||||||| |||||||| 0. USOOS 1589.40A United States Patent 19) 11 Patent Number: 5,158,940 LaRocca et al. (45) Date of Patent: Oct. 27, 1992

54) USE OF SURAMIN TO TREAT (56) References Cited RHEUMATOLOGIC DISEASES PUBLICATIONS 75) Inventors: Renato V. LaRocca, Sterling. Va.; Cy Horne et al, Blood vol. 71. (2) pp. 273-279 (1988). A. Stein, Gaithersburg, Md.; Michael Mohan et al, Journal of Medicinal Chemistry 34(1) pp. R. Cooper, Gaithersburg, Md.; 212-217 (1991). Charles E. Myers, Rockville, Md. Akerpelpt et al, Journal of Medicinal Chemistry vol. 14(7) (1971). 73 Assi 73) Assignee: Therepresented United Statesby the GovernmentSecretary, DHHS, as Primary Examiner-S. J. Friedman Washington, D.C. Attorney, Agent, or Firm-John E. Tarcza (57) ABSTRACT 21 Appl. No.: 479,817 Polysulfonated compounds such as suramin are used to (22 Filed: Feb. 14, 1990 treat immunoregulatory disorders. Particular use in the treatment of rheumatologic diseases such as rheumatoid 51 Int. Cl...... A61K 31/715 arthritis is shown, 52 U.S. C...... 514/54 58) Field of Search ...... 514/54 11 Claims, 3 Drawing Sheets Vuolo a UCL. A 1, 1994 SeeU UI ) V, VV91 TV

FIG 1B

U.S. Patent Oct. 27, 1992 Sheet 3 of 3 5,158,940

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CP. SURAMIN TREATMENT

TIME (MONTHS) FIG. 3 5,158,940 1. 2 six grams to treat parasitic infections. This protocol is USE OF SURAMIN TO TREAT RHEUMATOLOGIC generally effective for treating parasitic infections. DISEASES SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 5 The inventors have discovered that rheumatoid ar Rheumatoid arthritis is a chronic debilitating disease thritis and other immunoregulatory diseases are effec which is believed to be autoimmune in nature. While tively treated using suramin and related polysulfonated many drugs have been used to treat it with varying compounds and their pharmaceutically acceptable salts. degrees of clinical benefit, numerous side effects and Further, it has been discovered that much higher doses toxicities often accompany the treatment. Furthermore, O are needed to produce the anti-autoimmune effect than the long term effect of these medications on rheumatoid are needed to treat parasitic infections. Doses at this arthritis remains controversial in as much as some pa level require frequent pharmacological analysis of the tients require medication for life while many others serum level in as much as levels over 350 ug/ml are have periodic episodes of recrudescence and remission neurotoxic and have a 40% chance of causing reversible or become progressively worse despite drug therapy. 15 paralysis. Drug treatments typically include nonsteroidal anti-in flammatory drugs, hydroxychloroquin, gold salts, ste BRIEF DESCRIPTION OF THE DRAWINGS roids, methotrexate and penicillamine. Much the same FIG. 1A shows the right hand of a patient at the start can be said for all autoimmune diseases, especially those of treatment. believed to be influenced by the cellular immune re 20 FIG. 1B shows the right hand of the same patient sponse. after seven months of treatment. Suramin, the hexasodium salt of 8,8'-(carbonyl-bis (inino-3, 1-phenylenecarbonylimino(4-methyl-3, 1 FIG. 2A shows the elbows of a patient at the start of phenylene)carbonylimo))bis-1,3,5-naphthalenetrisul treatinent. fonic acid is a polysulfonated napthtylurea which has 25 FIG. 2B shows the elbows of the same patient after found clinical use as an antiparasitic agent since the seven months of treatment. 1920s. It has a long plasma half-life of 45-55 days. Afri DETAILED DESCRIPTION OF THE can trypanosomiasis and onchocerciasis are usually INVENTION treated with suramin. It has also been tested as a possi ble treatment for acquired immunodeficiency syndrome 30 Patients suffering from immunoregulatory diseases (AIDS), because of its ability to inhibit the reverse such as autoimmune diseases requiring immunomodula transcriptase enzyme and revert the cytopathic effect of tion may be treated with a number of polysulfonated human immunodeficiency virus (HIV) in vitro (JAMA organic compounds, especially those containing sulfo 258 p. 1347-51 (1987)). Suramin also has demonstrated nated ring systems. These therapeutic compounds in an ability to inhibit the activity of various growth fac 35 clude heparin sulfate, dextran sulfate, polysulfonated tors in vitro (J. Cellular Physiology 132 p. 143-8 (1987)) glycosaminoglycans and suramin. While not wishing to and has therefore been used clinically to treat various be bound by any particular theory, these compounds cancers. The compound has also been noted to bind to are believed to have agonist/antagonist properties on a variety of cytoplasmic and intranuclear enzymes various cell growth factors, cytokines, and may even (Cancer Res. 47 p. 4694-8 (1987) and J. CLin. Onc. 7 p. unbind those already bound to cellular or other recep 499-508 (1989)) but the exact mode of its action is still tors. These compounds are believed to function by not fully understood. suppressing the immune system through interference In recent years, people have attempted to use suramin with the activity of various growth factors and cyto and related compounds for several other purposes such kines. This may result in blockage of the mitogenic as a collagenase inhibitor and for inhibition of the com 45 proliferation of the cellular immune system, which is plement activators associated with angioneurotic edema responsible for causing the disease state. A variety of (Quinke's Disease) (U.S. Pat. Nos. 4,591,604, 4,391,824, immunological disorders, especially those operating by 4,297,372, and 4,180,587). While these same patents analogous mechanisms, are treatable in accordance with have speculated on the use of suramin to treat rheuma the invention. The particular autoimmune and allergic toid arthritis and related diseases, no evidence has ever diseases include Crohn's disease, ulcerative colitis, sar been presented that suramin effectively has any activity coidosis, rheumatoid arthritis, scleroderma, polyarteri against any autoimmune disorder. Recent patents and tis, psoriasis, interstitial and glomerular nephrites, sys publications show the opposite and use suramin as an temic lupus erythematosus, polymyositis, Sjogren's immunostimulant (U.S. Pat. No. 4,737,521 and the syndrome, asthma and other inflammatory alveolar AIDS and cancer treatments citations above) instead of 55 disorders. Rheumatologic disorders are the preferred as an immunosuppressant. diseases to treat according to the invention. Historically, treatment with suramin has been at When treating a patient, the dose and protocol for tempted in numerous other diseases and many reports of administrating it differs from the conventional way of its use have been suggested. However, these appear to using suramin. While the approved protocol for using be no more than desperation attempts to treat patients 60 suramin is a one gram bolus dose given once a week for with then otherwise incurable diseases by any means six weeks for a total dose of six grams, the treatment of available, and without success. Similar desperation at rheumatologic diseases involves generating a much tempts have been tried with any of a wide assortment of higher plasma level of suramin and maintaining it for a drugs prior to FDA regulation and the advancements of longer period of time. Typically, about 10 to 30 grams, recent decades. 65 preferably greater than about 15 grams total dose, are Suramin has only one approved dosage and treatment given over a period of several months and may be given protocol-namely using one gram bolus doses given par in about one to about three week periods of therapy. enterally once per week for six weeks for a total dose of During the treatment period it is preferred to maintain 5,158,940 3 4. a plasma level from about 100 to about 350 ug/ml, pref. In vitro assays and even animal testing has its merits erably above 200 ug/ml and more preferably above 300 but neither stands up perfectly in drug testing and hence ug/ml. Since levels above 350 ug/ml are potentially the need for human trials to prove efficacy. This is neurotoxic, the patient should be frequently monitored particularly true for immunoregulatory and autoim to ensure that the plasma levels are within the desired mune diseases where the nature of the disease mecha range. The treatments may be repeated or maintained as nism is unclear and animal models are imperfect. Be long as necessary. Comparable doses of the other active cause suramin is already an FDA approved drug, is well compounds of the invention would be determined by known and has been used for seventy years, it was the routine optimization. logical choice for use in clinical trials. As for the disease The therapeutic compounds of the invention may be 10 to treat, rheumatoid arthritis is a well known autoim given orally except for when plasma levels are not mune disease which is objectively quantifiable by mea achieved by this route due to poor adsorption or degra suring the titer of rheumatoid factor, the shrinkage and dation in the digestive tract. For these situations, paren disappearance of rheumatoid nodules, and the diminu teral administration is preferred. The compounds may tion of joint inflammation. Further, subjective patient also be provided transdermally or adsorbed through 15 reports of pain stiffness and other arthritic symptoms one or more of the mucus membranes. The drug may be are most important but are not available with either in given in one or more bolus doses or it may be given by vitro or animal models. Accordingly, the following continuous infusion. In general, a suitable initial contin representative example is presented. uous infusion rate of about 350 mg/m2/day for suramin may be used. A desired dose may also be provided in 20 EXAMPLE several increments at regular intervals throughout the A 57 year old Caucasian male was initially diagnosed day or sustained release formulations. The doses will in 1975 with polyarthritis and an elevated serum rheu need to be modified according to the condition of the matoid factor level. Since then, the patient had required patient and his ability to tolerate the side effects, his almost uninterrupted treatment with either supraphysi clinical needs and the nature of whatever other treat 25 ologic doses of steroid or remission-inducing agents. ment is being employed. Any of the standard pharma These included hydroxycloroquine, gold salts, cytoxan ceutical stabilizers, carriers, salts and preparations used and most recently, penicillamine together with predni with other conventional drugs may also be used for the sone. Tapering of these invariably resulted in exacerba preparation and delivery of suramin. tion of his arthritic symptoms. The desired plasma level may be achieved, for exam 30 Prior to initiating suramin therapy, penicillamine and ple, by intravenous injection of 0.1% to 50%, preferably prednisone were discontinued and the patient was about 10%, concentration in solution of the active in placed on physiologic replacement doses of hydrocorti gredient. sone. At this time, the patient demonstrated synovial Formulations for transdermal administration include 35 proliferation of the metacarpophalangeal joints of both a suitable carrier such as a cream or base of other mate hands, osteopenia and diffuse biopsy proven rheuma rial to facilitate contact with the skin or mucus mem toid nodules involving the thenar aspect of both fore branes. The active ingredient(s) contained therein may arms, the dorsum of each hand as well as along his left be charged, or converted into a salt in order to permit achilles tendon. His serum rheumatoid factor titer was crossing the surface under the influence of an electrical 1:2560. Serum antinuclear antibodies were absent and field. Alternatively, the active ingredient may be both anti-DNA screen and LE cell test were negative. derivatized in order to enhance absorption or transport Over six and one half months, the patient received across the cell layer. three cycles of suramin by continuous infusion at eight The compounds of the invention in either a fine pow week intervals, for a cumulative dose of 23.4 grams. In der or liquid form with suitable carriers as needed may 45 this period the patient did not experience any significant be aerosolized for inhalation to deliver the compounds. hematologic, hepatic or renal toxicity. Over the same Formulations for administration to a mucus mem period plus an additional three months afterwards with brane surface may be presented with a suitable carrier out suramin treatment, the patient manifested decreased or salt of inert ingredients to aid in contact or absorp synovial swelling and improvement in his arthritic tion or the active compounds. Such carriers as are 50 symptoms. In addition, regression in the size of his mul known in the art to be appropriate. tiple rheumatoid nodules occurred; this was initially Formulations suitable for parenteral administration documented after three months and was even more include aqueous and non-aqueous, isotonic and isos pronounced at the start of the third cycle of therapy at notic sterile injection solutions which may contain five months with the complete disappearance of as antioxidants, buffers, bacteriostats, and solutes which 55 many as a third. Although a follow up hand photograph render the formulation isotonic with the body fluids of failed to show any significant change in his minimal the intended recipient and aqueous and non-aqueous joint abnormalities, the patient's serum rheumatoid titer sterile suspensions which may include suspending fell to 1:1280 after three months and 1:160 after six agents and thickening agents. The formulations may be months. Upon formal rheumatologic evaluation at the presented in unit-dose or multi-dose sealed containers, end of therapy, the patient showed virtually no inflam such as ampules and vials, and may be stored in a freeze matory joint disease with only minimal synovial prolif dried (lyophilized) condition requiring only the addi eration in the ulnar carpal region of his right wrist. The tion of the sterile liquid carrier (e.g. water, saline) for patient did not receive further treatment with suramin injection immediately prior to use. Extemporaneous subsequent to his third cycle at six months, and by nine injection solutions and suspensions may be prepared 65 months after the initial start continued to remain with from powders, granules and tablets of the kind previ out arthritic symptoms, although his rheumatoid titer ously described. In all cases, the final product is prefera has increased to 1:320. The size of his remaining rheu bly free of pyrogens. matoid nodules at this time also remained unchanged. 5,158,940 5 6 The foregoing description of the specific embodi 4. The method of claim 2 further comprising main ments will so fully reveal the general nature of the in taining serum levels between about 100 and about 350 vention that others can, by applying current knowl ug/ml. edge, readily modify and/or adapt for various applica 5. The method of claim 2 further comprising main tions such specific embodiments without departing 5 taining serum levels above 300 ug/ml. from the generic concept, and, therefore, such adapta 6. The method of claim 2 further comprising main tions and modifications should and are intended to be taining serum levels of suramin or a salt thereof for at comprehended within the meaning and range of equiva least four months. lents of the disclosed embodiments. It is to be under 7. The method of clain 6 wherein said levels are stood that the phraseology or terminology employed O maintained for at least 8 months. 8. A method for treating rheumatoid arthritis con herein is for the purpose of description and not of limita prising administering Suramin or a salt thereof to a pa tion. Other modifications of the above embodiments of tient for sufficient duration and at sufficient dosage to the invention which are obvious to those skilled in the alleviate the signs and symptoms of rheumatoid arthri art or are within the invention's true spirit and scope are 15 tlS. intended to be within the scope of the following claims. 9. The method of claim 8 wherein the signs and symp We claim: toms remain alleviated for at least three months after 1. A method for treating immunoregulatory or auto finishing treatment. immune diseases by administering to a patient an im 10. The method of claim 8 further comprising main munomodulating amount of suramin or a salt thereof. 20 taining the serum levels of suramin or a salt thereof 2. A method for treating rheumatologic diseases by above about 100 ug/ml. administering to a patient an effective amount of sura 11. The method of claim 8 further comprising main minor a salt thereof. taining the serum levels of suramin or its salts below 3. The method of claim 2 further comprising adminis about 350 ug/ml. tering suramin or a salt thereof by continuous infusion. 25 k k z ak

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