FIELD OF THE INVENTION

The present invention relates to the use of PHY906 for treating a bowel disorder, such as, for example, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).

BACKGROUND OF THE INVENTION

1. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) encompasses a group of conditions that exhibit inflammation of the large and, in some cases, small intestine. The two main forms of IBD are Crohn's disease and ulcerative colitis (UC). Other much less common manifestations of IBD are collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, infective colitis, and indeterminate colitis. Diagnosis is generally by colonoscopy with biopsy of pathological lesions.

In the US, in 2001, the prevalence of Crohn's disease and UC was 162 and 246 cases per 100,000, respectively(1). Although the mortality rate from IBD is low, hospitalizations for 2002 totaled 169,000 (62% for Crohn's disease) and ambulatory care visits approximated 5.9 million per year in 1999-2000(2,3). In the early 1990s, over 160,000 people in the US with IBD were considered disabled(4).

The majority of Crohn's cases start in the terminal ileum, but it can affect any part of the gastrointestinal tract. In contrast, UC is restricted to the colon. From a microscopic point of view, whereas Crohn's disease affects the entire bowel wall, UC is restricted to the epithelial lining of the gut. Both UC and Crohn's show extra-intestinal manifestations, e.g. liver problems, arthritis, eye problems, skin manifestations, they are present in different proportions in each disease.

Most medical treatment for IBD is aimed at controlling the ongoing inflammation and is directed to achieving and maintaining remission. Since the symptoms, course of disease, and prognosis vary from patient to patient, no standard treatment exists for IBD. An accurate diagnosis, usually achieved through the use of endoscopic, radiological, and pathologic examinations, is imperative for designing a proper course of treatment. Currently, for 1BD, the five main classes of medications used are: aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologies(5).

Aminosalicylates:

Aminosalicylates are effective in treating mild to moderate cases of IBD as well as preventing relapses and maintaining remission. They are usually administered orally or rectally. Sulfasalazine (Azulfidine®), the first aminosalicylate to be widely used for IBD, is effective in achieving and maintaining remission in people with mild-to-moderate disease. It delivers 5-aminosalicylic acid (5-ASA) to the intestine but comes with disagreeable side effects in some patients, such as headache, nausea, loss of appetite, vomiting, rash, fever, and decreased white blood cell count. Sulfasalazine can decrease sperm production and function in men while they are taking the medication. It has been associated with pancreatitis in rare cases. The headaches, nausea, and rash are thought to be due to the release of the sulfapyridine moiety that is necessary for delivery of the 5-ASA to the intestine.

Other derivates of 5-ASA have also been synthesized. Those derivatives include mesalamine (Asacol®, Pentasa®), olsalazine (Dipentum®), and balsalazide (Colazal™). Local mesalamine preparations bypass the stomach to avoid early digestion, and then release close to the inflamed section of the bowel. Oral, delayed-release preparations such as Pentasa® and Asacol® can release 5-ASA directly to the small intestine and colon, or to the ileum and/or colon, respectively. Rowasa®, an enema formulation of mesalamine, allows the drug to be applied directly to the left colon. Rowasa® is effective in 80% of patients with mild-to-moderate colitis that affects only the left side of the colon. Mesalamine suppositories (Canasa®) that deliver the drug directly from the rectum up to the sigmoid colon are effective in a high proportion of patients with UC limited to the rectum and the lower end of the colon. Dipentum®, an oral, delayed-release preparation of olsalazine, delivers 5-ASA directly to the colon only.

Corticosteroids:

As fast-acting anti-inflammatory and immunosuppressive agents, corticosteroids have been used for treating acute flare-ups of IBD for over 50 years. Since that time, these powerful agents have been the mainstay of treatment for disease. Most patients notice an improvement in symptoms within days of starting corticosteroids(6). This group of medications is available in oral, rectal, and intravenous (IV) forms. Corticosteroids are not effective in preventing flare-ups and therefore are rarely used for maintenance therapy in IBD. Since long-term use results in side effects, these agents are recommended only for short-term use in order to achieve remission, but they are not used frequently in the latter case. For people with moderate to severe active disease, oral corticosteroids include prednisone (Deltasone®), methylprednisolone (Medrol®), and hydrocortisone. Aminosalicylates are often taken together with corticosteroids.

Budcsonide (Entocort®), an oral corticosteroid, is used to treat mild-to-moderate Crohn's disease involving the end of the small intestine and/or the first part of the large intestine. This nonsystemic steroid targets the intestine rather than the whole body. Corticosteroids may also be given rectally as enemas (hydrocortisone, methylprednisone, Cortenema®), foams (hydrocortisone acetate, ProctoFoam-HC®), and suppositories. Such preparations are used for mild-to-moderate ulcerative colitis that is limited to the rectum or lower part of the colon. When used in combination with other therapies, these agents are also effective against more widespread disease that starts at the rectum. Methylprednisone and hydrocortisone are often given by IV infusion to patients with severe and extensive disease. Acute IBD does not respond to corticosteroid therapy in 20-30% of cases and in 30-40% of cases with moderate to severe disease, corticosteroids cannot be abruptly discontinued without occurrence of a disease flare-up.

Immunomodulators:

Since IBD appears to be caused by an overactive immune system, immunomodulators play an important role in the treatment of this disease(7). These drugs are used for those who have one of the following characteristics: (a) side effects with corticosteroid treatment, (b) steroid-dependent disease, (c) do not respond to aminosalicylates, antibiotics, or corticosteroids, (d) perineal disease that does not respond to antibiotics, and (e) need to maintain remission. These drugs may be combined with a corticosteroid to speed up response during active flares of disease.

Azathioprine (Imuran®, Azasan®) and 6-mercaptopurine (6-MP, Purinethol®) are oral immunomodulators that are used to maintain remission in Crohn's disease and UC. Since these agents have a slow onset of action, they are usually given along with another faster-acting drugs, e.g. corticosteroids. Other immunomodulators used for IBD are cyclosporine A (Sandimmune®, Neoral®) and tacrolimus (Prograf®). Of these agents, cyclosporine A has the fastest onset of action. When given IV at high doses, cyclosporine A is useful against active Crohn's disease. This drug is effective against severe UC as is tacrolimus. The latter agent can be used against Crohn's when corticosteroids are not effective or when fistulas develop. Tacrolimus may be applied topically to treat Crohn's disease of the mouth or perineal area. An option for people with Crohn's disease who do not respond to other treatments and cannot tolerate other immunosuppressants is IV-administered Methotrexate (MTX, Rheumatrex®, Mexate®)).

Antibiotics:

Although no specific infectious agent has been identified as the cause of IBD, antibiotics are frequently used as a primary treatment(8). Antibiotics are effective as long-term therapy in Crohn's disease patients who have fistulas (between loops of intestine or between intestine and adjacent organs, e.g. skin) or recurrent abscesses near the anus. Patients whose active disease is successfully treated with antibiotics may be kept on these as maintenance therapy. Generally, antibiotics are not considered useful for those with UC; the exception is toxic megacolon.

The most frequently prescribed broad-spectrum antibiotics for IBD are metronidazole (Flagyl®) and ciprofloxacin (Cipro®). Metronidazole is a primary therapy for active Crohn's and has been shown to reduce the recurrence of Crohn's for the first three months after ileum resection surgery. This drug is effective in managing perineal Crohn's in over 50% of cases. Ciprofloxacin, much safer than metronidazole, is commonly used to treat active Crohn's disease. Both oral and IV metronidazole and ciprofloxacin are used for IBD treatment.

Biologics:

Possible targets by which biologics may interfere with the body's inflammatory response in IBD include tumor necrosis factor-alpha (TNF-u), interleukins, adhesion molecules, colony-stimulating factors, and others(9). Since their mechanism is targeted, biologic therapies offer a distinct advantage in IBD treatment. Unlike corticosteroids, which tend to suppress the entire immune system and thereby produce major side effects, biologic agents act selectively. Biologics are targeted to particular enzymes and proteins that have already been proven defective, deficient, or excessive in people with IBD or in animal models of colitis.

Anti-TNF agents have been used in both Crohn's disease and UC. The chimeric monoclonal antibody Infliximab (Remicade®) is approved for Crohn's disease and fistulizing Crohn's disease, as well as for UC. Given as an IV drip, it is used for people with moderately-to-severely active disease who have not responded well to other therapies. Adalimumab (Humira®), a fully human monoclonal antibody given by injection, is used for people with moderately to severely active Crohn's disease who have not responded well to other therapies and who have lost response or are unable to tolerate infliximab. Certolizumab pegol (currently known as Cimzialm), is currently being investigated for use in Crohn's disease.

Adhesion molecule inhibitors are being evaluated as IBD therapies. These drugs work by binding to particular cells in the bloodstream that are key players in inflammation. Natalizumab (Tysabri®), already approved for multiple sclerosis, is an adhesion molecule inhibitor currently under investigation for the treatment of Crohn's disease.

Visilizumab (Nuvion®), a humanized monoclonal antibody directed against CD3 receptors on activated T cells, and alicaforsen, a drug that inhibits ICAM-1 (plays a key role in intestinal inflammation) are currently being investigated as possible treatments for UC. Other potential IBD agents include thalidomide, the interleukins IL-6, IL-10, IL-11, and IL-12, interferon gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF).

Surgery:

In spite of the above medication options for IBD, 66-75% of Crohn's patients and 25-40% of those with UC will eventually undergo surgery(10,11)Surgery for Crohn's disease depends upon the location of the disease. If it is in the small intestine, areas of diseased bowel may alternate with areas of normal bowel, The areas of active disease may narrow, forming strictures, which can block the passage of digested food. If the lesions are separated, strictureplasty is often used. Here, the structured areas are widened and the small intestine is spared. Resection and anastimosis may be needed if the stricture is long or if there are multiple strictures close to each other. Although resection may offer years of relief, disease can recur at or near the site of the anastimosis.

In patients with severe Crohn's in the colon, colectomy may be done. If the rectum is unaffected the end of the ileum may be rejoined to the rectum; thus, stool may be passed normally, If both the colon. and rectum are involved, proctocolectomy with subsequent ileostomy may be performed. Fistulas and/or abscesses eventually develop in about 25% of patients with Crohn's disease. If fistulas are unresponsive to medication, they are removed by resection of the affected bowel followed by anastimosis. Abscesses must be drained; in some cases, this requires resection. For years, the standard surgery for UC, has been proctocolectomy with ileostomy. Now the most common procedure is restorative proctocolectomy; this allows the patient to continue to pass stool through the anus. Unlike Crohn's disease, which can recur after surgery, UC is “cured” once the colon is removed.

2. Irritable Bowel Syndrome

Irritable bowel syndrome (IBS, spastic colon) is a functional bowel disorder characterized by abdominal pain and changes in bowel habits. Unlike IBD. IBS is not associated with abnormalities seen on clinical testing. The most frequent symptoms of IBS are the lower abdominal pain and bloating associated with alteration of bowel habits, and abdominal discomfort relieved by defecation. IBS is may be classified as diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or with alternating stool pattern (IBS-A). Sometimes, IBS may have an acute onset and develop after an infectious illness characterized by two or more of the following symptoms: fever, vomiting, acute diarrhea, and positive stool culture; this form,

which has been termed post-infective IBS (IBS-PI), consists mostly of IBS-D.

Approximately 20 percent of people in the US have symptoms of IBS and these symptoms occur before the age of 35 in about 50 percent of cases 0). About one-third of all patients suffer from IBS-D. Although mortality from IBS is very low, hospitalizations in 2002 totaled 190,000, ambulatory care visits totaled 1.3 million per year in 1999-2000, and 46,000 patients with IBS were deemed disabled in 1990-1992(2-4). In 1985, 2.2 million prescriptions per year were written for IBS(13). IBS in general and IBS-D in particular have a significant negative impact on the quality of life (QOL) for the many people who suffer from this condition; it causes lost days from work and interferes significantly with home-based, social, and leisure activities.

IBS treatment involves reassuring patients that their disease is not life-threatening, giving dietary advice, and prescribing medication Immune response to some foods may play a role in the reduction or elimination of IBS symptoms in some cases(14′ 15)IBS patients are sensitive to fats, insoluble fibers, caffeine, carbonation, alcohol, fructose, foods with elevated levels of IgG4 antibodies, and foods that may increase colonic contractions(15-20).

For IBS-C patients, medications include stool softeners and laxatives. For IBS-D sufferers, medications consist of antidiarrheals, e.g. opiods or opiod analogs (loperamide, ImodiumCGt; diphenoxylate; diphenoxylate plus atropine, Lomotil®). Severe cases may be treated with codeine or propoxyphene (Darvon®) and refractory cases may be treated with paregoric or even morphine. Low doses of tricyclic and selective serotonin reuptake inhibitory antidepressants are widely prescribed for the relief of pain and diarrhea, respectively. Alosetron (Lotronex®), a selective 5-HT3 antagonist is available for women in the US who have IBS-D only. Cilansctron (Calmactin®), another selective 5-HT3 antagonist, is currently in clinical trials in Europe for the treatment of IBS-D in both men and women. In 2005, the sponsor of cilansetron withdrew its application for approval from the US FDA on the basis of a “non-approvable” letter (additional clinical trials were requested). Tegaserod (Zelnorm®), a selective 5-HT4 antagonist for IBS-C, is the only agent approved to treat constipation, abdominal pain, and bloating in women in the US; it is not approved in the EU, however. The potential role of bacterial overgrowth in some patients with IBS is suggested by recent studies suggesting that rifaximin is an effective treatment for abdominal bloating and flatulence (21, 22).

Alternative treatments for IBS include probiotics (potentially beneficial strains of bacteria and yeast found in the human gut, e.g.Lactobacillus planarinmLP299V andBifidobacterium ifantis(23, 24). Clinical studies with probiotics are currently being conducted in the US(25 29).

3. Traditional Chinese Medicine for Treating Bowel Disorders

Mixtures of botanical extracts have been widely used throughout the world for the management of disease and are gaining increased acceptance in Western countries (35-38) The use of herbal Traditional Chinese Medicine (TCM) is based on many chemical components in an herbal preparation that interact and act simultaneously through multiple molecular targets and cellular mechanisms. These multiple components serve various functions; some may be responsible for efficacy while others may decrease toxicity or increase bioavailability. Chinese herbal formulations are perhaps the best-known botanical medicines to have been derived from empirical observations in humans over the millennia. The claimed indication of a given Chinese medicinal preparation is multiple rather than single. This is not surprising, many phytochemical ingredients in a formulation can exert actions at multiple targets and biological pathways.

Aspects of Traditional Chinese Medicine (TCM), including acupuncture and herbal medicines, have also been examined as possible IBS treatments. The benefits of acupuncture for the treatment of IBS have not been proven conclusively(30). Many studies were not of adequate size and/or were uncontrolled or poorly controlled. In a well-controlled study of 43 IBS patients where the efficacy of acupuncture following the rules of TCM was compared with that of sham (placebo) acupuncture, an insignificant difference was seen between the two groups(31). Two clinical studies on the effects of acupuncture on IBS have recently been completed in the US, but the results have not yet been published(32).

Several clinical studies in China have suggested the potential of TCM herbal formulations in the treatment of IBS, but these have lacked adequate trial design, poor randomization techniques, and/or lack of blinding(33). In a randomized, placebo-controlled trial where 116 patients were treated with placebo, with a “standard” formulation of 20 herbs, or with “individualized” herbal formulations, patients treated with the herbal formulations had more symptom improvement than placebo controls(33). In contrast, in a randomized double-blinded placebo-controlled trial involving 119 patients with IBS-D treated with either placebo or an eleven-herb TCM

formulation, no significant difference was seen between the two arms in terms of global symptom improvement(34).

In summary, IBD and IBS are common chronic illnesses with multiple symptoms that can be very serious and debilitating. Numerous treatments for IBD and IBS have been developed, but most of these treatments do not have desirable efficacy or are single-symptom remedies.

SUMMARY OF TIE INVENTION

In one embodiment, the present invention provides 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 havingScutellaria, Glycyrrhiza, ZiziphusandPaeonia.

In another embodiment, the present invention provides a method of inhibiting a 6-opioid receptor or a tachykinin NK-1 receptor by contacting the 6-opioid and tachykinin NK-1 receptors with a composition comprising an herbal preparation having Scutellaria,Glycyrrhiza, ZiziphusandPaeonia.

In another embodiment, the present invention provides a method of inhibiting a nuclear factor-kappa B (NF-KB) by contacting the NF-KB with a composition comprising an herbal preparation havingScutellaria, Glycyrrhiza, ZiziphusandPaeonia.

