Use of PHY906 as treatment for inflammatory bowel disease and/or irritable bowel syndrome

Abstract

The present invention includes a method of using PHY906 for treating a bowel disorder including inflammatory bowel disease and irritable bowel syndrome. Particularly, the present invention provides a multiple symptoms treatment for the bowel disorder.

Claims

1. A method of treating a bowel disorder comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising an herbal preparation consisting essentially of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora.

2. The method of claim 1, which treats multiple symptoms of the bowel disorder.

3. The method of claim 2, wherein the multiple symptoms comprises two or more symptoms selected from the group consisting of visceral pain, intestinal motility, inflammation, lower abdominal pain, bloating associated with alternation of bowel habits, abdominal discomfort relievable by defecation, fever, vomiting, acute diarrhea, positive stool culture, and combinations thereof.

4. The method of claim 1, wherein the bowel disorder is inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS).

5. The method of claim 4, wherein the inflammatory bowel disease comprises a condition selected from the group consisting of Crohn's disease, ulcerative colitis (UC), collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, infective colitis, indeterminate colitis, and combinations thereof.

6. The method of claim 4, wherein the irritable bowel syndrome comprises a condition selected from the group consisting of diarrhea-predominant IBS, constipation-predominant IBS, alternating stool pattern IBS, post-infective IBS, and combinations thereof.

7. The method of claim 1, further comprising co-administering to the patient in need thereof a therapeutically effective amount of at least one additional active agent.

8. The method of claim 7, wherein the additional active agent is selected from the group consisting of an aminosalicylate, a corticosteroid, an immunomodulator, an antibiotic, a biologic, and combinations thereof.

9. The method of claim 7, wherein the additional active agent is selected from the group consisting of a stool softener, a laxative, an antidiarrheal, an opioid or opioid analog, a tricyclic, a selective serotonin reuptake inhibitor, a probiotic, and combinations thereof.

10. The method of claim 1, further comprising acupuncture or surgery.

11. The method according to claim 1 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

12. The method according to claim 2 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora are mixed together in said herbal preparation in a weight ratio of 1.5:1:1:1.

13. The method according to claim 3 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

14. The method according to claim 4 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

15. The method according to claim 5 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

16. The method according to claim 6 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

17. The method according to claim 7 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of 1.5:1:1:1.

18. The method according to claim 1 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

19. The method according to claim 2 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora are mixed together in said herbal preparation in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

20. The method according to claim 3 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

21. The method according to claim 4 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

22. The method according to claim 5 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

23. The method according to claim 6 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

24. The method according to claim 7 wherein said herbal preparation is a mixture of Scutellaria baicalensis, Glycyrrhiza uralensis, Ziziphus jujuba and Paeonia lactiflora in a weight ratio of about 0.286:about 0.214:about 0.286:about 0.214.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A is a graph showing the change of initial tumor size after various days of CPT-11 treatment and thereby demonstrating the antitumor efficacy of the combination of PHY906 and CPT-11. Methods: A single bolus dose (360 mg/kg) of CPT-11 was administered to BDF-1 mice bearing murine Colon 38 tumors on day 0, 30 min after PHY906 (500 mg/kg). PHY906 administration was continued bid for 4 days. Treatment groups consisted of 5 mice each. FIG. 1A shows antitumor effects. Vertical lines indicate + (up) or − (down) one standard derivation (SD).

(2) FIG. 1B is a graph showing the change of body weight after various days of CPT-II treatment and thereby demonstrating the reduction of CPT-11 toxicity by PHY906. Methods: A single bolus dose (360 mg/kg) of CPT-11 was administered to BDF-1 mice bearing murine Colon 38 tumors on day 0, 30 min after PHY906 (500 mg/kg). PHY906 administration was continued bid for 4 days. Treatment groups consisted of 5 mice each. FIG. 1B shows body weights. Vertical lines indicate + (up) or − (down) one standard derivation (SD).

(3) FIG. 2 is a Kaplan-Meyer survival curve demonstrating the reduction of toxicity CPT-11 toxicity by PHY906. Methods: A single bolus dose (360 mg/kg) of CPT-11 was administered to BDF-1 mice bearing murine Colon 38 tumors on day 0, 30 min after PHY906 (500 mg/kg). PHY906 administration was continued bid for 4 days. Treatment groups consisted of 5 mice each.

(4) FIG. 3 is a graph demonstrating the inhibitory effect of PHY906 against both intrinsic and TNF-induced NF-kB.

DETAILED DESCRIPTION OF THE INVENTION

(5) During a literature search of Chinese medicinal formulations that have been used to treat symptoms similar to those that are associated with modern cancer chemotherapy, PHY906 was selected from among the several formulations found. PHY906, a decoction of a mixture of four herbs, was established more than 1500 years ago for the treatment of diarrhea, abdominal spasms, fever, headache, vomiting, nausea, extreme thirst, and subcardial distention.sup.(39).

(6) PHY906 includes at least four herbs commonly known as Scute, Licorice, Peony Alba and Ziziphi Fruit (Table 3). Thus, one plant species is chosen from each one of the four plant groups provided in Table 3 in order to produce the desired herbal compositions of the present invention. While particular combinations of the listed plant species are provided as examples of preferred PHY906 formulations, the compositions and methods of this invention encompass any combination of four plant species wherein a plant species is selected from each one of the four groups in Table 3. This invention encompasses any such combination of such herbs which have at least one of the biological activities or desired effects ascribed to PHY906 as described herein.

(7) TABLE-US-00001 TABLE 1 Examples of Particular Species of Four Genera which can be Used to make PHY906. Common English Name of TCM Herbal Group Scutellaria Licorice Peony Alba Ziziphi Fruit Anemone rivularis Abrus mollis Hance Paeonia delavayi Ziziphusjujuba Mill. Buch.-Ham. ex DC. Franch. var. lutea (Delavay ex Mill. Franch.) Finet et Gagnep. Thalictrum omelense Glycyrrhiza aspera Paeonia lactiflora Ziziphusjujuba Mill. W. T. Wang et S. H. Pall. Pall. var. inermis Wang Mahonia bealei (Fort.) Glycyrrhiza eurycarpa Paeonia mairei Levi. Carr. P. C. Li Nandina domestica Glycyrrhiza glabra L. Paeonia obovata Thunb. Maxim. var. willmottiae (Stapi) Stern Scutellaria amoena Glycyrrhiza inflata Daphne papyracea C. H. Wright Bat. Wall. ex Steud. Scutellaria amoena Glycyrrhiza Cynanchum C. H. Wright var. squamulosa Franch. otophyllum Schneid. cinerea Hand.-Mazz. Onuma Scutellaria baicalensis Glycyrrhiza uralensis Codonopsis Georgi Fisch. lanceolara Sieb. et Zucc. Trautv. Scutellaria baicalensis Phlomis betonicoides Georgi var. albiflora K. Diels Scutellaria hypericifolia Levl Scutellaria likiangensia Diels Scutellaria obtusifolia Hemsl. var. trinervata (Vant.) C. Y. Wu et H. W. Li Scutellaria regeliana Nakai Scutellaria regeliana Nakai var. ikonnikovii (Juz.) C. Y. Wu et H. W. Li Scutellaria ehderiana Diels Scutellaria Licorice Peony Alba Ziziphi Fruit Scutellaria tenax W. W. Smith var. patentipilosa (Hand.- Marz.) C. Y. Wu Scutellaria viscidula Bunge
In one embodiment, PHY906 includes Scutellaria baicalensis Georgi (scute baical skullcap root), Paeonia lactiflora Pall. (white peony root). Glycyrrhiza uralensis Fisch. (licorice root), and Ziziphus jujube Mill. (date fruit); which are mixed in a ratio of 1.5:1:1:1 by weight, respectively. Each of the four herbs of PHY906 is reported to possess a distinct pharmacological profile; these include anticancer and antiviral activity, hematological and immunological stimulation, analgesic activity, liver protection, and appetite improvement.sup.(40). An alternative formulation of PHY906 has the herbs Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia in the following relative proportions: 4/14:3/14:4/14:3/14, respectively.

(8) While specific ratios of the herbs of PHY906 are provided as examples, the compositions and methods of this invention encompass any ratios of the four herbal components which have the desired biological activity as described herein.

(9) In one embodiment, PHY906 can be produced by a process as described hereinbelow. First, the proper ratios of the ingredients of the herbal raw materials are placed in a jacketed reactor and extracted with water at an elevated constant temperature with mixing. The ratios are set forth in the Manufacturing Instruction reproduced from Master Formula Record. The solid materials are then separated from the liquid with a 120-mesh screen. The filtrate is collected and then concentrated by evaporating the water under reduced pressure. The concentrated liquor is spray dried at an elevated temperature to yield dry powder which is then processed to yield granulated powder. This bulk substance is then formulated into the desired dosage form.

(10) Process controls are utilized to ensure the uniformity and integrity of the product. Such process controls include, but are not limited to, checking the volume of the process liquor, HPLC determinations to establish Chemical Fingerprintings to verify identity of the raw materials, and inspections and tests of intermediate and final products. Accepted Quality Level (AQL) Limits are established for each conducted analysis and for each step of the manufacturing and control of production. All of the components used in the production process are assigned a specific lot number in the Production Instruction Record. Quality control records are reviewed before a batch is released. Purified marker substances are used for identification and quality control of the raw materials as well as the herbal substances. Table 2 lists the marker substances of each raw material used in the preparation of PHY906 herbal substance.

(11) TABLE-US-00002 TABLE 2 Marker Substances for Herbal Ingredients of PHY906 Herb Origin of Herb Producing Place Marker Substance Scutellaria baicalensis Georgi. Shang Xi Province, China Baicalin Glycyrrhiza uralensis Fisch. Inner Mongolia, China Glycyrrhizin Ziziphus jujuba Mill. Hebei/Shangtong Province, China Chelidonic Acid Paeonia lactiflora Pall. An Hwei Province, China Paeoniflorin

(12) The compositions of the present invention can be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the effect desired.

(13) The pharmaceutical formulation for systemic administration according to the invention may be formulated for enteral, parenteral, or topical administration. Indeed, all three types of formulations may be used simultaneously to achieve systemic administration of the active ingredient. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.

(14) In addition to the pharmacologically active agent, the compositions of the present invention may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically for delivery to the site of action.

(15) PHY906 can be used in the form of a medicinal preparation, for example, in solid, semi-solid or liquid form which contains PHY906, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.

(16) Formulations of the present invention encompass those which include talc, water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in manufacturing preparations, in solid, semisolid or liquid form and in addition auxiliary, stabilizing, thickening and coloring agents, and perfumes may be used.

(17) For preparing solid compositions such as tablets or capsules, PHY906 is mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a substantially homogeneous mixture of PHY906, or a non-toxic pharmaceutically acceptable salt thereof. When referring to the preformulation compositions as substantially homogenous, it is meant that the active ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

(18) This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing an effective amount of the composition of the present invention, preferably in capsules.

(19) The tablets or pills containing PHY906 can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

(20) The liquid forms, in which PHY906 may be incorporated for administration orally or by injection, include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

(21) Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); and artificial or natural colors and/or sweeteners.

(22) For buccal administration, the compositions of the present invention may take the form of tablets or lozenges formulated in conventional manners.

(23) PHY906 may also be formulated for parenteral administration by injection, which includes using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredients may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

(24) Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

(25) Liposomes can also be used to encapsulate the agent for delivery into the cell.

(26) In practicing the methods of this invention, PHY906 may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be coadministered along with other compounds typically prescribed for cancer chemotherapy according to generally accepted medical practice. The compounds of this invention can be utilized in vivo, ordinarily in mammals, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

(27) Actual methods for preparing administrable compositions and adjustments necessary for administration to subjects will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), which is incorporated herein by reference.

(28) PHY906 has proven to be efficacious in enhancing the therapeutic indices of a variety of anticancer agents including CPT-11 (irinotecan, Camptosar®). CPT-11 is a water-soluble derivative of camptothecin (an antitumor alkaloid isolated from Camptobea acumiauta) that exhibits a wide spectrum of antitumor activity because of its inhibition of DNA topoisomerase I.sup.(41) CPT-11 is a component of some of the most widely used chemotherapy treatment regimens (e.g. the “Saltz” regimen [CPT-11 plus 5-fluorouracil/leucovorin], IFL, FOLFIRI, AIO) for colorectal cancer.sup.(43-42). Diarrhea has long been recognized as one of the most common limiting side effects associated with CPT-11 use, regardless of the schedule of administration.sup.(44-46). It causes two types of diarrhea: (a) early acute diarrhea that occurs soon after CPT-11 administration and (b) late-onset diarrhea that occurs usually after an average period of 6 days. In about 40% of patients, this side effect is classified grade 3 (serious) or grade 4 (life-threatening) according to the National Cancer Institute Common Toxicity criteria.sup.(47). High-dose loperamide is considered standard treatment for CPT-11-induced diarrhea in Europe and the US, but the success of this approach is limited.sup.(48).

(29) CPT-11 is hydrolysed by hepatic carboxylesterase to its active (as an anticancer agent) metabolite, SN-38.sup.(49). This metabolite can then be conjugated to SN-38 glucuronide (SN-38G, an inactive metabolite) by UDP-glucuronyltransferase.sup.(50). CPT-11, SN-38, and SN-38G are excreted into the bile.sup.(50). Once in the intestine, SN-38G can be deconjugated to SN-38 by bacterial P-glucuronidase in the cecum and colon.sup.(51). SN-38 is believed to be responsible for CPT-11 treatment-related diarrhea.sup.(52).

(30) In preclinical studies, when PHY906 was used in combination with CPT-11 in mice bearing Colon 38 tumors, the antitumor efficacy of the combination was greater than that of CPT-11 alone (FIG. 1A), and the toxicity (as measured by body weight loss and mortality) seen with PHY906+CPT-11 was reduced over that seen with CPT-11 alone (FIG. 1B).sup.(53). The reduced toxicity of the combination is also shown by Kaplan-Meyer survival curves (FIG. 2) that depict the reduced mortality of the combination vs. CPT-11 alone. Although the effects of PHY906 on CPT-induced diarrhea were not directly measured, the reduction by PHY906 of body weight loss induced by CPT-11 acts as a “surrogate” marker for diarrhea reduction. In mice bearing Colon 38 tumors and treated with a high dose of CPT-11, PHY906 proved to be much more effective in reducing body weight loss than other “antidiarrheals” including loperamide and the Chinese herbal formulations TJ-14ST, TJ-15, and PHY915.sup.(54).

(31) The reduction in CPT-11-induced diarrhea by PHY906 may be due to its potent inhibition of bacterial 13-glucuronidase (deconjugates SN-38G to SN-38, the toxic form of CPT-11) 1). Baicalein, found in Scutellaria baicalensis Geogi (one of the constituent herbs of PHY906) is a feedback inhibitor of 13-glucuronidase (55). In addition, PHY906 contains compounds that are alternative substrates for 13-glucuronidase; these could compete with SN-38G for binding to the enzyme.

(32) On the basis of the above and other preclinical studies, an FDA-approved Phase I/Ha multicentered and randomized double-blind placebo-controlled safety study with cross-over dose escalation was launched in 2002 in patients with advanced, refractory colorectal cancer. In the study, the combination of CPT-11 plus 5-fluorouracil/leucovorin (5-FU/LV) supplemented by PHY906 or placebo was used as first-line treatment. PHY906 was shown to be safe with no serious adverse events (SAEs) attributed to the study drug. PHY906 was found to have no appreciable effect on the metabolism of CPT-11 or 5-FU in controlled metabolic testing (pharmacokinetic study). Fifteen of seventeen patients treated showed either a partial response or stable disease after two courses of treatment. Reduction of diarrhea/nausea/vomiting induced by CPT-11 treatment was observed in the cross-over, internal, patient controls. PHY906 reduced the amount of loperamide necessary to treat CPT-11-induced diarrhea. At a dose of 1.2 g/day, PHY906 reduced the severity of diarrhea by one grade and, at a dose of 2.4 g/day, it reduced nausea/vomiting by one grade.sup.(56,57).

(33) In one embodiment, the present invention provides a method of relieving side effects of a chemotherapeutic compound in a patient in need thereof comprising administering to the patient a composition comprising PHY906.

(34) In another embodiment, the present invention provides a method of treating a bowel disorder, such as, for example, IBD and IBS, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising an herbal preparation having Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In one preferred embodiment, the present invention provides a multiple symptoms (multi-symptom) treatment for the bowel disorder. For example, the present treatment can treat or relieve at least two or more symptoms of the bowel disorder. Exemplary symptoms include, but are not limited to visceral pain, intestinal motility, inflammation, lower abdominal pain, bloating associated with alternation of bowel habits, abdominal discomfort relievable by defecation, fever, vomiting, acute diarrhea, positive stool culture, and combinations thereof.

(35) As used herein, the term “patient” includes mammal, preferably, human. By “therapeutically effective amount”, it is meant the amount of PHY906 or other active agent(s) that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease or relief of symptoms of the disease. The “therapeutically effective amount” will vary depending on the age, weight, and severity of conditions of the patient to be treated.

(36) In another embodiment, one or more additional active agents are co-administered to the patient for the treatment of the bowel disorder. The additional active agents can be any compound or biologics that has effect of treating the bowel disorder. Examples of the additional agent includes, but are not limited to the compound and biologics described in the Background section of this application. By “co-administering”, it is meant to administer PHY906 and the additional active agent simultaneously or sequentially in such a manner to achieve a coordinated or synergistic therapeutic effect.

(37) Opioid receptors have long been known to be involved in pain perception, but they also play other important roles. In the gut, activation of opioid receptors (by opiate drugs) in the gut wall results in decreased transit times.sup.(58). Circular muscle contractility plays a dominant role in segmentation and peristalsis in the gut.sup.(59). Both μ- and δ-opioid receptors are involved in neurogenic circular muscle contractions; when these receptors are activated, such contractions are inhibited.sup.(60). In one embodiment, PHY906, at a dose of 300 μg/ml, was shown to significantly inhibit 6-opioid receptors in vitro assays.

(38) Common symptoms of IBS and IBD include visceral pain and/or discomfort.sup.(61). Tachykinin NK-1 receptors are believed to play an important role in mediating perception of such visceral pain (62). In addition, tachykinin NK-1 receptors are upregulated in the intestinal lamina propria of mice with IBD and thus are involved in the inflammatory cascade that that triggers and maintains intestinal lesions of IBD.sup.(63). As indicated by Table 3, four different batches of PHY906 were shown to inhibit tachykinin NK-1 by using a radioligand binding assay with human recombinant CHO cells.

(39) TABLE-US-00003 TABLE 3 Inhibition of Tachykinin NK-1 by PHY906. ICso K.sub.i Batch No. (μg/ml) (μg/ml) 906-6 263 144 906-7 247 135 906-8 486 265 906-9 430 235
Methods for the Tachykinin NK-1 Assay:

(40) Human recombinant CHO cells were incubated in 20 mM HEPES buffer pH 7.4 with 1 mM MnCl.sub.2 and 0.01% bovine serum albumin and reacted with the ligand 0.25 nM [.sup.3H] SR-140333 according to the method of Patacchini and Maggi.sup.(70). The non-specific ligand was 2 μM L703606. IC 50 values were determined by a non-linear, least squares regression analysis using Data Analysis Toolbox™ MDL Information Systems, San Leandro, Calif.). K. values were calculated according to the equation of Cheng and Prusoff.sup.(71).

(41) In one embodiment, the present invention provides a method of inhibiting a 6-opioid receptor and/or a tachykinin NK-1 receptor by contacting the 6-opioid and tachykinin NK-1 receptors with a composition comprising PHY906. The 8-opioid receptor and/or a tachykinin NK-1 receptor can be present in a cell, tissue, or organism. In another embodiment, the present invention provides a method of treating a disease or condition associated with a disregulated 6-opioid receptor or tachykinin NK-1 receptor comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising PHY906.

(42) Dysregulated cytokine production and signaling mechanisms by epithelial cells, mucosal lymphocytes, and macrophages in the gut have been implicated in the pathogenesis of both Crohn's and UC.sup.(64). In models of Crohn's disease, the production of large amounts of cytokines such as interferon-y (IFN-y) and tumor necrosis factor (TNF), whose promoters are regulated by the transcription factor nuclear factor KB (NF-KB), is a major feature of the inflammation (65, 66) Thus, downregulation of NF-KB activity appears to be a potential key event in the control of chronic intestinal inflammation.sup.(67) Inhibition of NF-KB activity has been suggested as a major component of the anti-inflammatory activity of glucocorticoids used to treat chronic intestinal inflammation (68-69) As shown in FIG. 3, PHY906 has inhibitory activity against both intrinsic and TNF-activated NF-KB; this implies that PHY906 also has anti-inflammatory activity and may be useful as a treatment for the chronic intestinal inflammation that characterizes IBD.

(43) In one embodiment, the present invention provides a method of inhibiting a nuclear factor-kappa B (NF-KB) by contacting the NF-icB with a composition comprising PHY906. The NF-KB can be present in a cell, tissue, or organism. In another embodiment, the present invention provides a method of treating a disease or condition associated with a disregulated NF-KB comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising PHY906.

(44) While the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in forms and details may be made without departing from the spirit and scope of the invention. It is therefore intended that the present invention not be limited to the exact forms and details described and illustrated but fall within the scope of the appended claims.

(45) Furthermore, all publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

REFERENCES

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