CA2146988A1 - Treatment of cachexia and inhibition of il-6 activity - Google Patents

Treatment of cachexia and inhibition of il-6 activity

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Publication number
CA2146988A1
CA2146988A1 CA002146988A CA2146988A CA2146988A1 CA 2146988 A1 CA2146988 A1 CA 2146988A1 CA 002146988 A CA002146988 A CA 002146988A CA 2146988 A CA2146988 A CA 2146988A CA 2146988 A1 CA2146988 A1 CA 2146988A1
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cachexia
suramin
sulfate
infection
result
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Gideon Strassmann
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/02Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
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Abstract

The present invention relates to methods for treating cachexia in a patient and inhibiting IL-6 bioactivity. This is accom-plished by administering to a patient an effective amount of a sulfate-containing compound, for example, suramin, a derivative of suramin, Pentosan polysulfate, or Dextran sulfate. The present invention is also effective in combating IL-6 related diseases.

Description

W 0 94/08574 2 1 ~ 6 9 8 ~ P ~ /US93/09527 FIELD OF INVENTION
The present invention relates to a method for treating cachexia in a patient, particularly a human being, and a method for the inhibition of IL-6 activity.
BACKGROUND OF THE INVENTION
Cachexia, a potentially lethal syndrome afflicting mammals, frequently complicates the treatment of infection, inflammation and cancer. It is characterized by profound weight loss caused by wasting of body fat (adipose) and muscle (protein). Tracey et al., J. EXP. Med., Vol. 167, 1211-1227 (Mar. 1988). Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982). Anorexia, anemia, and weakness may also occur in cachexia. Tracey et al., suPra. Cachexia may further be characterized by, inter alia, depression of glucose level (hypoglycemia) and elevation of triglyceride level (hypertriglyceridemia).
Cachexia may result from diverse causes such as age, cancer, and infections by parasites and by microorganisms such as bacteria, fungi, viruses and protozoa. Both acute and chronic infections or illnesses frequently cause cachexia. In fact, most chronic, fatal, nonneoplastic diseases terminate in cachexia (e.g. chronic disseminated infections, or prolonged insufficiency of heart, lungs, liver, kidneys, or the small intestines). Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982). Moreover, the syndrome is not alleviated by adequate caloric uptake. Indeed, weight loss may continue in cachexia even while an adequate diet is consumed. Silva et al., J. General Microbioloqy, Vol. 134, 1629-1633 (1988).
Researchers have studied cachexia induced by microbial infections, and by parasitic infections such as trypanosomiasis and leishmaniasis. Sherry et al., J. Cell Bioloqy, Vol. 107, 1269-1277 (Oct. 1988). The study of cachexia induced by microbial infections has shown that the syndrome may result from either the direct effect of the microorganism or from a toxin produced by the microorganism.

~ ~9~S - 2 - --.

Indeed, the toxin produced by a microorganism has been used to create a model for the study of cachexia. In this regard, cachexia has been induced by intraperitoneal injection into mice of trehalose dimycolate (TDM) isolated from Nocardia asteroides. Silva et al., J. General Microbioloqy, Vol. 134, 1629-1633 (1988). Researchers have studied the mechanism by which TDM, also known as cord factor (CF), a toxic glycolipid from mycobacteria, induces cachexia.
Silva et al., Infection and ImmunitY, Vol. 56, No. 12, 3067-3071 (Dec. 1988). That laboratory observed that administra-tion of CF markedly reduced body weight: the animals became severely wasted and exhibited hypertriglyceridemia, hypoglycemia, and high levels of tumor necrosis factor in plasma. Dexamethasone was found to partially inhibit the cachexia-inducing action of CF.
Recent research has focused on the physiology related to cachexia. For example, the increase in circulating triglycerides observed has been attributed to systemic suppression of lipoprotein lipase (LPL). Tracey et al., J.
ExP. Med., Vol. 167, 1211-1227 (Mar. 1988). It has been reported, however, that transplantable adenocarcenoma of the colon (MAC16) produces cachexia symptoms without concomitant hypertriglyceridemia. Mahony et al., Br. J. Cancer, 57, 385-389 (1988).
It has also been suggested that tumor necrosis factor, hereinafter "TNF", also known as cachectin", Beutler et al., Advances in Immunoloqy, Vol. 42, 213-231 (1988), may play a central role in cachexia. Tracey et al., J. ExP. Med., vol.
167, 1211-1227 (Mar. 1988). Michie et al., Surqery, Vol.
104, No. 2, 280-286 (Aug. 1988), reports that TNF may represent the primary stimulus that initiates many of the metabolic responses associated with sepsis and endotoxemia.
The role of TNF, however, is not clear. Although cachexia in cancer patients has been associated with the presence of TNF, this factor has not been uniformly detectable in the serum of cachectic patients with cancer.
Sherry et al., The FASEB J., Vol. 3, 1956-1962 (June, 1989).

W094/08574 2 1 ~ ~ 9 8 ~ PCT/US93/~527 In one study, using both cachexia-inducing (MAC16) and non-cachexia-inducing (MAC13) adenocarcinomas, researchers concluded that weight loss produced by TNF arises from an anorexic effect that differs from the complex metabolic changes associated with cancer cachexia. Mahony et al., Br.
J. Cancer, 57, 385-389 (1988). Similarly, in a study on viral-related cachexia, using mice infected persistently with lymphocytic choriom~ningitis virus (LCMV), the laboratory concluded that the greater than 20% cachexia-like weight loss observed was apparently not associated with a measurable increase in TNF. Lathey et al., Am. J. Pathol., 132(3):586-92 (Sep. 1988).
The severe weight loss and debilative wasting of lean body mass of cachexia frequently complicates the treatment of patients suffering from malignancy or chronic infection.
Indeed, cachexia contributes to cancer mortality. Some data indicate that as many as 30% of cancer patients die from cachexia, rather than tumor burden. Tracey et al., suPra.
One medical textbook notes that:

"[t]he most common way in which malignancy leads to death is cachexia: the development of progressive weakness, weight loss, and wasting. Usually, there is a close correlation between the amount of malignant disease present and the severity of cachexia... In this weakened state, cancer patients are particularly susceptible to terminal infections, such as pneumonia, which often precipitates death." van Eys, Ann. Rev.
Nutr., 5:435-61 (1985) (based on the second edition of Robbins' Text~ook o f Pa thol ogy) .
The severity of cachexia may be unrelated to tumor size or parasite load, and profound wasting has been observed in patients with tumor burdens of only 0.01 to 5.0% body mass.
If not reversed, physiological changes associated with cachexia lead to immunological deficiencies, organ failure, and multiple metabolic abnormalities. Tracey et al., J. Exp.
Med., 167, 1211-1227 (Mar. i988). Theologides, Cancer, May Supp7ement, 43, 2004-2012 (1979).

W094/08574 69~ PCT/US93/09527 The physiological changes due to cachexia decrease the patient's tolerance to chemotherapy and radiation therapy, as well as increase the frequency of post-surgical complications. The nausea, vomiting, and anorexia induced by chemotherapeutic agents as well as radiation injury can be very severe. In addition, chemotherapy is a major factor in malnutrition. It is well recognized that therapy is often as debilitating as the cancer itself. The malnourished patient has a much narrower safe therapeutic margin for most oncologic therapy. van Eys, supra.
Further, median survival has been found to be significantly shorter in patients who had lost weight with most types of tumor examined. Lawson et al., Ann. Rev.
Nutr., 2:277-301 (1982).
The precise mechanisms by which the cachexia syndrome may cause death in some patients and perhaps contribute to it in others are not completely understood. Lawson et al., Ann.
Rev. Nutr., 2:277-301 (1982). Thus, the art has co~tinued to search for effective methods for treating cachexia resulting from etiologies such as cancer or infectious diseases.
SUMMARY OF THE INVENTION
The present invention provides a method for treating cachexia, comprising the step of administering to a patient an amount of a sulfate-containing compound, such as suramin or a derivative thereof, effective for said treatment.
The invention contemplates treating all forms of cachexia, whether induced by infection, cancer, age or otherwise.
The present invention also provides a method for the inhibition of interleukin 6 ("IL-6") activity, comprising the step of administering to a patient an amount of a sulfate-containing compound, such as suramin or a derivative thereof, effective for said inhibition.
Additional objects and advantages of the present invention will be set forth in part in the description which follows. It is to be understood that the general description above and the following detailed description are exemplary W094/08574 2 15~ 6 9 ~ 8 PCT/US93/09527 -and explanatory only and do not limit the present invention, as claimed.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 sets forth the time dependent inhibition of C-26 cachexia with the use of suramin.
Figure 2 sets forth the lack of effect of suramin on tumor (C-26) growth in vivo.
Figure 3 sets forth the dose dependent inhibition of C-26 cachexia with the use of suramin.
Figure 4 sets forth the prevention of turpentine-induced wasting with the use of suramin.
Figure 5 sets forth the inhibition of bioactivity of IL-6 with the use of suramin.
Figure 6 sets forth the prevention of the binding of IL-6 to human myeloma cells with the use of suramin in a dose dependent manner.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides a method for treating cachexia resulting from infection, cancer, age or otherwise.
The claimed method can also be used to treat any of the symptoms associated with the cachexia syndrome. Thus, the method of the instant invention may be employed to mitigate or completely eliminate weight loss due to wasting of body fat and muscle, hypertriglyceridemia, hypoglycemia, and anorexia. In addition, the claimed invention may be used to prevent loss of tissue in vital organs. The instant method is particularly useful in treating cachexia due to cancer or chronic infections.
The method of the instant invention may be used, for example, to treat cachexia arising as a result of infection, chronic or otherwise, caused by a unicellular or multicellular parasite, or microbe such as a bacteria, fungus, protozoa or virus, or a combination of these organisms. For example, the present invention contemplates treatment of cachexia due to:

W094/08574 ~69~ 6 - PCT/US93/09527 - infections by gram-negative or gram-positive bacteria, such as gram-positive cocci (pneumococcal, staphylococcal and streptococcal infections), - infections due to gram-negative cocci (meningoccal infections), - infections due to enteric gram-negative bacilli (coliform bacterial infections, typhoid fever, Salmonella infections, Shigella infections, cholera), - infections due to bacteria of the Hemophi 1 us group (pertussis~ influenza bacillus infections), - tuberculosis infections, - fungal infections ( Candida ), - spirochetal and rickettsial infections, viral infections (influenza, hepatitis, Sendai, herpes), and - infections due to protozoa (malaria, leishmaniasis).

The method of the instant invention is also useful in treating cachexia resulting from cancer. Treatment of cachexia resulting from either a TNF- or non-TNF-producing cancer is within the scope of the instant invention. Thus, for example, all forms or cachexia produced by carcinomas or leukemias are treatable by the instant method. Treatment according to the claimed invention will mitigate or totally eliminate the symptoms of cachexia, such as wasting and other physiological changes. This treatment may allow the patient to better tolerate chemotherapy or radiation therapy, W094/08574 2 1 4 6 9 8 8 PCT/US93/~SZ7 _ - 7 -improving the patient's overall prognosis and quality of life.
Further, the present invention inhibits the bioactivity of interleukin 6 ('IL-6"), which is now believed to be a central cause in cachexia, polyclonal B-cell abnormalities or autoimmune diseases, cardiac myxoma, rheumatoid arthritis, Castleman's disease, AIDS, alcoholic liver cirrhosis, proliferative diseases, mesangial proliferative glomerulonephritis, psoriasis, malignancies, plasmacytoma, myeloma, lymphoma, leukemia, and renal cell carcinoma. (See, Hirano et al., J. of ImmunoloqY Today, 11:443-449 (1990) and Hirano et al., Pro. Nat'l. Acad. Sci., U.S.A. 84:228 (1987).) The measurement of the bioactivity of IL-6 is known in the art and can be accomplished by a variety of methods including B-9 assay.
Cachexia is treated and the bioactivity of IL-6 is inhibited by the use of sulfate-containing compounds. The sulfate-cont~ining compounds to be used in the present invention can be any sulfate-containing compound which will inhibit the bioactivity of IL-6 and/or will be effective in the treatment of cachexia as described above.
One example of a sulfate-containing compound that is effective in the inhibition of IL-6 bioactivity and is also effective in the treatment of cachexia is suramin.
The suramin used in the present invention is also known as suramin sodium or 8-8'-[Carbonylbis[imino-3,1-phenylenecarbonyl-imino(4-methyl-3,1-phenylene)carbonylimino]]bis-1,3,5-napntha-lenetrisulfonic acid hexasodium salt. Commercially available suramin is preferred and is known by the tradenames Bayer 205, 309F, Antrypol, Ger~nin~ Moranyl, Naganol, Naganin, and Naphuride Sodium.
Derivatives of suramin can also be used in the present invention. Examples of such derivatives include, but are not limited to, the derivatives described in Baghdiguian et al., Cancer Letters, 60 (1991) pp. 213-219 which is incorporated W094/08574 ~65~ - 8 - PCT/US93/09S27 herein by reference. Other examples of effective sulfate-containing compounds include, but are not limited to, Pentosan polysulfate and Dextran sulfate or a combination of sulfate-containing compounds. Any form of a sulfate-containing compound, for example, suramin or derivatives thereof, Dextran sulfate or Pentosan polysulfate, that provides the desired mitigation or total elimination of cachexia or the inhibition of IL-6 activity is contemplated within the present invention.
According to the methods of the instant invention, sulfate-containing compounds, such as suramin or derivatives thereof, Dextran sulfate and Pentosan polysulfate, may be administered to patients in the commercially obtained form, or may be first formulated into pharmaceutical compositions comprising an effective amount of the sulfate-containing compound and one or more pharmacologically acceptable nontoxic carriers, diluents or adjuvants. Such compositions are, for example, in the form of liquid preparations including solution, suspension, and emulsion preparations.
Such compositions may also be solid preparations given as is or reconstituted to a liquid for use by addition of a suitable carrier.
Pharmaceutical carriers may be sterile liquids, such as water and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients may be used. These compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release formulations and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
Sulfate-containing compounds of the present invention may be administered in the appropriate form according to methods known to those skilled in the art, such as orally, intravenously, subcutaneously, intracutaneously or 2146g88 W O 94/08574 ~`- P(~r/US93/09527 intramuscularly. Intravenously is the preferred method of administration.
It is particularly preferred to administer the sulfate-containing compounds of the present invention, such as the suramin or derivatives thereof, according to the methods of the invention before, as well as after, the onset of cachexia or exposure to the factor giving rise to cachexia.
Persons of ordinary skill in the art will be able to determine the dosage of the sulfate-containing compound effective to achieve the objects of the present invention.
Dosages selected are those which mitigate or completely eliminate the symptoms associated with cachexia (e.g. weight loss) or dosages which inhibit IL-6 activity, which symptoms are familiar to those skilled in the art. Determination of the appropriate dosages for treatment are routinely made by those of ordinary skill in the art and are within the array of tasks routinely performed by them without undue experimentation. While the amount of the sulfate-containing compound, such as suramin or derivatives thereof, to be given in any form is not limited specifically, and can be deter-mined suitably according to the age and sex of the patient, the degree of disease, etc., the sulfate-containing compound, for example, suramin or derivatives thereof, may be administered, for example, at a dose of about 0.01 g to about 10 g per week, wherein a week is understood to be 5-7 days.
The dose may be given once per week or the dose may be divided and given daily, or the dose may be staggered throughout the week, e.g., biweekly, triweekly.
The term 'patient" is used herein in its broadest sense to mean mammals, including humans, as well as other mammals such as farm and laboratory animais, for example, horses, cows, dogs, cats, guinea pigs, mice, and rats.
The present invention is further illustrated by the following examples, which are intended solely to exemplify and not to limit the present invention.

W094/08574 4~9 ~S 1 o PCT/US93/0~27 EXAMPLE 1:
The effects against cachexia using an effective amount of suramin are shown by the example below.
Eleven male mice (CD)2F1 obtained from Charles Rivers Laboratories were weighed and then were inoculated with 0.5 X
106 C-26.IVX cells derived from the colon adenocarcinoma (by the procedure described in Strassmann et al., J. Clin.
Invest., 89, pp. 1681-84 (May 1992) which is incorporated herein by reference). The day of inoculation was identified as day 0 (dO). On days 7 and 13, five of these mice each received intraperitoneally 0.5 ml of PBS (phosphate buffered saline) and the other six mice each received intraperitoneally 200 mg/kg body weight of suramin diluted in 0.5 ml PBS. On day 19, all the mice were sacrificed and the final total weight, the host weight, the tumor weight, epididymal fat, and dry weight were measured. Table 1 sets forth the results. As can be seen from the results, the average percent weight loss for the mice receiving suramin was 12.0 +/- 6.0% while with PBS alone the average percent weight loss of the mice was 30.5 +/- 4.8 ~. Thus, suramin clearly prevented weight loss in comparison to control animals.

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W094/08574 ~9~ - 12 - PCT/US93/~527 EXAMPLE 2:
In subsequent experiments, eight mice obtained from the same source as above were injected with 0.5 ml PBS
intraperitoneally and eight other mice from the same source as above were injected with 100 mg/kg body weight of suramin intraperitoneally. The injections were given on days 7 and 12. The weight of the two groups was measured several times a week. As can be seen in Figure 1, the suramin inhibited C-26 mediated weight loss in a significant time dependent manner. In the same experiment, tumor volume was also measured and the results are set forth in Figure 2. As can be seen in Figure 2, the suramin had no significant effect on the tumor (C-26) growth in-vivo except on day 19. This indicates that the treatment of the present invention affects the host directly.
EXAMPLE 3:
Mice were obtained and injected with C-26 cells as set forth above for Example 1, and then were put into four groups of five mice each. The mice were injected intraperitoneally with increasing amounts of suramin as indicated in Figure 3 except for the control mice. On day 17, the total weight of each group was compared to a control group of five mice which had been injected with 0.5 ml PBS intraperitoneally. As can be seen in Figure 3, increasing concentrations of suramin resulted in decreased percentage of weight loss. Thus, suramin inhibited wasting in a dose dependent manner.
EXAMPLE 4:
Figure 4 sets forth results of treatment with suramin in the prevention of turpéntine-induced wasting, an acute type of inflammation. (See Gershenwald et al., "Interleukin 1 receptor blockade attenuates the host inflammatory response"
Proc. Natl. Acad. Sci., 87 4966-70, (July, 1990) for a description of the turpentine-induced wasting procedure). In this experiment, three days before day 0 (day -3), five male (CD)2Fl mice, obtained from Charles Rivers Laboratories, each received intraperitoneally 0.5 ml of PBS. Five other mice obtained from the same source each received intraperitoneally W094/08574 2 I ~ 6 9 8 8 PCT/US93/~527 100 mg/kg body weight suramin diluted with 0. 5 ml of PBS. On day 0, all 10 mice received intramuscularly 0.1 ml of turpentine. As can be seen in Figure 4, the mice which received only PBS suffered from an acute reaction to the turpentine which caused a rapid or acute weight loss on day 3. The mice treated with suramin exhibited no such weight loss.
EXAMPLE 5:
Increasing amounts of suramin were preincubated with various dosages of IL-6 as indicated in Figure 5. A standard proliferation assay, Strassmann et al., J. Immunol., 147:1279-1285 (1991), was conducted using 96 well plates.
The medium used was RPMI with 10% fetal calf serum. B-9 cells were added and were cultured for 3 days. The extent of proliferation of B-9 cells was determined by the incorporation of radioactive thymidine as described in Strassmann et al., J. Clin. Invest., 89, pp. 1681-84 (May 1992). As set forth in Figure 5, suramin inhibits the bioactivity of IL-6 in-vitro which was shown to be an important mediator of cachexia in the C-26 tumor model. (See Strassmann et al., J. Clin. Invest., 89, pp. 1681-84 (May 1992), incorporated herein by reference.) EXAMPLE 6:
This experiment analyzed whether suramin inhibits IL-6 bioactivity by interfering with binding to the IL-6 receptor.
Into eighteen test tubes was placed U266 indicator cells (obtained from ATCC), a binding buffer, made up of RPMI
medium, 0.1 mg BSA and 25 uM Hepes, and 100,000 cpm (0.8 ng) of 125I-IL-6. The tubes were divided into six groups of three tubes each and received suramin as follows: group 1 had 300 uM suramin; group 2 had 100 uM suramin; group 3 had 30 uM
suramin; group 4 had 10 uM suramin; and group 5 had no suramin, but only medium (control for m~Xim~l binding). In addition, group 6 received excess unlabeled IL-6 without suramin for use in determining the background of binding in this assay.

2 ~4G1988 W~' PCT/US93/~527 After 90 minutes of incubation at 4C and the centrifugation of cells on oil (a standard radioreceptor assay) Strassmann, J. Immunol., 147:1279-1289 (1991), the amount of radioactivity bound to the cells was determined. As can be seen in Figure 6, suramin prevents binding of the IL-6 to the U266 cells in a dose dependent manner. Also, the addition of increasing amounts of suramin prevented the binding of radioactive IL-6 to U266 human myeloma indicator cells in vitro as reflected in the results set forth in Figure 6. Together, these results suggest that suramin prevents the binding of IL-6 to cell surface receptors and therefore inhibits IL-6 bioactivity.
EXAMPLE 7:
The ability to prevent binding of IL-6 in vivo was analyzed as follows. Eight mice received 5.0 mg/mouse of suramin intravenously and eight other mice received 0.2 ml PBS/mouse intravenously 0.5 hour. Thereafter, all sixteen of the mice received an injection of 300,000 cpm (2.4 ng) of 125I-IL-6. Four mice from each group were sacrificed 30 minutes after receiving the 125I-IL-6 and the remaining four mice from each group were sacrificed 60 minutes after receiving the 125I-IL-6. The liver, kidney, and spleen were removed and measured for radioactivity (cpm). As can be seen in Table 2, suramin injected mice had approximately 50% less radioactivity measured in the liver, indicating that suramin may prevent~binding of radioactive IL-6 to the liver. In addition, suramin may accelerate clearance of IL-6 from the body as indicated by the increase of radioactive IL-6 present in the kidney. These results indicate that suramin prevents the binding of IL-6 to the liver and may therefore inhibit IL-6 pathology (for example, cachexia) in vivo.

W O 94/08574 21 4 B 9 8 8 PC~r/US93/09527 Table 2: Modulation of 125I-IL-6 Sequestration by Suramin I n Vi vo Expt. 1 30 minutes 60 minutes Treatment PBS Suramin PBS Suramin Liver 16583 + 323 8385 + 1525 7899 + 168 4275 + 91 Kidney 19283 + 530 70151 + 125 9975 + 532 36595 + 1760 Spleen 1059 i 20 1347 + 295 728 + 5 630 + 6 Results are expressed as mean cpm + 0.5 range of 2 mice per point. Liver radioactivity is expressed as cpm/gm.

PBS (0.2 ml) or Suramin (5mg/mouse) was injected 0.5 hour before injection of 300,000 cpm (2.4 ng) of 125I-IL-6.

W 094/08574 PC~r/US93/09527 ~69~ - 16 -Expt. 2 30 minutes 60 minutes Treatment PBS Suramin PBS Suramin Liver 15002 + 1989277 + 235 8589 + 2495512 + 379 Kidney 19953 + 757287 + 2849 7569 + 3038254 + 466 Spleen 1098 + 151306 + 4 549 + 10631 + 25 EXAMPLE 8:
The same procedures set forth in Example 5 was followed except that a different sulfate-containing compound, Pentosan polysulfate, was used. As set forth in Table 3, Pentosan polysulfate prevented the proliferation of B-9 cells in response to IL-6.

W094/08574 2 1 ~ ~ 9 8 ~ PCT/US93/09527 Table 3: Pentosan polysulfate inhibits proliferation of B-9 cells in response to IL-6.

added (pg/ml) 30 10 3 Pentosan polysulfate 300 ~M 60287 114562648 1567 1000 ~M 26727 3586 1062 795 Results are expressed in cpm of 3H-thymidine.

EXAMPLE 9:
The same procedure set forth in Example 6 was followed, except that Pentosan polysulfate was used instead of Suramin.
As set forth in Table 4, increasing amounts of Pentosan polysulfate inhibited the binding of radioactive IL-6 to U266 human myeloma cells.

W O 94/08574 PC~r/US93/09527 ~ 9~ 18 -Table 4: Pentosan polysulfate inhibits binding of radioactive IL-6 to U266 cells.

Addition to cpm 125I-IL-6 radioreceptor bound to U266 cells assay medium 4072 pentosan polysulfate 300 ~M 2003 30 ~M 2575 3 ~M 3000 hIL-6 270 ng/ml 1416 EXAMPLE 10:
The same procedure set forth in Example 5 was followed except in this example, Dextran sulfate and Dextran, were used instead of Suramin. As set forth in Table 5, Dextran sulfate prevented the proliferation of B-9 cells in response to IL-6. Also, as set forth in Table 5, Dextran did not prevent the proliferation of B-9 cells in response to IL-6.
These combined results suggest that the sulfate in the Dextran sulfate is an active ingredient which prevented the proliferation of B-9 cells in response to IL-6.

W O 94/08~74 2 1 ~ 6 ~ 8 ~ PC~r/US93/09527 Table 5: Dextran sulfate but not dextran inhibit IL-6 dependent proliferation of B-9 cells.

IL-6 30 pg/ml 10 pg/ml 3 pg/ml No Compound 254937 143846 32373 Dextran sulfate 300 ~M 112835 16573 2461 100 ~M 150233 31678 8075 30 ~M 204155 68066 7603 Dextran 300 ~M 245701 140903 27015 100 ~M 230321 136191 29577 30 ~M 231856 143003 24007 Results are expressed in cpm of 3H-thymidine incorporation.

Other embodiments of the present invention will be apparent to those skilled in the art from a consideration of the specification and practice of the present invention disclosed herein. It is intended that the present specification and examples be considered as exemplary only, with the true scope and spirit of the present invention being indicated by the following claims.

~ ~ ~ . j c;

Claims (20)

WHAT IS CLAIMED IS:
1. A method for treating cachexia comprising the step of administering to a patient in need of such treatment an amount of Pentosan polysulfate or Dextran sulfate, effective for said treatment.
2. The method of claim 1, wherein said cachexia is the result of infection by one or more microbes.
3. The method of claim 2, wherein said cachexia is the result of infection by a bacterium.
4. The method of claim 3, wherein said cachexia is the result of infection by a gram-negative bacterium.
5. The method of claim 3, wherein said cachexia is the result of infection by a gram-positive bacterium.
6. The method of claim 2, wherein said cachexia is the result of infection by a virus.
7. The method of claim 2, wherein said cachexia is the result of infection by a protozoa.
8. The method of claim 2, wherein said cachexia is the result of infection by a fungus.
9. The method of claim 1, wherein said cachexia is the result of infection by a parasite.
10. The method of claim 1, wherein said cachexia is the result of one or more forms of cancer.
11. The method of claim 1, wherein said amount is a dose of about 0.01 to about 10 g per week.
12. The method of claim 11, wherein said amount is administered in divided dosages.
13. A method for the inhibition of IL-6 bioactivity comprising the step of administering to a patient a sulfate-containing compound in an amount effective to inhibit said IL-6 bioactivity.
14. The method of claim 13, wherein said sulfate-containing compound is selected from the group consisting of suramin, a derivative of suramin, Pentosan polysulfate and Dextran sulfate.
15. The method of claim 13, wherein said amount is from about 0.01 to about 10 g per week.
16. The method of claim 15, wherein said amount is administered in divided dosages.
17. A method to mitigate or eliminate weight loss due to wasting of body fat and muscle comprising the step of administering to a patient a sulfate-containing compound in an amount effective to mitigate or eliminate said weight loss.
18. The method of claim 17, wherein said sulfate-containing compound is selected from the group consisting of suramin, a derivative of suramin, Pentosan polysulfate, and Dextran sulfate.
19. A method for treating IL-6 related diseases comprising the step of administering to a patient a sulfate-containing compound in an amount effective to treat said IL-6 related disease.
20. The method of claim 19, wherein said IL-6 related diseases are cachexia, polyclonal B-cell abnormalities, autoimmune diseases, cardiac myxoma, rheumatoid arthritis, Castleman's disease, AIDS, alcoholic liver cirrhosis, proliferative diseases, mesangial proliferative glomerulonephritis, psoriasis, malignancies, plasmacytoma, myeloma, lymphoma, leukemia, and renal cell carcinoma.
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US6261560B1 (en) * 1995-02-13 2001-07-17 Chugai Seiyaku Kabushiki Kaisha Method for inhibiting muscle protein proteolysis with antibodies to interleukin-6 receptor
FR2808687B1 (en) * 2000-04-27 2003-12-05 Goemar Lab Sa MEDICAMENT CONTAINING POLYSACCHARIDE SUBSTANCES FOR THE ACTIVATION OF APOPTOSIS
EP1552823A3 (en) * 2000-06-30 2005-09-21 Polydex Pharmaceuticals Limited Cellulose sulfate and other sulfated polysaccharides to prevent and treat papilloma virus infection and other infections
ATE308329T1 (en) 2000-06-30 2005-11-15 Polydex Pharma USE OF CELLULOSE SULFATE AND OTHER SULFATED POLYSACCHARIDES FOR PREVENTING AND TREATING PAPPILOMA VIRUS INFECTIONS
WO2002034292A1 (en) 2000-10-25 2002-05-02 Chugai Seiyaku Kabushiki Kaisha Preventives or remedies for psoriasis containing as the active ingredient il-6 antagonist
US20030181416A1 (en) * 2002-01-10 2003-09-25 Comper Wayne D. Antimicrobial charged polymers that exhibit resistance to lysosomal degradation during kidney filtration and renal passage, compositions and method of use thereof
BRPI0916895A2 (en) * 2008-08-04 2016-02-10 Sammy Opiyo use of lysine, arginine and other amino compounds, product and product dosage administration
CN102985091B (en) 2010-03-03 2016-11-23 新科蒂斯公司 Use antimicrobial peptide chelate compound treatment dermatosis and abnormal compositions and method
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