US007067159B2

(12) United States Patent (10) Patent No.: US 7,067,159 B2 Newmark et al. (45) Date of Patent: *Jun. 27, 2006

(54) METHODS FOR TREATING PROSTATE 6,261,607 B1 * 7/2001 Newmark et al...... 424,727 CANCER WITH HERBAL COMPOSITIONS 6,387.416 B1* 5/2002 Newmark et al...... 424,725 6,469,040 B1 10/2002 Seibert et al. (75) Inventors: Thomas Newmark, St. Louis, MO 2, R ck 1328 R ------424/439 indneSS et al. (US); Paul Schulick, Brattleboro, VT 6,541,045 B1 * 4/2003 Charters et al...... 424.737 (US); Aaron Katz, New York, NY (US) FOREIGN PATENT DOCUMENTS (73) Assignee: New Chapter, Inc., Brattleboro, VT (US) WO WO 94,13635 6, 1994 WO WO 94,15932 T 1994 (*) Notice: Subject to any disclaimer, the term of this W W is RE: patent is extended or adjusted under 35 WO WO 94,2798O 12/1994 U.S.C. 154(b) by 170 days. WO WO95/005O1 1, 1995 WO WO95/15316 6, 1995 This patent is Subject to a terminal dis- WO WO 96.03387 2, 1996 claimer. WO WO 96.03388 2, 1996 WO WO 96,06840 3, 1996 (21) Appl. No.: 10/728,087 WO WO 96,25405 8, 1996 (22) Filed: Dec. 5, 2003 OTHER PUBLICATIONS Chandrasekharan, N.V. et al. “COX-3, a cyclooxygenase-1 (65) Prior Publication Data variant inhibited by acetaminophen and other analgesic/ US 2005/O123631 A1 Jun. 9, 2005 antipyretic drugs: Cloning, structure, and expression'. PNAS, vol. 99 (21), pp. 13926-13931, 2002. (51) Int. Cl. k . AOIN 65/00 (2006.01) cited by examiner (52) U.S. Cl...... 424/725; 424/729; 424/745; Primary Examiner Christopher R. Tate 424/756 (74) Attorney, Agent, or Firm Nath & Associates PLLC; (58) Field of Classification Search ...... None Gary M. Nath: Jerald L. Meyer See application file for complete search history. (57) ABSTRACT (56) References Cited The inventive subject matter relates to methods for treating U.S. PATENT DOCUMENTS prostate cancer, comprising administration of a composition comprising therapeutically effective amounts of Supercriti 5,344.991 A 9, 1994 Reitz et al. cal extracts of rosemary, turmeric, oregano and ginger; and 5,380,738 A 1/1995 Norman et al. therapeutically effective amounts of hydroalcoholic extracts E. A 22 I l, of holy basil, ginger, turmeric, Scutellaria baicalensis, rose 5.466,823 A 11, 1995 Tall et al. mary, green tea, huZhang, Chinese goldthread, and barberry. 5,474,995 A 12/1995 Ducharme et al. 5,510,368 A 4, 1996 Lau et al. 35 Claims, 5 Drawing Sheets U.S. Patent Jun. 27, 2006 Sheet 1 of 5 US 7,067,159 B2

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0Seeup|O. — US 7,067,159 B2 1. 2 METHODS FOR TREATING PROSTATE excessive urination at night, incontinence, bone pain or CANCER WITH HERBAL COMPOSITIONS tenderness, hematuria, abdominal pain, anemia, weight loss, and lethargy. BACKGROUND OF THE INVENTIVE SUBJECT The appropriate treatment of prostate cancer is often MATTER controversial. Treatment options vary based on the stage of the tumor. In the early stages, Surgical removal of the 1. Field of the Inventive Subject Matter prostate and radiation therapy may be used to eradicate the The present inventive subject matter relates to novel tumor. Metastatic cancer of the prostate may be treated by methods for treating prostate cancer, comprising adminis hormonal manipulation, reducing the levels of testosterone tration of a composition comprising therapeutically effective 10 by drugs or removal of the testes, or by chemotherapy. amounts of Supercritical extracts of rosemary, turmeric, Surgical removal of the prostate has several possible oregano and ginger; and therapeutically effective amounts of complications, including impotence and urinary inconti hydroalcoholic extracts of holy basil, ginger, turmeric, nence. Removal of the testes alters hormone production and Scutellaria baicalensis, rosemary, green tea, huZhang, Chi may be recommended for metastatic cancer, and has pos nese goldthread, and barberry. 15 sible complications including loss of testosterone produc 2. Background tion, leading to problems with sexual function, osteoporosis, and loss of muscle mass. Radiation therapy has possible Prostate Cancer. Prostate cancer is the third most common complications including loss of appetite, fatigue, skin reac cause of death from cancer in men of all ages and is the most tions such as redness and irritation, rectal burning or injury, common cause of death from cancer in men over 75 years diarrhea, cystitis, and blood in the urine. Hormonal manipu old. Prostate cancer is rarely found in men younger than 40. lation, which is mainly used to relieve symptoms without Men at higher risk include black men older than 60, farmers, curing the prostate cancer, has possible complications tire workers, painters, and men exposed to cadmium. The including nausea and Vomiting, hot flashes, anemia, leth lowest incidence occurs in Japanese men and vegetarians. argy, osteoporosis, reduced sexual desire, liver problems, The cause of prostate cancer is unknown, although some 25 diarrhea, enlarged breasts, and erectile dysfunction, along studies have shown a relationship between high dietary fat with the obvious lack of treatment of the disease itself. intake or increased testosterone levels. Chemotherapy, using medications such as mitoxantrone, Prostate cancer is a serious and often life-threatening prednisone, paclitaxel, docetaxel, estramustine, and adria condition. Prostate cancer, which is characterized by rap mycin, has possible complications which are numerous and idly-proliferating cell growth, continues to be the subject of 30 specific to a given chemotherapy drug. worldwide research efforts directed toward the identification Sufferers of prostate cancer often experience significant of therapeutic agents which are effective in the treatment lifestyle changes, including disrupted sexual desire or per thereof. Effective therapeutic agents prolong the survivabil formance on either a temporary or permanent basis; impo ity of the patient, inhibit the rapidly-proliferating cell growth tence; extensive monitoring for progression of the disease; associated with the disease, or effect a regression of the 35 stress of illness; and urinary incontinence. Thus, there is a disease. Research in this area is primarily focused on iden continuing need for alternative treatments for prostate can tifying agents which are therapeutically effective in humans cer and for improved treatments for prostate cancer. and other mammals. Cyclooxygenase Inhibitors. Cyclooxygenase is an With prostate cancer, as with all solid tumors, it is the enzyme-protein complex with a variety of biochemical metastatic encroachment of the tumor on other vital function 40 actions. There are at least three primary COX isoenzymes, that causes the demise of the patient. Approximately 10% of COX-1, COX-2, and COX-3. COX-1 is a constitutive patients are diagnosed initially with metastatic disease. enzyme, produced at a reasonably consistent level at all Ultimately, 30–40% of patients with this cancer will develop times. It plays an important role in, for example, gastrointes metastatic disease. Once metastasis occurs, the cancer fol tinal protection, kidney function, and the aggregation of lows a relentless progression unless interrupted by effective 45 blood platelets. COX-2 production is not constant; it varies treatment. Prostate cancers are classified based on their depending on signals from various biochemical catalysts. aggressiveness and how different they are from the Sur For example, in the case of arthritis inflammation and pain, rounding prostate tissue. There are several different ways to COX-2 responds to tissue damage by oxidizing arachidonic classify tumors; one of the more common is the Whitmore acid, creating prostaglandins which in turn produce local Jewett system, in which tumors are rated as follows: 50 inflammation. COX-3 has been identified relatively recently A: tumor is unable to be felt on physical examination, and (Chandrasekharan, et al., PNAS U.S.A., 99(21): 13926–31 is usually detected by accident after prostate Surgery (2002)). In humans, COX-3 mRNA is expressed most abun done for other reasons. dantly in the cerebral cortex and heart tissues. COX-3 B: tumor is confined to the prostate and usually detected activity is selectively inhibited by analgesic/antipyretic 55 drugs. It has been suggested that inhibition of COX-3 could by physical examination or PSA testing. represent a mechanism by which these drugs decrease pain C: extension of tumor beyond the prostate capsule without and possibly fever. spread to lymph nodes. Prostaglandins play a major role in the inflammatory D: cancer has metastasized to regional lymph nodes or process and the inhibition of prostaglandin production, other parts of the body, Such as the bone and lungs for 60 especially production of PGG, PGH, and PGE has been example. a common target of anti-inflammatory drug discovery. How With the advent of Prostate Specific Antigen (hereinafter ever, common non-steroidal anti-inflammatory drugs (here “PSA) testing, most prostate cancers are now found before inafter "NSAIDs) that are active in reducing the prostag they cause symptoms. The symptoms listed below are pos landin-induced pain and Swelling associated with the sible indicators of prostate cancer: urinary hesitancy, urinary 65 inflammation process are also active in affecting other dribbling, urinary retention, pain with urination, pain with prostaglandin-regulated processes not associated with the ejaculation, lower back pain, pain with bowel movement, inflammation process. US 7,067,159 B2 3 4 NSAIDs have been found to prevent the production of Berberine, found in barberry and Chinese goldthread, has prostaglandins by inhibiting enzymes in the human arachi also been found to inhibit COX-2 without inhibiting COX-1 donic acid/prostaglandin pathway, including the cyclooxy activity. genase enzymes. Traditional non-steroidal anti-inflamma In U.S. Pat. No. 6,387.416, Applicants disclosed the tory drugs, such as aspirin, work by inhibiting both COX-1 inventive compositions and their use for reducing inflam and COX-2. Thus, non-specific NSAIDs can have a dam mation. The contents of U.S. Pat. No. 6,387,416 are hereby aging effect on the gastrointestinal tract, kidneys, and liver, incorporated by reference in their entirety. Surprisingly, as blocking COX-1 can make the stomach lining more Vulner discussed in greater detail below, it has been determined that able, and reduced thromboxane production thins the blood, the inventive compositions are useful for treating prostate making gastrointestinal hemorrhage more likely, and may 10 cancer as well. cause inadequate regulation of cellular immune functions Use of COX-2 Inhibitors for Treating Cancer. It has been and the secretion of various cytokines. The use of high doses postulated that COX-2 inhibitors may be useful for treating of most common NSAID’s can produce severe side effects, cancer. Yet only a very few patents actually disclose the use including life threatening ulcers, that limit their therapeutic of COX-2 inhibitors for treating any cancers. In U.S. Pat. potential. 15 No. 5,466,823 to Talley, et al., (Pyrazol-1-yl)benzene sul COX-2 is associated with inflammation and provides a fonamides are disclosed as inhibitors of cyclooxygenase-2, viable target of inhibition which more effectively reduces and for use in the treatment of inflammation, arthritis, and inflammation and produces fewer and less drastic side pain, and as being useful for preventing colon cancer. effects. Thus, researchers have been motivated to develop However, their use for actually treating colon cancer or for selective COX-2 inhibitors to reduce inflammation and treating or preventing other neoplasias is not disclosed. relieve pain without the gastrointestinal damage brought on U.S. Pat. No. 6,469,040 to Seibert, et al., discloses a by inhibiting COX-1. In addition, the current scientific method of using a specific, disclosed class of cyclooxyge understanding in the art Suggests that COX-2 inhibition may nase-2 inhibitor derivatives in preventing and treating epi serve an important function in promoting normal cell growth thelial cell neoplasia in a Subject. in the colon, pancreas, breast tissue, and other organ sys 25 U.S. Pat. No. 6,534,540 to Kindness, et al., discloses a temS. combination of the proprietary HMG-COA reductase inhibi Some compounds which selectively inhibit cyclooxyge tor lovastatin and the proprietary COX-2 inhibitor rofecoxib nase-2 have been described in U.S. Pat. Nos. 5,380,738, for the treatment of cancer, especially prostate cancer, and a 5,344,991, 5,393,790, 5,434,178, 5,474,995, 5,510,368 and method of treatment of cancer, especially prostate cancer, by WO documents WO96/06840, WO96/03388, WO96/03387, 30 that combination. WO96/25405, WO95/15316, WO94/15932, WO94/27980, Based on the limited body of art disclosing the use of WO95/00501, WO94/13635, WO94/20480, and WO94/ COX-2 inhibitors for treating any cancer, and the need for 26731. effective treatments for prostate cancer in particular, it is Drugs such as Valdecoxib, celecoxib, and rofecoxib are apparent that there is a great and immediate need for new intended to selectively inhibit COX-2 with minimal effect on 35 COX-2 inhibitors for treating prostate cancer. This need is COX-1. However, despite the emphasis on COX-2 inhibi met by the inventive methods and compositions, which treat tion, even these drugs appear to have serious long term side prostate neoplasias without significant side effects. effects, such as the breakdown indigestive protective mucus and prevention of normal healing processes. There is thus a SUMMARY OF THE INVENTIVE SUBJECT continuing need for more specific and non-specific COX-2 40 MATTER inhibitors which avoid side effects associated with COX-1 The present inventive subject matter relates to a method inhibition. for treating prostate neoplasia in a Subject, comprising the Natural COX-2 Inhibitors. Several herbs have been found step of administering an effective amount of a composition to inhibit the COX-2 enzyme. For example, holy basil has 45 to said subject to treat or prevent said prostate neoplasia, been found to possess significant anti-inflammatory proper said composition comprising therapeutically effective ties and is capable of blocking both the cyclooxygenase and amounts of Supercritical extracts of rosemary, turmeric, lipoxygenase pathways of arachidonate metabolism. Ursolic oregano and ginger; and therapeutically effective amounts of acid and oleanolic acid, two of the recognized phytonutients hydroalcoholic extracts of holy basil, ginger, turmeric, of holy basil, have been found to have a significant COX-2 50 Scutellaria baicalensis, rosemary, green tea, huZhang, Chi inhibitory effect. nese goldthread, and barberry, provided that said prostate Similarly, shogaols and gingerols, pungent components of neoplasia is not prostatic intraepithelial neoplasia. ginger, have been found to inhibit cyclooxygenase. Eugenol, The present inventive subject matter further relates to a another active constituent of several medical herbs, has also method for treating at least one cancerous tumor of the been found to be a 5-lipoxygenase inhibitor and to possess 55 prostate in a subject, comprising the step of administering an potent anti-inflammatory and/or anti-rheumatic properties. effective amount of a composition to said Subject to treat Scutellaria baicalensis also has been found to inhibit the said tumor, said composition comprising therapeutically COX-2 enzyme. According to the USDA database, green tea effective amounts of Supercritical extracts of rosemary, contains six constituents having cyclooxygenase-inhibitor turmeric, oregano and ginger; and therapeutically effective activity. According to the Napralert database, green tea 60 amounts of hydroalcoholic extracts of holy basil, ginger, contains fifty one constituents having anti-inflammatory turmeric, Scutellaria baicalensis, rosemary, green tea, activity. The polyphenols in green tea were found to cause huzhang, Chinese goldthread, and barberry. a marked reduction in COX-2. Flavan-3-ol derivatives (+)- In addition, the present inventive subject matter is drawn catechin, also present in green tea, have been reported to be to a method for treating side effects associated with prostate COX-1 and COX-2 inhibitors. In addition, salicylic acid, 65 neoplasia in a Subject, comprising the step of administering another constituent of green tea, also has been found to be an effective amount of a composition to said Subject to treat a COX-2 inhibitor. said side effects, said composition comprising therapeuti US 7,067,159 B2 5 6 cally effective amounts of Supercritical extracts of rosemary, Supercritical Fluid Methods and Protocols, Humana Press, turmeric, oregano and ginger; and therapeutically effective 2000, the contents of which are incorporated by reference amounts of hydroalcoholic extracts of holy basil, ginger, herein. turmeric, Scutellaria baicalensis, rosemary, green tea, The term “supercritical extraction” as used herein refers huZhang, Chinese gold thread, and barberry, wherein said to the technique in which hydrophobic compounds can be side effects are selected from the group consisting of dis extracted from samples utilizing a Supercritical fluid. The rupted sexual desire or performance on either a temporary or Solvation power of a Supercritical fluid is increased as the permanent basis, impotence, extensive monitoring for pro pressure and temperature are increased above their critical gression of the disease, stress of illness, and urinary incon points, producing an effective solvent for the isolation of tinence. 10 hydrophobic molecules. The term “hydroalcoholic extraction' as used herein BRIEF DESCRIPTION OF THE DRAWINGS refers to to the technique in which hydrophillic compounds can be extracted from a sample utilizing a solution of alcohol FIG. 1 is a graph which depicts COX-2 inhibition pro and water, followed by evaporation of the solution to pro duced by the inventive compositions. 15 duce a extract consisting of dissolved solids. The term “neoplasia” as used herein refers broadly to FIG. 2 is a photograph which depicts a Western blot of neoplastic, pre-malignant, and proliferative disease, includ COX-s expression in LNCaP cells following treatment with ing specifically benign, premalignant, or malignant neo the inventive compositions. plasms in individuals with or without any prior history or FIG. 3 is a graph which depicts the growth-inhibitory diagnosis of neoplastic, pre-malignant, or proliferative dis effects of the inventive compositions on LNCaP cells. ease. The term "neoplasia” includes neoplasia that produce FIG. 4 is a photograph which depicts a Western blot of prostaglandins or express a cyclooxygenase, including both PARP cleavage fragments produced by treatment of LNCaP benign and cancerous tumors, growths, and polyps. cells with the inventive compositions. The term “prostate neoplasia” as used herein refers FIG. 5 is a graph which depicts Caspase-3 activity in 25 broadly to epithelial cancers, epitheliomas, carcinomas, Sar LNCaP cells following treatment with the inventive com comas, or other malignant tumors or neoplasia of glandular positions. origin in the prostate. The term “subject’ as used herein refers to any human or DETAILED DESCRIPTION OF THE INVENTIVE mammal Subject who has a prostate neoplasia, preferably a SUBJECT MATTER 30 human Subject. For methods of prevention, the Subject is any human or animal Subject, preferably a human Subject, who Definitions is at risk for developing an epithelial cell-derived prostate neoplasia. The Subject may be at risk due to exposure to The term “therapeutically effective amount’ as used carcinogenic agents, being genetically predisposed to have a herein refers to that amount of the extract which will 35 prostate neoplasia, and the like. contribute to the cancer-treating ability of the composition. The term “cyclooxygenase-2 inhibitor or “COX-2 inhibitor” as used herein refers to a compound or composi The term “treating as used herein refers to partial or total tion which is able to inhibit cyclooxygenase-2 without inhibition of the growth, spreading, or metastasis of prostate adverse inhibition of cyclooxygenase-1. neoplasia, as well as partial or total destruction of the cancer 40 cells. The term “treating includes the reduction or elimi Methods for Treating Prostate Cancer nation of prostate neoplasia, and also the reduction in the incidence of the disease. Although the occurrence rate of localized, latent forms of The term “preventing as used herein refers to either prostate cancer is consistent throughout the world, the preventing the onset of prostate neoplasia, or preventing the 45 occurrence of metastatic prostate cancer is much greater in onset of a preclinically evident stage of prostate neoplasia in western countries compared to eastern countries. This strik individuals at risk. Also intended to be encompassed by this ing disparity Suggests the involvement of environmental definition is the prevention of initiation for malignant cells, factors in the development of metastatic prostate cancer, and and the arrest or reversal of the progression of premalignant has prompted the initiation of several epidemiological stud cells to malignant cells. “Preventing also includes the 50 ies which Suggest a link between high fat diets and risk of prevention of growth or spreading of the prostate neoplasia. metastatic prostate cancer. Both arachidonic acid and its This includes prophylactic treatment of those at risk of precursor, linoleic acid, are present in significant quantities developing a prostate neoplasia. in animal fats and a variety of vegetable oils. Physiologi The term "supercritical gas” or “supercritical fluid as cally, these fatty acids are integral components of cellular used herein refers to a gas is that heated to a temperature 55 membranes and also function as Substrates for the produc critical point, over which the gas will maintain its gaseous tion of an important group of potent, signaling lipids, termed state and not turn to a liquid regardless of pressure. A gas eicosanoids. Eicosanoids are known to be involved in the heated to a temperature above its critical point will become initiation of the inflammatory response, fever production, very dense on compression, so that its characteristics regulation of blood pressure, blood clotting, control of resemble those of a fluid, but will become liquid. Carbon 60 reproductive processes and tissue growth, and regulation of dioxide is commonly used in applications requiring a Super the sleep/wake cycle. Additionally, these powerful media critical fluid. The general properties of supercritical fluids tors and the enzymes that produce them, cycloxygenases and the general use of Supercritical fluids in extraction (COX) and lipoxygenases (LO), are implicated in tumor processes are described in, e.g. Taylor, Supercritical Fluid development, progression, and metastasis. Extraction, Wiley, 1996; McHugh and Krukonis, Supercriti 65 The three main isoforms of cycloxygenase are COX-1, cal Fluid Extraction: Principles and Practice, 2nd ed., COX-2, and COX-3, and these enzymes are responsible for Butterworth-Heinemann, 1994; and Williams and Clifford, the production of the group of eicosanoids, prostaglandins. US 7,067,159 B2 7 8 The COX-1 isoform has many important housekeeping (A) from about 4.5% to about 7.5%, and more preferably functions in the cell, and is therefore constitutively produced from about 5.5% to about 6.5%, by weight of the throughout the body. COX-2, however, is usually absent hydroalcoholic extract of ginger, until induced by specific stimuli. It is therefore not surpris (B) from about 5.5% to about 8.5%, and more preferably ing that COX-2 is implicated in the progression of many from about 6% to about 8%, by weight of the super disease states, including cancer. COX-2 has been found to be critical extract of ginger; present in elevated levels in a variety of cancers, including (C) from about 1.0% to about 1.5%, and more preferably lung, colon, pancreatic, head and neck, and prostate cancer. from about 1.2% to about 1.4%, by weight of the As discussed above, COX-3 has only been relatively Supercritical extract of turmeric; recently identified. 10 (D) from about 10.0% to about 16.0%, and more prefer Regarding prostate cancer, it has been demonstrated that ably from about 11.5% to about 14.5%, by weight of elevated levels of COX-2 are present in some tumor the Supercritical extract of rosemary; samples, and there is an increased level of COX-2 enzyme (E) from about 4.0% to about 6.0%, and more preferably expression with disease progression. COX-2 activity and from about 4.5% to about 5.5%, by weight of the resultant prostaglandin production is also involved in tumor 15 Supercritical extract of oregano; induced angiogenesis, which we expect to be mediated by (F) from about 10.0% to about 16.0%, and more prefer certain COX-2 inhibitors. Additionally, we expect that cer ably from about 11.5% to about 14.5%, by weight of tain COX-2 inhibitors produce a re-initiation of apoptosis the hydroalcoholic extract of turmeric; pathways, overcoming the anti-apoptotic factors secreted by (G) from about 5.5% to about 8.0%, and more preferably cancer cells and leading to cell death. from about 6.0% to about 7.0%, by weight of the The centuries old natural remedy of using white willow hydroalcoholic extract of rosemary: bark (Salix alba) to provide some pain relief led to the (H) from about 10.0% to about 16.0%, and more prefer discovery of aspirin, and eventually, to the elucidation of its ably from about 11.5% to about 14.5%, by weight of mechanism of action as a COX inhibitor. Based on this lead the hydroalcoholic extract of holy basil; and other traditional Eastern medicinal practices, many 25 (I) from about 10.0% to about 16.0%, and more preferably researchers have looked to a variety of natural plant extracts from about 11.5% to about 14.5%, by weight of the and natural products for the discovery of both non-specific hydroalcoholic extract of green tea; COX and specific COX-2 inhibitors. Some herbal extracts (J) from about 8.0% to about 12.0%, and more preferably and natural products that have peaked interest amongst from about 9.0% to about 11.0%, by weight of the researchers include curcumin, ginger, holy basil, resveratrol, 30 hydroalcoholic extract of huZhang; thundergod vine, and berberine from barberry and Chinese (K) from about 4.0% to about 6.0%, and more preferably goldthread. from about 4.5% to about 5.5%, by weight of the Applicants have developed a mixture comprised of herbal hydroalcoholic extract of Chinese goldthread: extracts, and the mixture has COX-2 inhibitory activity. (L) from about 4.0% to about 6.0%, and more preferably Applicants’ compositions are unique, in that they are pre 35 from about 4.5% to about 5.5%, by weight of the pared via a Supercritical CO extraction process. Unlike hydroalcoholic extract of barberry; and traditional solvent based extraction methods, Supercritical (M) from about 2.0% to about 3.0%, and more preferably CO, extraction allows the natural products in the herbs to be from about 2.25% to about 2.75%, by weight of the obtained without leaving chemical residues behind in the hydroalcoholic extract of Scutellaria baicalensis. preparation. 40 The hydroalcoholic extract of ginger used in the present Surprisingly, in addition to the anti-inflammatory action invention is preferably prepared as follows. The ginger disclosed in U.S. Pat. No. 6,387.416, we have found that rhizome, which is preferably cryogenically ground to pre using the inventive compositions and methods produce serve heat sensitive components, is subjected to Supercritical COX-2 inhibition in prostate cancer cell lines. We also extraction, preferably with carbon dioxide, to obtain: (i) an expect that the inventive methods induce apoptosis and 45 oil extract, referred to herein as “the supercritical extract of inhibit cell growth in cancer cells which have deactivated ginger, containing delicate lipophilic components, and (ii) apoptotic pathways. an oil-free residue. The oil-free residue is then extracted in The inventive subject matter is based on the discovery a waterfalcohol, preferably water?ethanol, mixture com that a combination of certain herbs properly extracted and posed of 60–80 parts alcohol and 40–20 parts water. The blended in appropriate proportions can used in treating 50 alcohol/water liquid is then evaporated off, leaving a pow prostate neoplasia. Thus, the present inventive Subject mat dered extract residue, referred to herein as “the hydroalco ter relates to a method for treating prostate neoplasia in a holic extract of ginger. Subject, comprising the step of administering an effective In a preferred aspect, the weight ratio of the Supercritical amount of a composition to said Subject to treat or prevent extract of ginger to the hydroalcoholic extract of ginger is said prostate neoplasia, said composition comprising thera 55 from about 0.9:1 to about 1.4:1. peutically effective amounts of supercritical extracts of The Supercritical extracts of ginger, rosemary, turmeric rosemary, turmeric, oregano and ginger; and therapeutically and oregano used in the present invention can be prepared effective amounts of hydroalcoholic extracts of holy basil, according to known Supercritical extraction methods. Such ginger, turmeric, Scutellaria baicalensis, rosemary, green as disclosed, e.g., in E. Stahl, K. W. Quirin, D. Gerard, tea, huZhang, Chinese goldthread, and barberry, provided 60 Dense Gases for Extraction and Refining, Springer Verlag 4 that said prostate neoplasia is not prostatic intraepithelial 1988, which is hereby incorporated by reference herein. neoplasia. The hydroalcoholic extracts of rosemary, turmeric, holy In one aspect, said composition is administered orally. basil, green tea, huzhang, Chinese goldthread, barberry and In another preferred embodiment, the orally administered Scutellaria baicalensis used in the present invention can be composition is in the form of one or more capsules, one or 65 prepared according to conventional hydroalcoholic extrac more tablets, or one or more pills tion techniques. For example, the hydroalcoholic extracts In another aspect, the composition comprises: can be prepared by extracting the plant portion in a water/ US 7,067,159 B2 10 alcohol, preferably water/ethanol, mixture preferably com (B) from about 5.5% to about 8.5% by weight of the posed of 60–80 parts alcohol and 40–20 parts water, and Supercritical extract of ginger, wherein the extract then evaporating off the waterfalcohol liquid, leaving a comprises from about 24% to about 36% by weight of powdered extract residue referred to herein as “the hydroal pungent compounds and from about 6.4% to about coholic extract’. 5 9.6% by weight of Zingiberene; In yet another aspect, the weight ratio of the hydroalco (C) from about 1.0% to about 1.5% by weight of the holic extract of turmeric to the supercritical extract of supercritical extract of turmeric, wherein the extract turmeric is from about 8:1 to about 12:1. comprises from about 36% to about 54% by weight of In an alternate aspect, the weight ratio of the Supercritical turmerones; extract of rosemary to the hydroalcoholic extract of rose- 10 (D) from about 10.0% to about 16.0% by weight of the mary is from about 1.6:1 to about 2.4:1. Supercritical extract of rosemary, wherein the extract In a still further aspect, the hydroalcoholic extract of comprises from about 18.4% to about 27.6% by weight ginger comprises from about 2.4% to about 3.6%, more of total phenolic antioxidants; preferably from about 2.7% to about 3.3%, and most pref (E) from about 4.0% to about 6.0% by weight of the erably about 3.0%, by weight of pungent compounds. 15 Supercritical extract of oregano, wherein the extract In another aspect, the Supercritical extract of ginger comprises from about 0.64% to about 0.96% by weight comprises from about 24% to about 36%, more preferably of total phenolic antioxidants; from about 27% to about 33%, and most preferably about (F) from about 10.0% to about 16.0% by weight of the 30%, by weight of pungent compounds; and from about hydroalcoholic extract of turmeric, wherein the extract 6.4% to about 9.6%, more preferably from about 7.2% to 20 comprises from about 5.6% to about 8.4% by weight of about 8.8%, and most preferably about 8%, by weight of curcumin; Zingiberene. (G) from about 5.5% to about 8.0% by weight of the In a further aspect, the Supercritical extract of turmeric hydroalcoholic extract of rosemary, wherein the extract comprises from about 36% to about 54%, more preferably comprises from about 18.4% to about 27.6% by weight from about 40.5% to about 49.5%, and most preferably 25 of total phenolic antioxidants; about 45%, by weight of turmerones. (H) from about 10.0% to about 16.0% by weight of the In another aspect, the Supercritical extract of rosemary hydroalcoholic extract of holy basil, wherein the comprises from about 18.4% to about 27.6%, more prefer extract comprises from about 1.6% to about 2.4% by ably from about 20.7% to about 25.3%, and most preferably weight of ursolic acid; about 23%, by weight of total phenolic antioxidants. 30 (I) from about 10.0% to about 16.0% by weight of the In yet another aspect, the Supercritical extract of oregano hydroalcoholic extract of green tea, wherein the extract comprises from about 0.64% to about 0.96%, more prefer comprises from about 36% to about 54% by weight of ably from about 0.72% to about 0.88%, and most preferably polyphenols; about 0.8%, by weight of total phenolic antioxidants. (J) from about 8.0% to about 12.0% by weight of the In a still further aspect, the hydroalcoholic extract of 35 hydroalcoholic extract of huZhang, wherein the extract turmeric comprises from about 5.6% to about 8.4%, more comprises from about 6.4% to about 9.6% by weight of preferably from about 6.3% to about 7.7%, and most pref resveratrol; erably about 7%, by weight of curcumin. (K) from about 4.0% to about 6.0% by weight of the In another aspect, the hydroalcoholic extract of rosemary hydroalcoholic extract of Chinese goldthread, wherein comprises from about 18.4% to about 27.6%, more prefer- 40 the extract from about 4.8% to about 7.2% by weight of ably from about 20.7% to about 25.3%, and most preferably berberine; about 23%, by weight of total phenolic antioxidants. (L) from about 4.0% to about 6.0% by weight of the In a further embodiment, the hydroalcoholic extract of hydroalcoholic extract of barberry, wherein the extract holy basil comprises from about 1.6% to about 2.4%, more from about 4.8% to about 7.2% by weight of berberine; preferably from about 1.8% to about 2.2%, and most pref 45 and erably about 2%, by weight of ursolic acid. (M) from about 2.0% to about 3.0% by weight of the In a further aspect, the hydroalcoholic extract of green tea hydroalcoholic extract of Scutellaria baicalensis, comprises from about 36% to about 54%, more preferably and wherein said composition further comprises: from about 40.5% to about 49.5%, and most preferably (i) the Supercritical extract of ginger and the post-Super about 45%, by weight of polyphenols. 50 critical hydroalcoholic extract of ginger at a weight In another aspect, the hydroalcoholic extract of huZhang ratio of from about 0.9 to about 1.4 parts of supercriti comprises from about 6.4% to about 9.6%, more preferably cal extract per 1 part of post-Supercritical hydroalco from about 7.2% to about 8.8%, and most preferably about holic extract; 8%, by weight of resveratrol. (ii) the hydroalcoholic extract of turmeric and the super In another embodiment, the hydroalcoholic extract of 55 critical extract of turmeric at a weight ratio of from Chinese goldthread comprises from about 4.8% to about about 8 to about 12 parts of hydroalcoholic extract per 7.2%, more preferably from about 5.4% to about 6.6%, and 1 part of Supercritical extract; and most preferably about 6%, by weight of berberine. (iii) the supercritical extract of rosemary and the hydroal In a further aspect, the hydroalcoholic extract of barberry coholic extract of rosemary at a weight ratio of from comprises from about 4.8% to about 7.2%, more preferably 60 about 1.6 to about 2.4 parts of supercritical extract per from about 5.4% to about 6.6%, and most preferably about 1 part of hydroalcoholic extract. 6%, by weight of berberine. In a preferred embodiment, the composition is adminis In an alternate aspect, said composition comprises: tered in a daily dosage of at least about 700 mg. (A) from about 4.5% to about 7.5% by weight of the In another aspect, the composition is administered on a hydroalcoholic extract of ginger, wherein the extract 65 daily basis for at least 4 weeks. comprises from about 2.4% to about 3.6% by weight of A still further aspect of the present inventive subject pungent compounds; matter is drawn to a method for treating at least one US 7,067,159 B2 11 12 cancerous tumor of the prostate in a subject, comprising the cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, step of administering an effective amount of a composition deZaguanine, dideoxycytidine, dideoxyguanosine, didox, to said Subject to treat said tumor, said composition com Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck prising therapeutically effective amounts of Supercritical & Co. EX-015, fazarabine, floxuridine, fludarabine phos extracts of rosemary, turmeric, oregano and ginger; and 5 phate, 5-fluorouracil, N-(2-furanidyl)-5-fluorouracil, Daii therapeutically effective amounts of hydroalcoholic extracts chi Seiyaku FO-152, isopropyl pyrrolizine, Lilly of holy basil, ginger, turmeric, Scutellaria baicalensis, rose LY-188011, Lilly LY-264618, methobenzaprim, methotrex mary, green tea, huZhang, Chinese goldthread, and barberry. ate, Wellcome MZPES, norspermidine, NCI NSC-127716, In a still further embodiment of the present inventive NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Subject matter, the at least one cancerous tumor is detected 10 Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, during Surgery on the prostate of said subject, having not Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, been felt by a physician on physical examination of said tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase Subject. inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, and Yet still further, the present inventive subject matter uricytin. includes the at least one cancerous tumor being confined to 15 A second class of antineoplastic agents which may be the prostate of said subject and is detected by a physician on used in combination with an inventive composition consists physical examination of said Subject. of alkylating-type antineoplastic agents. Suitable alkylating An additional aspect of the present invention includes the type antineoplastic agents may be selected from the group cancer related to said at least one cancerous tumor extends consisting of Shionogi 254-S, aldo-phosphamide analogues, beyond the prostate capsule of said Subject, but has not altretamine, anaxirone, Boehringer Mannheim BBR-2207. spread to lymph nodes in said Subject. bestrabucil, budotitane, Wakunaga CA-102, carboplatin, A further additional aspect of the present inventive subject carmustine, Chinoin-139, Chinoin-153, chlorambucil, cispl matter is directed to the cancer related to said at least one atin, cyclophosphamide, American Cyanamid CL-286558, cancerous tumor is metastasized to regional lymph nodes or Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto other parts of said Subject. 25 DACHP(Myr)2, diphenylspiromustine, diplatinum cyto A preferred aspect of the present invention is directed to static, Erba distamycin derivatives, Chugai DWA-2114R, a method for treating side effects associated with prostate ITI E09, elmustine, Erbamont FCE-24517, estramustine neoplasia in a Subject, comprising the step of administering phosphate sodium, fotemustine, Unimed G-6-M, Chinoin an effective amount of a composition to said Subject to treat GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, said side effects, said composition comprising therapeuti 30 mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI cally effective amounts of Supercritical extracts of rosemary, NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn turmeric, oregano and ginger; and therapeutically effective PCNU, prednimustine, Proter PTT-119, ranimustine, semus amounts of hydroalcoholic extracts of holy basil, ginger, tine, SmithKline SK&F-101772, Yakult Honsha SN-22, turmeric, Scutellaria baicalensis, rosemary, green tea, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temo huZhang, Chinese goldthread, and barberry, 35 Zolomide, teroxirone, tetraplatin, and trimelamol. wherein said side effects are selected from the group A third class of antineoplastic agents which may be used consisting of disrupted sexual desire or performance on in combination with an inventive composition consists of either a temporary or permanent basis, impotence, extensive antibiotic-type antineoplastic agents. Suitable antibiotic monitoring for progression of the disease, stress of illness, type antineoplastic agents may be selected from the group and urinary incontinence. 40 consisting of Taiho 4181-A, aclarubicin, actinomycin D, A further preferred embodiment is drawn to the method actinoplanone, Erbamont ADR-456, aeroplysinin derivative, wherein the side effect treated comprises disrupted sexual Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda ani performance. Somycins, anthracycline, azino-mycin-A, bisucaberin, Bris In an alternate aspect, the composition comprises an tol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol additional agent selected from the group consisting of anti 45 Myers BMY-25551, Bristol-Myers BMY-26605, Bristol neoplastic agents, growth inhibiting agents, and nutrients. Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin There are large numbers of antineoplastic agents available sulfate, bryostatin-1, Taiho C-1027, calichemycin, chro in commercial use, in clinical evaluation and in pre-clinical moximycin, dactinomycin, daunorubicin, Kyowa Hakko development, which optionally are selected for treatment of DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, prostate neoplasia by combination drug chemotherapy. Such 50 Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisa antineoplastic agents fall into several major categories: rubicin B, Shionogi DOB-41, doxorubicin, doxorubicin antimetabolite agents, antibiotic-type agents, alkylating fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, agents, hormonal agents, immunological agents, interferon esperamicin-A1, esperamicin-A1b, Erbamont FCE-2 1954, type agents, metallomatrix proteases, Superoxide dismutase Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glido mimics or CléD. inhibitors. Thus, in a preferred embodiment, 55 bactin, gregatin-A, grincamycin, herbimycin, idarubicin, said antineoplastic agent is selected from the group consist illudins, kaZusamycin, kesarirhodins, Kyowa Hakko ing of antimetabolite agents, antibiotic-type agents, alkylat KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko ing agents, hormonal agents, immunological agents, inter KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, feron-type agents, metallomatrix proteases, Superoxide American Cyanamid LL-D49194, Meiji Seika ME 2303, dismutase mimics, and O?3 inhibitors. 60 menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, One class of antineoplastic agents which may be used in neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT combination with an inventive composition consists of anti 01, SRI International NSC-357704, oxalysine, oxaunomy metabolite-type antineoplastic agents. Suitable antimetabo cin, peplomycin, pilatin, pirarubicin, porothramycin, pyrin lite antineoplastic agents may be selected from the group damycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, consisting of 5-FU-fibrinogen, acanthifolic acid, aminothia 65 sibanomicin, siwenmycin, Sumitomo SM-5887, Snow diazole, brequinar sodium, carmofur, Ciba-Geigy CGP Brand SN-706, Snow Brand SN-07, Sorangicin-A, sparso 30694, cyclopentyl cytosine, cytarabine phosphate Stearate, mycin, SS Pharmaceutical SS-21020, SS Pharmaceutical US 7,067,159 B2 13 14 SS-7313B, SS Pharmaceutical SS-9816B, steflimycin B, adchnon, amifostine analogues, detox, dimeSna, 1-102, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, MM-159, N-acylated-dehydroalanines, TGF-Genentech, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and transdermal, nabumetone, Superoxide dismutase (Chiron), Zorubicin. and Superoxide dismutase Enzon. A fourth class of antineoplastic agents which may be used Thus, in a further preferred embodiment, said antineoplas in combination with an inventive composition consists of a tic agent is selected from the group consisting of 5-FU miscellaneous family of antineoplastic agents selected from fibrinogen, acanthifolic acid, aminothiadiazole, brequinar the group consisting of alpha-carotene, alpha-difluorom sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl ethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, 10 cytosine, cytarabine phosphate Stearate, cytarabine conju alstonine, amonafide, amphethinile, amsacrine, Angiostat, gates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, ankinomycin, anti-neoplaston A10, antineoplaston A2, anti dideoxycytidine, dideoxyguanosine, didox, Yoshitomi neoplaston A3, antineoplaston A5, antineoplaston AS2-1, DMDC, doxifluridine, Wellcome EHNA, Merck & Co. Henkel APD, aphidicolin glycinate, asparaginase, Avarol, EX-015, fazarabine, floxuridine, fludarabine phosphate, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour 15 5-fluorouracil, N-(2-furanidyl)-5-fluorouracil, Daiichi Seiy BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar aku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly boron-10, bromofosfamide, Wellcome BW-502, Wellcome LY-264618, methobenzaprim, methotrexate, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajino MZPES, norspermidine, NCI NSC-127716, NCI NSC moto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, 264880, NCI NSC-39661, NCI NSC-612567, Warner-Lam Chemex CHX-100, Warner-Lambert CI-921, Warner-Lam bert PALA, pentostatin, piritrexim, plicamycin, Asahi bert CI-937, Warner-Lambert CI-941, Warner-Lambert Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, CI-958, clanfenur, claviridenone, ICN compound 1259, ICN Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, compound 4711, Contracan, Yakult Honsha CPT-11, crisna tyrosine protein kinase inhibitors, Taiho UFT, uricytin, tol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz Shionogi 254-S, aldo-phosphamide analogues, altretamine, D-609, DABIS maleate, dacarbazine, datelliptinium, didem 25 anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, nin-B, dihaematoporphyrin ether, dihydrolemperone, dina budotitane, Wakunaga CA-102, carboplatin, carmustine, line, distamycin, Toyo Pharmar DM-341, Toyo Pharmar Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclo DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium phosphamide, American Cyanamid CL-286558, Sanofi acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP fenretinide, Fujisawa FR-57704, gallium nitrate, genkw 30 (Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba adaphnin, Chugai GLA-43, Glaxo GR-631 78, grifolan distamycin derivatives, Chugai DWA-2114R, ITI E09, NMF-5N, hexadecylphosphocholine, Green Cross HO-221, elmustine, Erbamont FCE-24517, estramustine phosphate homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofos sodium, fotemustine, Unimed G-6-M, Chinoin GYKI ine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, 17230, hepsul-fam, ifosfamide, iproplatin, lomustine, Otsuak K-76COONa, Kureha Chemical K-AM, MECT 35 mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI Corp KI-8110, American Cyanamid L-623, leukoregulin, NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI PCNU, prednimustine, Proter PTT-119, ranimustine, semus (US) MAP marycin, Merrel Dow MDL-27048, Medco tine, SmithKline SK&F-101772, Yakult Honsha SN-22, MEDR-340, merbarone, merocyanine derivatives, methyla spiromustine, Tanabe Seiyaku TA-077, tauromustine, temo nilinoacridine, Molecular Genetics MGI-136, minactivin, 40 Zolomide, teroxirone, tetraplatin, trimelamol, Taiho. 4181-A, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku aclarubicin, actinomycin D, actinoplanone, Erbamont ADR Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour 456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajino Milling N-021, N-acylated-dehydroalanines, nafazatrom, moto AN-3, Nippon Soda anisomycins, anthracycline, Taisho NCU-190, nocodazole derivative, Normosang, NCI azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bris NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI 45 tol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol NSC-95580, octreotide, Ono ONO-112, oduizanocine, Akzo Myers BMY-26605, Bristol-Myers BMY-27557, Bristol Org-10172, pancratistatin, pazelliptine, Warner-Lambert Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho PD-111707, Warner-Lambert PD-115934, Warner-Lambert C-1027, calichemycin, chromoximycin, dactinomycin, PD-131141, Pierre Fabre PE-1001, ICRT peptide D, pirox daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko antrone, polyhaematoporphyrin, polypreic acid, Efamol por 50 DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, phyrin, probimane, procarbazine, proglumide, Invitron pro Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, tease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubi RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc cin, erbstatin, esorubicin, esperamicin-A1, esperamicin RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F- A1b, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm 55 Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, SP-10094, spatol, spirocyclopropane derivatives, spiroger herbimycin, idarubicin, illudins, kaZusamycin, kesarirhod manium, Unimed, SS Pharmaceutical SS-554, Strypoldi ins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, none, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa superoxide dismutase, Toyama T-506, Toyama T-680, taxol. Hakko KT-6149, American Cyanamid LL-D49194, Meiji Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak 60 Seika ME 2303, menogaril, mitomycin, mitoxantrone, TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Nippon Kayaku NKT-01, SRI International NSC-357704, Kodak USB-006, vinblastine sulfate, Vincristine, vindesine, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, vinestramide, vinorelbine, vintriptol, Vinzolidine, withano porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, lides, and Yamanouchi YM-534. 65 rhizoxin, rodorubicin, Sibanomicin, Siwenmycin, Sumitomo Examples of radioprotective agents which may be used in SM-5887, Snow Brand SN-706, Snow Brand SN-07, sor the combination chemotherapy of this invention are AD-5, angicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS US 7,067,159 B2 15 16 Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, ogy for extracting herbs at low temperature without the use Steflimycin B, Taiho 4181-2, talisomycin, Takeda TAN of industrial chemical Solvents. Such extraction process 868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, allows for the highest potency of active compounds in the Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshi extracts, as much as 250 times the potency of the original tomi Y-25024, Zorubicin, alpha-carotene, alpha-difluorom fresh plant material. ethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, Set forth in Table I is a preferred embodiment of the orally alstonine, amonafide, amphethinile, amsacrine, Angiostat, administered composition, excluding inactive ingredients, as ankinomycin, anti-neoplaston A10, antineoplaston A2, anti used in the inventive methods. The amounts recited in Table neoplaston A3, antineoplaston A5, antineoplaston AS2-1, I represent the preferred dosage of the ingredients listed. Henkel APD, aphidicolin glycinate, asparaginase, Avarol, 10 baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour TABLE I BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome Herb Type Of Extract Plant Part Amount (mg) BW-773, caracemide, carmethizole hydrochloride, Ajino Rosemary Supercritical leaf 100 moto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, 15 Rosemary hydroalcoholic leaf 50 Chemex CHX-100, Warner-Lambert CI-921, Warner-Lam (23% TPA - 34.5 mg) Turmeric Supercritical rhizome 10 bert CI-937, Warner-Lambert CI-941, Warner-Lambert (45% turmerones - 4.5 mg) CI-958, clanfenur, claviridenone, ICN compound 1259, ICN Turmeric hydroalcoholic rhizome 100 compound 4711, Contracan, Yakult Honsha CPT-11, crisna (7% curcumin - 7 mg) tol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz Ginger Supercritical (30% pungent rhizome S4 compounds - 16.2 mg 8% D-609, DABIS maleate, dacarbazine, datelliptinium, didem Zingiberene - 4.3 mg) nin-B, dihaematoporphyrin ether, dihydrolemperone, dina Ginger hydroalcoholic rhizome 46 line, distamycin, Toyo Pharmar DM-341, Toyo Pharmar (3% pungent compounds - DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium .4 mg) 25 Holy basil hydroalcoholic leaf 100 acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, (2% ursolic acid - 2 mg) fenretinide, Fujisawa FR-57704, gallium nitrate, genkw Green tea hydroalcoholic leaf 100 adaphnin, Chugai GLA-43, Glaxo GR-631 78, grifolan (45% polyphenols - 45 mg) NMF-5N, hexadecylphosphocholine, Green Cross HO-221. Huzhang hydroalcoholic root & 8O (8% resveratrol - 6.4 mg) rhizome homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofos Chinese hydroalcoholic root 40 ine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, 30 Goldthread (6% berberine - 2.4 mg) Otsuak K-76COONa, Kureha Chemical K-AM, MECT Barberry hydroalcoholic root 40 Corp KI-8110, American Cyanamid L-623, leukoregulin, (6% berberine - 2.4 mg) Oregano Supercritical leaf 40 lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (0.8% TPA - 0.32 mg) (US) MAP marycin, Merrel Dow MDL-27048, Medco Scutellaria hydroalcoholic (5:1) root 2O MEDR-340, merbarone, merocyanine derivatives, methyla 35 Baicalensis nilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Preferably, the composition set forth in Table I also Milling N-021, N-acylated-dehydroalanines, nafazatrom, includes extra virgin olive oil and yellow beeswax. Taisho NCU-190, nocodazole derivative, Normosang, NCI 40 The inventive methods use a therapeutically effective NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI amount of the active compositions indicated above. This NSC-95580, octreotide, Ono ONO-112, oduizanocine, Akzo effective amount will generally comprise from about 0.1 mg Org-10172, pancratistatin, pazelliptine, Warner-Lambert to about 100 mg of the active agent per kilogram of patient PD-111707, Warner-Lambert PD-115934, Warner-Lambert body weight per day. This effective amount can vary depend PD-131141, Pierre Fabre PE-1001, ICRT peptide D, pirox 45 ing upon the physical status of the patient and other factors antrone, polyhaematoporphyrin, polypreic acid, Efamol por well known in the art. Moreover, it will be understood that phyrin, probimane, procarbazine, proglumide, Invitron pro this dosage of active agent can be administered in a single tease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries or multiple dosage units to provide the desired therapeutic RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc effect. If desired, other therapeutic agents can be employed RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F- 50 in conjunction with those provided by the present inventive 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm Subject matter. SP-10094, spatol, spirocyclopropane derivatives, spiroger The inventive methods use compositions which are pref manium, Unimed, SS Pharmaceutical SS-554, Strypoldi erably delivered to the patient by means of a pharmaceuti none, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, cally acceptable carrier. Such carriers are well known in the superoxide dismutase, Toyama T-506, Toyama T-680, taxol. 55 art and generally will be in either solid or liquid form. Solid Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak form pharmaceutical preparations which may be prepared TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko according to the present inventive subject matter include UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman powders, tablets, dispersible granules, capsules, and cachets. Kodak USB-006, vinblastine sulfate, Vincristine, vindesine, In general, Solid form preparations will comprise from about vinestramide, vinorelbine, vintriptol, Vinzolidine, withano 60 5% to about 90% by weight of the active agent. lides, Yamanouchi YM-534, AD-5, adohnon, amifostine A solid carrier can be one or more substances which may analogues, detox, dimesna, 1-102, MM-159, N-acylated also act as diluents, flavoring agents, solubilizers, lubricants, dehydroalanines, TGF-Genentech, tiprotimod, amifostine, Suspending agents, binders or tablet disintegrating agents; it WR-151327, FUT-187, ketoprofen transdermal, nabume can also be encapsulating material. In powders, the carrier is tone, and Superoxide dismutase. 65 a finely divided solid which is in admixture with the viscous A benefit provided by the inventive compositions is the active compound. In tablets, the active compound is mixed utilization of Supercritical extraction, an innovative technol with a carrier having the necessary binding properties in US 7,067,159 B2 17 18 Suitable proportions and compacted to the shape and size in amounts up to about 20% and preferably from about 1% desired. Suitable Solid carriers include magnesium carbon to about 15% by weight of the pharmaceutical composition. ate, magnesium Stearate, talc, Sugar, lactose, pectin, dextrin, Sweeteners which may be employed include those sweet starch, gelatin, tragacanth, methylcellulose, Sodium car eners, both natural and artificial, well known in the art. boxymethylcellulose, a low melting wax, cocoa butter, and Sweetening agents such as monosaccharides, disaccharides the like. The term preparation is intended to include the and polysaccharides such as Xylose, ribose, glucose, man formulation of the active compound with encapsulating nose, galactose, fructose, dextrose, Sucrose, maltose, par materials as a carrier which may provide a capsule in which tially hydrolyzed starch or corn Syrup Solids and Sugar the active component (with or without other carriers) is alcohols such as Sorbitol. Xylitol, mannitol and mixtures Surrounded by carrier, which is thus in association with it. 10 thereof may be utilized in amounts from about 10% to about Similarly, cachets are included. Tablets, powders, cachets, 60% and preferably from about 20% to about 50% by weight and capsules can be used as Solid dosage forms suitable for of the pharmaceutical composition. Water soluble artificial oral administration. If desired for reasons of convenience or Sweeteners such as saccharin and saccharin salts such as patient acceptance, pharmaceutical tablets prepared accord Sodium or calcium, cyclamate salts, acesulfame-K, aspar ing to the inventive Subject matter may be provided in 15 tame and the like and mixtures thereof may be utilized in chewable form, using techniques well known in the art. amounts from about 0.001% to about 5% by weight of the Also contemplated as Suitable carriers are solid form composition. preparations which are intended to be converted, shortly Flavorants which may be employed in the pharmaceutical before use, to liquid form preparations for either oral or products of the inventive subject matter include both natural parenteral administration. Such liquid forms include Solu and artificial flavors, and mints such as peppermint, men tions, Suspensions, and emulsions. These particular Solid thol, Vanilla, artificial Vanilla, chocolate, artificial chocolate, form preparations are most conveniently provided in unit cinnamon, various fruit flavors, both individually and dose form and as Such are used to provide a single liquid mixed, in amounts from about 0.5% to about 5% by weight dosage unit. Alternately, Sufficient Solid may be provided so of the pharmaceutical composition. that after conversion to liquid form, multiple individual 25 Colorants useful in the present inventive subject matter liquid doses may be obtained by measuring predetermined include pigments which may be incorporated in amounts of Volumes of the liquid form preparation as with a syringe, up to about 6% by weight of the composition. A preferred teaspoon, or other volumetric container. When multiple pigment, titanium dioxide, may be incorporated in amounts liquid doses are so prepared, it is preferred to maintain the up to about 1%. Also, the colorants may include other dyes unused portion of said liquid doses at low temperature (i.e., 30 Suitable for food, drug and cosmetic applications, known as under refrigeration) in order to retard possible decomposi F.D.&C. dyes and the like. Such dyes are generally present tion. The solid form preparations intended to be converted to in amounts up to about 0.25% and preferably from about liquid form may contain, in addition to the active material, 0.05% to about 0.2% by weight of the pharmaceutical flavorants, colorants, stabilizers, buffers, artificial and natu composition. A full recitation of all F.D.&C. and D.&C. dyes ral Sweeteners, dispersants, thickeners, Solubilizing agents, 35 and their corresponding chemical structures may be found in and the like. The liquid utilized for preparing useful liquid the Kirk-Othmer Encyclopedia of Chemical Technology, in form preparations may be water, isotonic water, ethanol, Volume 5, at pages 857–884, which text is accordingly glycerine, propylene glycol, and the like as well as mixtures incorporated herein by reference. thereof. Naturally, the liquid utilized will be chosen with Useful solubilizers include alcohol, propylene glycol, regard to the route of administration. For example, liquid 40 polyethylene glycol and the like and may be used to solu preparations containing large amounts of ethanol are not bilize the flavors. Solubilizing agents are generally present in amounts up to about 10%; preferably from about 2% to suitable for parenteral use. about 5% by weight of the pharmaceutical composition. The pharmaceutical preparation may also be in a unit Lubricating agents which may be used when desired in dosage form. In Such form, the preparation is Subdivided 45 the instant compositions include silicone oils or fluids Such into unit doses containing appropriate quantities of the as Substituted and unsubstituted polysiloxanes, e.g., dim active component. The unit dosage form can be a packaged ethyl polysiloxane, also known as dimethicone. Other well preparation, the package containing discrete quantities of known lubricating agents may be employed. preparation, for example, packeted tablets, capsules, and It is not expected that the inventive methods use compo powders in vials or ampoules. The unit dosage form can also 50 sitions which will display significant adverse interactions be a capsule, cachet, or tablet itself or it can be the with other synthetic or naturally occurring Substances. Thus, appropriate number of any of these in packaged form. a compound of the present inventive subject matter may be The pharmaceutical preparations of the inventive subject administered in combination with other compounds and matter may include one or more preservatives well known in compositions useful for treating prostate neoplasia. In par the art, Such as benzoic acid, Sorbic acid, methylparaben, 55 ticular the inventive methods use compositions which may propylparaben and ethylenediaminetetraacetic acid (EDTA). be administered in combination with other inventive com Preservatives are generally present in amounts up to about positions, other antineoplastic Substances, and the like. 1% and preferably from about 0.05 to about 0.5% by weight The optimal pharmaceutical formulations will be deter of the pharmaceutical composition. mined by one skilled in the art depending upon consider Useful buffers for purposes of the inventive subject matter 60 ations such as the route of administration and desired include citric acid-Sodium citrate, phosphoric acid-sodium dosage. See, for example, "Remington’s Pharmaceutical phosphate, and acetic acid-sodium acetate in amounts up to Sciences’, 18th ed. (1990, Mack Publishing Co., Easton, Pa. about 1% and preferably from about 0.05 to about 0.5% by 18042), pp. 1435–1712, which is hereby incorporated by weight of the pharmaceutical composition. Useful suspend reference in its entirety. Such formulations may influence the ing agents or thickeners include cellulosics like methylcel 65 physical state, stability, rate of in Vivo release, and rate of in lulose, carageenans like alginic acid and its derivatives, Vivo clearance of the present therapeutic agents of the Xanthan gums, gelatin, acacia, and microcrystalline cellulose inventive subject matter. US 7,067,159 B2 19 20 Route(s) of Administration evaporated off, leaving a powdered extract residue, referred to herein as “the hydroalcoholic extract of ginger. The compounds and compositions are preferably admin The composition of this invention will preferably contain istered orally in the form of capsules, tablets, aqueous the supercritical extract and the hydroalcoholic extract of Suspensions, or solutions. Tablets may contain carriers such 5 ginger at a weight ratio of preferably from about 0.9 to about as lactose and corn starch, and/or lubricating agents such as 1.4 parts, more preferably from about 1.1 to about 1.3 parts, magnesium Stearate. Capsules may contain diluents includ most preferably about 1.17 parts, of supercritical extract per ing lactose and dried corn starch. Aqueous Suspensions may 1 part post-Supercritical hydroalcoholic extract. contain emulsifying and Suspending agents combined with The Supercritical extracts of ginger, rosemary, turmeric the active ingredient. The oral dosage forms may further 10 and oregano used in the inventive compositions can be contain Sweetening, flavoring, coloring agents, or combina prepared according to known Supercritical extraction meth tions thereof. Delivery in an enterically coated tablet, caplet, ods, such as disclosed, e.g., in E. Stahl, K. W. Quirin, D. or capsule, to further enhance stability and provide release Gerard, Dense Gases for Extraction and Refining, Springer in the intestinal tract to improve absorption, is the best mode Verlag 4 1988, which is hereby incorporated by reference of administration currently contemplated. 15 herein. The hydroalcoholic extracts of rosemary, turmeric, holy Dosage basil, green tea, huzhang, Chinese goldthread, barberry and Scutellaria baicalensis used in the inventive compositions Dosage levels on the order of about 0.001 mg to about 100 can be prepared according to conventional hydroalcoholic mg per kilogram body weight of the active ingredient extraction techniques. For example, the hydroalcoholic compounds or compositions are useful in the treatment of extracts can be prepared by extracting the plant portion in a the above conditions, with preferred levels ranging from 200 waterfalcohol (preferably water/ethanol) mixture (prefer mg per day to 1600 mg per day. The compounds and ably composed of 60–80 parts alcohol and 40–20 parts compositions of the present inventive Subject matter may water), and then evaporating off the waterfalcohol liquid, usually be given in two or three doses daily. Starting with a 25 leaving a powdered extract residue (referred to herein as low dose (200–300 mg) twice daily and slowly working up “the hydroalcoholic extract’). to higher doses if needed is a preferred strategy. The amount In the composition of this invention, the hydroalcoholic of active ingredient that may be combined with the carrier extract of turmeric and the supercritical extract of turmeric materials to produce a single dosage form will vary depend will preferably be present at a weight ratio of preferably ing upon the host treated and the particular mode of admin 30 from about 8 to about 12 parts, more preferably from about istration. 9 parts to about 11 parts, most preferably about 10 parts, of It is understood, however, that a specific dose level for any hydroalcoholic extract per 1 part of Supercritical extract. particular patient will depend upon a variety of factors, The composition of this invention will preferably contain including the activity of the specific compound employed; the supercritical extract of rosemary and the hydroalcoholic the age, body weight, general health, sex and diet of the 35 extract of rosemary at a weight ratio of preferably from patient; the time of administration; the rate of excretion; about 1.6 to about 2.4 parts, more preferably from about 1.8 drug combination; the severity of the particular disorder to about 2.2 parts, most preferably about 2.0 parts, of being treated; and the form of administration. One of ordi Supercritical extract per 1 part of hydroalcoholic extract. nary skill in the art would appreciate the variability of such The hydroalcoholic extract of ginger used in the inventive factors and would be able to establish specific dose levels 40 compositions will preferably contain from about 2.4% to using no more than routine experimentation. about 3.6%, more preferably from about 2.7% to about 3.3%, most preferably about 3.0%, by weight of pungent EXAMPLES compounds (e.g., shogaol). The following examples are illustrative of the present 45 The Supercritical extract of ginger used in the inventive inventive subject matter and are not intended to be limita compositions will contain preferably from about 24% to tions thereon. Unless otherwise indicated, all percentages about 36%, more preferably from about 27% to about 33%, are based upon 100% by weight of the final composition. most preferably about 30%, by weight of pungent com pounds (e.g., shogaol) and preferably from about 6.4% to Example 1 about 9.6%, more preferably from about 7.2% to about 50 8.8%, most preferably about 8%, by weight of Zingiberene. Preparation of the Inventive Compositions The supercritical extract of turmeric used in the inventive compositions will contain preferably from about 36% to The inventive compositions are prepared by methods about 54%, more preferably from about 40.5% to about known in the art, and disclosed in Applicants’ U.S. Pat. No. 55 49.5%, most preferably about 45%, by weight of tur 6,387,416. The preparation of the component elements of COCS. the inventive compositions is Summarized as follows: The supercritical extract of rosemary used in the inventive The hydroalcoholic extract of ginger used in the inventive compositions will contain preferably from about 18.4% to compositions is preferably prepared as follows. The ginger about 27.6%, more preferably from about 20.7% to about rhizome, which is preferably cryogenically ground to pre 60 25.3%, most preferably about 23%, by weight of total serve heat sensitive components, is subjected to Supercritical phenolic antioxidants (“TPA). extraction to obtain: (i) an oil extract, referred to herein as The Supercritical extract of oregano used in the inventive “the Supercritical extract of ginger, containing delicate compositions will contain preferably from about 0.64% to lipophilic components, and (ii) an oil-free residue. The about 0.96%, more preferably from about 0.72% to about oil-free residue is then extracted in a waterfalcohol, prefer 65 0.88%, most preferably about 0.8%, by weight of TPA. ably water/ethanol, mixture composed of 60–80 parts alco The hydroalcoholic extract of turmeric used in the inven hol and 40–20 parts water. The alcohol/water liquid is then tive compositions will contain preferably from about 5.6% US 7,067,159 B2 21 22 to about 8.4%, more preferably from about 6.3% to about curcumin alone, demonstrating a synergistic effect between 7.7%, most preferably about 7%, by weight of curcumin. the extracts used in the inventive compositions. The hydroalcoholic extract of rosemary used in the inven tive compositions will contain preferably from about 18.4% Example 3 to about 27.6%, more preferably from about 20.7% to about 5 25.3%, most preferably about 23%, by weight of TPA. Effect of the Inventive Compositions on The hydroalcoholic extract of holy basil used in the Pre-malignant Prostate Neoplasia inventive compositions will contain preferably from about 1.6% to about 2.4%, more preferably from about 1.8% to A patient presents for treatment of a pre-malignant neo about 2.2%, most preferably about 2%, by weight of ursolic 10 plasia of the prostate. An inventive composition is admin acid. istered to said patient over a course of treatment lasting for The hydroalcoholic extract of green tea used in the several weeks, resulting in no significant side effects. The inventive compositions will contain preferably from about patient experiences a reversal in the growth of neoplastic 36% to about 54%, more preferably from about 40.5% to cells and death of existing neoplastic cells, resulting in the about 49.5%, most preferably about 45%, by weight of 15 neoplasia becoming undetectable. polyphonies. Example 4 The hydroalcoholic extract of huzhang used in the inven tive compositions will contain preferably from about 6.4% Effect of the Inventive Compositions on Prostate to about 9.6%, more preferably from about 7.2% to about Epithelioma 8.8%, most preferably about 8%, by weight of resveratrol. The hydroalcoholic extract of Chinese goldthread used in A patient presents for treatment of a malignant stage B the inventive compositions will contain preferably from epithelioma of the prostate, confirmed by elevated PSA test, about 4.8% to about 7.2%, more preferably from about 5.4% manual examination, and biopsy of the tumor. An inventive to about 6.6%, most preferably about 6%, by weight of 25 composition is administered to said patient over a course of berberine. treatment lasting for several months, resulting in no signifi The hydroalcoholic extract of barberry used in the inven cant side effects. The patient experiences a reversal in the tive compositions will contain preferably from about 4.8% growth rate of tumor cells, death of existing tumor cells and to about 7.2%, more preferably from about 5.4% to about reduction in tumor size, and no metastasis of the tumor. With 6.6%, most preferably about 6%, by weight of berberine. 30 continuing treatment, the patient continues to exhibit no secondary symptoms of prostate neoplasia, no long term Example 2 side effects of the treatment, and no metastasis of the tumor. The inventive subject matter being thus described, it will Effect of the Inventive Compositions on Prostate Cancer Cells be obvious that the same may be modified or varied in many 35 ways. Such modifications and variations are not to be regarded as a departure from the spirit and scope of the A series of dilutions of the inventive composition in inventive subject matter and all such modifications and DMSO were prepared, and the dilutions were added to variations are intended to be included within the scope of the LNCaP growth medium so that all doses tested had equiva following claims. lent (0.1%) DMSO levels. Cell growth curves were prepared 40 by counting cells at 24, 48, and 72 hours, and were compared We claim: to control cells treated at the same times with 0.1% DMSO 1. A method for treating prostate neoplasia in a Subject, alone. Apoptosis in these cultures was evaluated by Western comprising the step of administering an effective amount of blot analysis of PARP cleavage and measurement of a composition to said Subject to treat said prostate neoplasia, caspase-3 activity using a calorimetric Substrate assay. 45 said composition comprising therapeutically effective Effects on purified COX-2 enzyme activity was measured amounts of Supercritical extracts of rosemary, turmeric, using a calorimetric assay, and effects on COX-2 protein oregano and ginger; and therapeutically effective amounts of expression was determined via Western blot analysis of hydroalcoholic extracts of holy basil, ginger, turmeric, protein extracts from treated cells. Activities were also Scutellaria baicalensis, rosemary, green tea, huZhang, Chi compared to the effects of purified curcumin dissolved in 50 nese goldthread, and barberry, DMSO, at levels equivalent to those that would be found in provided that said prostate neoplasia is not prostatic the inventive compositions at similar doses. intraepithelial neoplasia. LNCaP cell growth was suppressed by the inventive 2. The method of claim 1, wherein said composition is compositions, and by 72 hours there was a 78% reduction in administered orally. cell number in treated cultures (7.9x10" vs 3.53x10 cells 55 3. The method of claim 2, wherein the orally administered per well, p=0.01) compared to controls. PARP cleavage composition is in the form of one or more capsules, one or fragments were evident and caspase-3 activity was upregu more tablets, or one or more pills. lated 2-fold by 72 hour treatment, demonstrating an apop 4. The method of claim 1, wherein the composition totic effect that was not found in controls. COX-2 activity comprises: was also significantly decreased in the presence of the 60 (A) from about 4.5% to about 7.5% by weight of the inventive compositions, while equivalent doses of curcumin hydroalcoholic extract of ginger, alone did not inhibit COX-2 in the assay utilized. COX-2 (B) from about 5.5% to about 8.5% by weight of the protein expression in LNCaP cells was not affected. The Supercritical extract of ginger; results are of this example are shown in FIGS. 1-5. (C) from about 1.0% to about 1.5% by weight of the These results demonstrate that the inventive compositions 65 Supercritical extract of turmeric; strongly suppress LNCaP cells and induce apoptosis. These (D) from about 10.0% to about 16.0% by weight of the effects appear to be more potent that those observed with Supercritical extract of rosemary; US 7,067,159 B2 23 24 (E) from about 4.0% to about 6.0% by weight of the (A) from about 4.5% to about 7.5% by weight of the Supercritical extract of oregano; hydroalcoholic extract of ginger, wherein the extract (F) from about 10.0% to about 16.0% by weight of the comprises from about 2.4% to about 3.6% by weight of hydroalcoholic extract of turmeric; (O) from about pungent compounds; 5.5% to about 8.0% by weight of the hydroalcoholic (B) from about 5.5% to about 8.5% by weight of the extract of rosemary: Supercritical extract of ginger, wherein the extract (H) from about 10.0% to about 16.0% by weight of the comprises from about 24% to about 36% by weight of hydroalcoholic extract of holy basil; pungent compounds and from about 6.4% to about (I) from about 10.0% to about 16.0% by weight of the 9.6% by weight of Zingiberene; hydroalcoholic extract of green tea; 10 (C) from about 1.0% to about 1.5% by weight of the (J) from about 8.0% to about 12.0% by weight of the supercritical extract of turmeric, wherein the extract hydroalcoholic extract of huZhang; comprises from about 36% to about 54% by weight of (K) from about 4.0% to about 6.0% by weight of the turmerones; hydroalcoholic extract of Chinese goldthread: (D) from about 10.0% to about 16.0% by weight of the (L) from about 4.0% to about 6.0% by weight of the 15 Supercritical extract of rosemary, wherein the extract hydroalcoholic extract of barberry; and comprises from about 18.4% to about 27.6% by weight (M) from about 2.0% to about 3.0% by weight of the of total phenolic antioxidants; hydroalcoholic extract of Scutellaria baicalensis. (E) from about 4.0% to about 6.0% by weight of the 5. The method of claim 1, wherein the weight ratio of the Supercritical extract of oregano, wherein the extract Supercritical extract of ginger to the hydroalcoholic extract comprises from about 0.64% to about 0.96% by weight of ginger is from about 0.9:1 to about 1.4:1. of total phenolic antioxidants; 6. The method of claim 1, wherein the weight ratio of the (F) from about 10.0% to about 16.0% by weight of the hydroalcoholic extract of turmeric to the supercritical extract hydroalcoholic extract of turmeric, wherein the extract of turmeric is from about 8:1 to about 12:1. comprises from about 5.6% to about 8.4% by weight of 7. The method of claim 1, wherein the weight ratio of the 25 curcumin; supercritical extract of rosemary to the hydroalcoholic (G) from about 5.5% to about 8.0% by weight of the extract of rosemary is from about 1.6:1 to about 2.4:1. hydroalcoholic extract of rosemary, wherein the extract 8. The method of claim 1, wherein the hydroalcoholic comprises from about 18.4% to about 27.6% by weight extract of ginger comprises from about 2.4% to about 3.6% of total phenolic antioxidants; by weight of pungent compounds. 30 (H) from about 10.0% to about 16.0% by weight of the 9. The method of claim 1, wherein the superoritical hydroalcoholic extract of holy basil, wherein the extract of ginger comprises from about 24% to about 36% by extract comprises from about 1.6% to about 2.4% by weight of pungent compounds and from about 6.4% to about weight of ursolic acid; 9.6% by weight of Zingiberene. (I) from about 10.0% to about 16.0% by weight of the 10. The method of claim 1, wherein the supercritical 35 hydroalcoholic extract of green tea, wherein the extract extract of turmeric comprises from about 36% to about 54% comprises from about 36% to about 54% by weight of by weight of turmerones. polyphenols; 11. The method of claim 1, wherein the supercritical (J) from about 8.0% to about 12.0% by weight of the extract of rosemary comprises from about 18.4% to about hydroalcoholic extract of huZhang, wherein the extract 27.6% by weight of total phenolic antioxidants. 40 comprises from about 6.4% to about 9.6% by weight of 12. The method of claim 1, wherein the supercritical resveratrol; extract of oregano comprises from about 0.64% to about (K) from about 4.0% to about 6.0% by weight of the 0.96% by weight of total phenolic antioxidants. hydroalcoholic extract of Chinese goldthread, wherein 13. The method of claim 1, wherein the hydroalcoholic 45 the extract from about 4.8% to about 7.2% by weight of extract of turmeric comprises from about 5.6% to about berberine; 8.4% by weight of curcumin. (L) from about 4.0% to about 6.0% by weight of the 14. The method of claim 1, wherein the hydroalcoholic hydroalcoholic extract of barberry, wherein the extract extract of rosemary comprises from about 18.4% to about from about 4.8% to about 7.2% by weight of berberine; and 27.6% by weight of total phenolic antioxidants. 50 15. The method of claim 1, wherein the hydroalcoholic (M) from about 2.0% to about 3.0% by weight of the extract of holy basil comprises from about 1.6% to about hydroalcoholic extract of Scutellaria baicalensis, 2.4% by weight of ursolic acid. and wherein said composition further comprises: 16. The method of claim 1, wherein the hydroalcoholic (i) the Supercritical extract of ginger and the hydroalco extract of green tea comprises from about 36% to about 54% 55 holic extract of ginger at a weight ratio of from about by weight of polyphenols. 0.9 to about 1.4 parts of supercritical extract per 1 part 17. The method of claim 1, wherein the hydroalcoholic of post Supercritical hydroalcoholic extract; extract of huzhang comprises from about 6.4% to about (ii) the hydroalcoholic extract of turmeric and the super 9.6% by weight of resveratrol. critical extract of turmeric at a weight ratio of from 18. The method of claim 1, wherein the hydroalcoholic 60 about 8 to about 12 parts of hydroalcoholic extract per extract of Chinese goldthread comprises from about 4.8% to 1 part of Supercritical extract; and about 7.2% by weight of berberine. (iii) the supercritical extract of rosemary and the hydroal 19. The method of claim 1, wherein the hydroalcoholic coholic extract of rosemary at a weight ratio of from extract of barberry comprises from about 4.8% to about about 1.6 to about 2.4 parts of supercritical extract per 7.2% by weight of berberine. 65 1 part of hydroalcoholic extract. 20. The method of claim 1, wherein said composition 21. The method of claim 1, said composition is adminis provided in step (a) comprises: tered in a daily dosage of at least about 700 mg. US 7,067,159 B2 25 26 22. The method of claim 1, wherein said composition is 30. The method of claim 23, wherein cancer related to administered on a daily basis for at least 4 weeks. said at least one cancerous tumor is metastasized to regional 23. A method for treating at least one cancerous tumor of lymph nodes or other parts of said Subject. the prostate in a subject, comprising the step of administer 31. A method for treating side effects associated with ing an effective amount of a composition to said subject to prostate neoplasia in a subject, comprising the step of treat said tumor, said composition comprising therapeuti administering an effective amount of a composition to said cally effective amounts of Supercritical extracts of rosemary, Subject to treat said side effects, said composition compris turmeric, oregano and ginger; and therapeutically effective ing therapeutically effective amounts of Supercritical amounts of hydroalcoholic extracts of holy basil, ginger, extracts of rosemary, turmeric, oregano and ginger; and turmeric, Scutellaria baicalensis, rosemary, green tea, 10 therapeutically effective amounts of hydroalcoholic extracts huZhang, Chinese goldthread, and barberry. of holy basil, ginger, turmeric, Scutellaria baicalensis, rose 24. The method of claim 23, wherein said composition is mary, green tea, huZhang, Chinese goldthread, and barberry, administered orally. wherein said side effects are selected from the group 25. The method of claim 24, wherein the orally admin consisting of disrupted sexual desire or performance on istered composition is in the form of one or more capsules, 15 either a temporary or permanent basis, impotence, one or more tablets, or one or more pills. extensive monitoring for progression of the disease, 26. The method of claim 23, wherein the composition stress of illness, and urinary incontinence. comprises: 32. The method of claim 31, wherein said composition is (A) from about 4.5% to about 7.5% by weight of the administered orally. hydroalcoholic extract of ginger, 33. The method of claim 32, wherein the orally admin (B) from about 5.5% to about 8.5% by weight of the istered composition is in the form of one or more capsules, Supercritical extract of ginger; one or more tablets, or one or more pills. (C) from about 1.0% to about 1.5% by weight of the 34. The method of claim 31, wherein the composition Supercritical extract of turmeric; comprises: (D) from about 10.0% to about 16.0% by weight of the 25 Supercritical extract of rosemary; (A) from about 4.5% to about 7.5% by weight of the (E) from about 4.0% to about 6.0% by weight of the hydroalcoholic extract of ginger, Supercritical extract of oregano; (B) from about 5.5% to about 8.5% by weight of the (F) from about 10.0% to about 16.0% by weight of the Supercritical extract of ginger; hydroalcoholic extract of turmeric; 30 (C) from about 1.0% to about 1.5% by weight of the (G) from about 5.5% to about 8.0% by weight of the Supercritical extract of turmeric; hydroalcoholic extract of rosemary: (D) from about 10.0% to about 16.0% by weight of the (H) from about 10.0% to about 16.0% by weight of the Supercritical extract of rosemary; hydroalcoholic extract of holy basil; (E) from about 4.0% to about 6.0% by weight of the (I) from about 10.0% to about 16.0% by weight of the 35 Supercritical extract of oregano; hydroalcoholic extract of green tea; (F) from about 10.0% to about 16.0% by weight of the (J) from about 8.10% to about 12.0% by weight of the hydroalcoholic extract of turmeric; hydroalcoholic extract of huZhang; (G) from about 5.5% to about 8.0% by weight of the (K) from about 4.0% to about 6.0% by weight of the hydroalcoholic extract of rosemary: hydroalcoholic extract of Chinese goldthread: 40 (H) from about 10.0% to about 16.0% by weight of the (L) from about 4.0% to about 6.0% by weight of the hydroalcoholic extract of holy basil; hydroalcoholic extract of barberry; and (I) from about 10.0% to about 16.0% by weight of the (M) from about 2.0% to about 3.0% by weight of the hyciroalcoholic extract of green tea; hydroalcoholic extract of Scutellaria baicalensis. (J) from about 8.0% to about 12.0% by weight of the 27. The method of claim 23, wherein said at least one 45 cancerous tumor is detected during Surgery on the prostate hydroalcoholic extract of huZhang; of said Subject, having not been felt by a physician on (K) from about 4.0% to about 6.0% by weight of the physical examination of said Subject. hydroalcoholic extract of Chinese goldthread: 28. The method of claim 23, wherein said at least one (L) from about 4.0% to about 6.0% by weight of the cancerous tumor is confined to the prostate of said subject 50 hydroalcoholic extract of barberry; and and is detected by a physician on physical examination of (M) from about 2.0% to about 3.0% by weight of the said Subject. hydroalcoholic extract of Scutellaria baicalensis. 29. The method of claim 23, wherein cancer related to 35. The method of claim 31, wherein said side effect said at least one cancerous tumor extends beyond the treated comprises disrupted sexual performance. prostate capsule of said subject, but has not spread to lymph 55 nodes in said subject. k k k k k