New Zealand female white rabbit, 2 mm from the limbus, followed by topical application of erythromycin ointment on the corneal surface. The animals were fed daily from the second day after implantation by gastric lavage with drug suspended in 0.5% carboxymethyl cellulose or 0.5% carboxymethyl cellulose alone. Thalidomide was purchased from Andrulus Pharmaceutical (Maryland) and EM-12 and Supidimide were kindly provided by Grunenthal GMBH (Germany). The animals were examined with a slit lamp on alternate days in a masked manner by the same cornea specialist. The area of neovascularization of the cornea was determined by measuring the length of the vessel (L) with a reticulum from the limbus and the number of hours (C) of the limbus involved. A formula was used to determine the area of a circular band segment: C / 12 * 3.1416 [r2- (r-L) 2] where r = 6 mm is the measured radius of the rabbit's cornea. Various mathematical models were used to determine the magnitude of the vascularized cornea, and it was found that this formula provides the most accurate approximation of the area of the neovascularization band that grows toward the pellet.

It is important to indicate that the rabbit cornea test is preferable because it will generally recognize compounds that are inactive per se but that are metabolized to provide active compounds. It is known that thalidomide-related compounds, as shown below in Example III, are teratogenic and are candidates for use in the present invention.

Example III

Inhibition of bFGF-induced corneal neovascularization by thalidomide and related analogues expressed as a percentage of the median control after 8 days

Pellets containing bFGF and sucralfate were implanted in the microbags of both rabbit corneas according to Example II. The internal growth of vessels in the transparent cornea from the limbus was observed for the first time on day 2 and the treatments (200 mg / kg orally) were started on that day. The area of corneal neovascularization was measured from day 4 to day 12. The eighth day measurements were used for comparison between groups. No regression of the vessels was observed and a quasi-maximal neovascularization was observed at that time. Statistical analysis was performed with ANOVA with data classified by ranges to account for interexperimental variation and prevent against non-normal distribution of the data (ie aberrant results) using a non-parametric method.

The compounds tested were the following:

image 1

image 1

Treatment with a dose (200 mg / kg) of thalidomide resulted in an inhibition of the vascularized area of the cornea that was between 30 and 51% in three experiments with a median inhibition of 36% (Figure 6) (n = 30 eyes, p = 0.0001, 2-way ANOVA with data classified by ranges). Inhibition of thalidomide angiogenesis was observed after only two doses (Figure 7). The rabbits showed no obvious sedation and there was no sign of toxicity or weight loss. The teratogenic analog EM-12, which shares the other properties of thalidomide, was also inhibitor, with a median inhibition of 42% (n = 10 eyes, p = 0.002, 1-way ANOVA with data classified by ranges). The supidimide, a non-teratogenic analog of thalidomide that retains the sedative properties of thalidomide, exhibited no activity (area 107% of the control, n = 10 eyes, statistically not different from the control). Other analogs, PGA and PG acid exhibited weaker inhibitory effects than thalidomide (data not shown). The internal growth density of vessels in animals treated with thalidomide was also markedly reduced.

Example IV

EM-12 assay in rabbit cornea

EM-12 was evaluated in the rabbit cornea test described in Example II at 100 mg / kg / day and exhibited 21% inhibition, and at 200 mg / kg / day the test exhibited 43% inhibition.

Example V

Phthaloyl-glutamic acid in CAM

Phthaloyl-glutamic acid was evaluated in the CAM test described above and exhibited an area devoid of vessels with a moderate scale.

Example VI

Phthaloyl-glutamic acid test in rabbit cornea

The phthaloyl-glutamic acid described above at 200 mg / kg exhibited 29% inhibition of angiogenesis.

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Example VII

Test of phthaloyl glutamic anhydride in CAM

Phthaloyl-glutamic anhydride was tested in the CAM test described above and exhibited an area devoid of vessels.

Example VIII

Crohn's disease treatment

A 32-year-old woman suffering from Crohn's disease was treated using the methods of the present invention. The patient had the characteristic symptoms of Crohn's disease, namely severe gastrointestinal complication (including diarrhea and cramps) and a large skin lesion in the lower leg. Thalidomide was administered orally to the woman at a dose of 100 mg twice daily. After continued treatment for a week, gastrointestinal symptoms, including diarrhea and cramps, were relieved and the skin lesion resolved.

Example IX

Test of the corneal microbags

Male C57B16 mice, 6 to 8 weeks old, were obtained from Jackson Laboratories, MA. Mice were anesthetized, and 0.4 x 0.4 mm bags were made in the stroma of the cornea of the mice adjacent to the limbus. Pellets containing 80 ng of bFGF or VEGF were implanted in the pellets (sic). Pellets containing bFGF were implanted 1.0-1.2 mm from the limbic vessels, while pellets containing VEGF were implanted at 0.50.7 mm from the limbic vessels. Erythromycin was applied topically.

Mice were then treated with varying doses of anti-inflammatory drugs as shown in the following table. The vascular response to the pellets was measured by the maximum length of the vessels and the number of hours of neovascularization 5 days after the implantation of the bFGF pellets and 6 days after the implantation of the VEGF pellets. The corneal neovascularization area was calculated using the following formula that was optimally close to the neovascularization area: Area (mm2) =: [π x hours x length (mm) x 0.2 (mm)]. The results are shown in the following table:

AGENT

 DOSE bFGF1 VEGF2 + n P value

Acetaminophen

100 mg / kg 0 - 8 ns

Aspirin

 10-160 mg / kg 0-11 - 8 ns

NDGA

25 mg / kg 30 - 8 ns

Rifle

 200 mg / kg fifteen - 8 0.02

Phenidone

100 mg / kg 17 - 8 <0.01

Quercetin

300 mg / kg 18 - 8 <0.01

Ibuprofen

 25 mg / kg 6 8 23/8 ns / ns

Ketoprofen

 80 mg / kg 30  41 8/8 <0.01

Indomethacin

 5 mg / kg 59 61 15/21 <0.01 / <0.01

Sulindac

25 mg / kg fifty 55 15/15 <0.01 / <0.01

1% Inhibition of bFGF-induced angiogenesis

2% inhibition of VEGF-induced angiogenesis

The inhibitory effect is expressed as a percentage representing the area of neovascularization of the cornea by bFGF or VEGF compared to the controls (n = 8 / experiment) of the experiments in which said particular drug was tested. N = the number of eyes that were tested, and the drugs were administered once daily by sc, ip or oral route as described.

Example X

Male C57B16 mice were obtained 6 to 8 weeks from Jackson Laboratories, MA. Mice were anesthetized, and 0.4 x 0.4 mm bags were made in the stroma of the cornea of the mice adjacent to the limbus. Pellets containing 80 ng of bFGF or VEGF were implanted. Pellets containing bFGF were implanted 1.0-1.2 mm from the limbic vessels, while pellets containing VEGF were implanted 0.5-0.7 mm from the limbic vessels. Erythromycin was applied topically.

Mice were then treated with thalidomide, indomethacin, sulindac, or combinations of thalidomide with indomethacin or sulindac. The vascular response to the pellets was measured by the maximum length of the vessels and the number of hours of neovascularization 5 days after the implantation of the bFGF pellets and 6 days after the implantation of the VEGF pellets. The corneal neovascularization area was calculated using the following formula that best approximates the neovascularization area: Area (mm2) = [π x hours x length (mm) x 0.2 (mm)]. The results are shown in the following table.

AGENT

 DOSE bFGF1  VEGF2  n

Thalidomide

 200 mg / kg 41 40 31/39

Indomethacin

 5 mg / kg 59 61 15/21

Sulindac

 25 mg / kg fifty 55 15/15

Thalidomide + Indomethacin

200 mg / kg + 5 mg / kg 67 61 15/21

Thalidomide + Sulindac

200 mg / kg + 25 mg / kg 633 743 15/16

1% Inhibition of bFGF-induced angiogenesis

10 2% Inhibition of VEGF-induced angiogenesis

3 The inhibitory effect is significantly different from that of any agent separately (p <0.01, tested by ANOVA).

The inhibitory effect is expressed as a percentage representing the area of neovascularization of the cornea by

15 bFGF or VEGF compared to the controls (n = 8 / experiment) of the experiments in which said particular drug was tested. N = the number of eyes that were tested, and the drugs were administered only once a day by sc, ip or oral route as described.

Example XI

Male C57B16 mice were anesthetized for 6 to 8 weeks, obtained from Jackson Laboratories, MA, and 0.4 x 0.4 mm bags were made in the stroma of the cornea of the mice adjacent to the limbus. Pellets containing 80 ng of bFGF were implanted 1.0-1.2 mm from the limbic vessels. Erythromycin was applied topically.

Mice were then treated with sulindac, or one of sulindac derivatives, sulindac-sulfone or

sulindac sulfide. The vascular response to the pellets was measured by the maximum length of the vessels and the number of

hours of neovascularization 5 days after implantation of bFGF pellets. The area of

Neovascularization of the cornea was calculated using the following formula that optimally approximates the area of neovascularization: Area (mm2) = [π x hours x length (mm) x 0.2 (mm)]. The results are shown in the following table.

AGENT

 DOSE % inhibition n

Sulindac

 25 mg / kg fifty fifteen

Sulindac sulfide

 25 mg / kg 50 mg / kg 31 34 8 8

Sulindac-sulfone

 25 mg / kg 31 16

The inhibitory effect is expressed as a percentage representing the area of neovascularization of the cornea by

bFGF compared to controls (n = 8 / experiment). N = the number of eyes that were tested, and the

Drugs were administered once a day by sc, ip or oral route as described.

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Example XII

Tumor Assay

White female rabbits from New Zealand, weighing approximately 1.5 kg, obtained from Charles River, MA, were used to spread V2 carcinoma. This tumor is caused by a papilloma induced by the 5 Shope virus. Small 0.5 x 0.5 cm fragments were implanted intramuscularly in the right thigh. Treatment with 200 mg / kg / day of thalidomide (n = 14), 60 mg / kg / day of sulindac (n = 5) or a combination of thalidomide and sulindac (n = 10) was started on day 10 after tumor implantation, when the average tumor volume was 6 cm3. Control animals (n = 13) were treated with methylcellulose. The rabbits were sacrificed 17 days after the start of treatment when the average volume of control tumors was 100 cm3. The 10 results of this experiment (Figure 8) indicate that the combination of thalidomide and sulindac is more effective in reducing the size of V2 carcinoma tumors than thalidomide or sulindac alone. The combination of thalidomide and sulindac inhibited tumor growth by 75% and was significantly different (p <0.05) from any agent alone or from the control group. Oral treatment with sulindac or thalidomide inhibited tumor growth by, respectively, 35% (n = 5, p <0.01) and 55% (n = 14, p <0.01). The data was collected in 3

15 separate experiments and each bar represents the standard error of the average value.

Claims (7)

1.- Thalidomide and dexamethasone for use in the treatment of a tumor carried by blood, where thalidomide and dexamethasone are administered to a human or animal together. 2. Thalidomide and dexamethasone for use in the treatment of a tumor carried by blood, where thalidomide and dexamethasone are administered sequentially to a human or animal. 3.- Thalidomide and dexamethasone for use in the treatment of a solid tumor, where thalidomide and dexamethasone are administered to a human or animal jointly or sequentially. 4. Thalidomide and dexamethasone, according to any of the preceding claims, wherein the amount of thalidomide is 0.1 to 300 mg / kg / day. 5. Thalidomide and dexamethasone according to any of claims 1 to 3, wherein the amount of thalidomide is 0.5 to 50 mg / kg / day. 6. Thalidomide and dexamethasone, according to any of claims 1 to 3, wherein the amount of thalidomide is 1 to 10 mg / kg / day. 7. Thalidomide and dexamethasone, according to any of claims 1 to 3, wherein thalidomide 15 and dexamethasone should be administered parenterally. 8. Thalidomide and dexamethasone, according to any of claims 1 to 3, wherein thalidomide and dexamethasone should be administered orally.