Combination herbal medicines for the treatment of diverticular disease

Abstract

The present invention provides compositions and methods based on herbal extracts of Curcumin and Berberine (Coptis chinensis), and uses thereof for the treatment of common bowel diseases, and specifically Diverticular Disease and related chronic conditions.

Description

[0001] COMBINATION HERBAL MEDICINES FOR THE TREATMENT OF DIVERTICULAR DISEASE

[0002] TECHNOLOGICAL FIELD

[0003] The invention pertains to the field of herbal medicines and their applications to the treatment of several common bowel diseases, and Diverticular Disease in particular.

[0004] BACKGROUND

[0005] Diverticular disease (DD) or diverticulosis of the colon is a general name for a common condition involving formation of small bulges or sacs (diverticula) from the large intestine (colon) wall, predominantly in the sigmoid colon portion which is close to the rectum. DD is especially prevalent in the Western populations, where it occurs in 10% of people over age 40, 50% of people over age 60, and 67% of people by the age of 85. Singular diverticula are usually asymptomatic. But many diverticula can affect normal bowel function and lead to secondary problems due to altered bowel motility, ongoing inflammation of the gut wall and sometimes perforation and infection, manifested as abdominal pain, bloating, constipation, hematochezia, fever, nausea and vomiting.

[0006] In about 5-10% of the patients, DD begins as an acute problem, i.e., Acute Diverticulitis (AD), which is treatable, for the most part, by antibiotics, change of diet and surgery in rare cases. However, in about 20% of the patients the situation becomes chronic and complicated by recurring (repeat) episodes of AD and chronic inflammation that may lead to rupture of diverticula and scarring of the inner lining of the colon.

[0007] A specific problem, which is relatively common, is post-AD Symptomatic Uncomplicated Diverticular Disease (SUDD) or post-AD SUDD, wherein after recovery from an AD episode, the patients continue to manifest partial AD symptoms in absence of apparent signs of acute inflammation. More recent studies pointed to certain evidence of subclinical chronic inflammatory processes in SUDD, including chronic inflammatory infiltrates in the affected colon tissue (e.g., increased levels of fecal calprotectin), increased tissue pro-inflammatory cytokines (e.g., increased TNFa, IL-6 and IL-ip) and increased lymphocytes and lymphocytes aggregates in the affected mucosa, owing to which the International Consensus on Diverticulosis and Diverticular Disease has recently characterized this clinical entity as a chronic inflammatory disease [1-4]. Nonetheless, there is currently no effective therapy for post-AD SUDD. Clinical studies assessing the use of anti-inflammatory therapies for this indication, such as 5 ASA (5-aminosalicylic acid, also known as mesalazine or mesalamine) and / or certain types of antibiotics such as rifaximin, were essentially inconclusive [5-10]. Therefore, as of now, there is an unmet need for clinically approved and effective treatment for post-AD SUDD, or for a verified treatment protocol which would be safe and effective and would likely to be reciprocated by high patients’ compliance.

[0008] References

[0009] 1. Tursi A et al. International Consensus on Diverticulosis and Diverticular Disease. Statements from the 3rdInternational Symposium on Diverticular Disease. J Gastrointestin Liver Dis 2019 Vol 28 Suppl 4: S57-S65.

[0010] 2. Tursi A et al. Faecal calprotectin in colonic diverticular disease: a casecontrol study. Int J Colorectal Dis 2009 Vol 24: 49-55.

[0011] 3. Tursi A et al. Mucosal tumor necrosis factor a in diverticular disease of the colon is overexpressed with disease severity. Colorectal Dis 2012 Vol 14: e258-263.

[0012] 4. Lahat et al. Prolonged recurrent abdominal pain is associated with ongoing underlying mucosal inflammation in patients who had an Episode of Acute Complicated Diverticulitis. J Clin Gastroenterol 2019 May / Jun;53(5): el78-el85.

[0013] 5. Kruis W et al; German SAG-20 Study Group. Randomized clinical trial: mesalazine (Salofalk granules) for uncomplicated diverticular disease of the colon - a placebo-controlled study. Aliment Pharmacol Ther 2013 Vol 37: 680-690.

[0014] 6. Bianchi M et al. Meta- analysis: long-term therapy with rifaximin in the management of uncomplicated diverticular disease. Aliment Pharmacol Ther 2011 Vol 33: 902-910.

[0015] 7. Tursi A et al. Randomised clinical trial: mesalazine and / or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease - a doubleblind, randomized, placebo-controlled study. Aliment Pharmacol Ther 2013 Vol 38: 741- 751.

[0016] 8. Lahner E et al. High-fiber diet and Lactobacillus paracasei B21060 in symptomatic uncomplicated diverticular disease. World J Gastroenterol 2012 Vol 18: 5918-5924. 9. Colecchia A et al. Efficacy of long-term cyclic administration of the poorly absorbed antibiotic rifaximin in symptomatic, uncomplicated colonic diverticular disease. World J Gastroenterol 2007 Vol 13: 264-269.

[0017] 10. Campanini A et al. A primary-care interventional model on the diverticular disease: Searching for the optimal therapeutic schedule. J Clin Gastroenterol 2016 Vol 50 Suppl 1: S93-S96.

[0018] GENERAL DESCRIPTION

[0019] The incentive behind the invention has been to find an effective and affordable treatment for a group of relatively common clinical conditions affecting the large intestine (large bowel) that are typically characterized by subclinical, moderate-to- severe clinical and often chronic clinical presentations. One example is Diverticular Disease or Diverticulosis of the colon (DD), which in many cases manifest as Acute Diverticulitis (AD). AD is often treatable by conventional therapies, but in a non-negligible proportion of patients AD may have significant post-recovery manifestations, commonly referred to as post-AD Symptomatic Uncomplicated Diverticular Disease (SUDD).

[0020] The hallmark of DD is the formation of small bulges or pockets (diverticula) in the lining of the large intestine (colon), the presence of which can be detected by abdominal CT scan and / or colonoscopy. DD transitions from asymptomatic to acutely symptomatic (i.e., AD) when diverticula become inflamed or infected, with manifestation of characteristic symptoms of lower abdominal pain and sometimes fever. The leading risk factors for DD are aging, obesity, and lifestyle, specifically smoking, lack of exercise, high animal fat and low fiber diet, and certain drugs such as steroids, opioids and NSAIDs (e.g., ibuprofen - Advil, Motrin IB and naproxen sodium - Aleve).

[0021] In most cases AD is treatable and not recurrent. Soft / liquid diet and paracetamol are often used to ease AD symptoms, but not aspirin or ibuprofen because of related stomach upsets. AD, especially if severe, may be further treated with antibiotics. More serious cases may need hospitalization to prevent and treat complications. Surgical interventions are rare but may be used in cases with serious complications to remove affected areas of the intestine.

[0022] Despite relative accessibility of treatments for singular AD episodes, a substantial group of AD patients continue to suffer from post-recovery chronic symptoms that share some similarity with mild AD, manifested as feeling bloated, frequent bowel movements or constipation, nausea / vomiting - designated as post AD SUDD. Post-AD SUDD is a more subtle chronic inflammatory condition believed to results from altered bowel motility in the bowel segment affected by DD, which is exacerbated after an AD episode and by localized tissue specific inflammatory responses, such as elevated levels of tissue inflammatory cytokines and systemic inflammatory markers, and inflammatory infiltrates in the colonic tissue. Currently, there is no consensus evidence-based approach to the treatment of SUDD. The general guidelines are to treat it by painkillers, antiinflammatory drugs and antibiotics. These, however, are often ineffective, costly and may have non-negligible side effects, especially with prolonged use, and therefore usually suffer from poor patients’ compliance.

[0023] It has been generally known that herbal medicines can be beneficial for long term management of chronic conditions in general, and inflammatory chronic conditions in particular. In the context of DD and AD and more recalcitrant conditions such as post AD SUDD, the use of herbal medicines has been sporadic, leaving some open questions as to which herbal medicines or combinations of herbal medicines should be used and what would be the most effective therapeutic regimen under which such herbal medicines should be provided, and further, whether such herbal medicines or combinations can replace or reduce the use of conventional medicines for these conditions.

[0024] The present invention stems from previous findings by the inventors, showing that Curcumin (Cur), an active ingredient of the Indian herb Rhizoma Curcuma Longa, alone or in combination with conventional therapies can be effective for treating certain chronic and acute presentations of Inflammatory Bowel Disease (IBD). In a controlled trial of patients with active ulcerative colitis (UC), the inventors showed that oral administering of Cur alone, without additional bio-absorption enhancers, had led to clinical and endoscopic remission of IBD and that it was safe and well tolerated at therapeutic doses of up to 3 gr / day (Lang A et al. Clin Gastroenterol Hepatol 2015 Vol 13: 1444-9. el). Subsequent studies corroborated and expanded these findings, showing that Cur was further effective for maintaining remission of mild to moderate UC at therapeutic doses of up to 2 gr / day dose, and that doses of up to 12,000 mg (1.2 gr) had no apparent adverse effects in healthy volunteers. Berberine (Ber), a phytochemical derived from plants such as Coptis chinensis, Goldenseal and Scutellaria, has been used in Chinese and European folk medicine to treat digestive inflammation and infectious diseases. In clinical trials, Ber was shown to be effective for reducing the recurrence of colorectal adenomas and ameliorating radiation enteritis, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome, among others, by modulating the intestinal microbiome. In clinical trials conducted so far, Ber was found to be safe and well tolerated, like Cur.

[0025] The inventors hypothesized that a combination of Cur and Ber can be effective for long-term management of recalcitrant conditions such as post- AD SUDD, and even potentially synergistic by acting on both - the anti-inflammatory pathways and the intestinal microbiome. The inventor were in particularly advantageous position to prove this notion by using the previously developed specific DICS scoring scale (Lahat A et al. Therap Adv Gastroenterol 2020 May 8;13:1756284820913210), which today is the only validated clinical scoring for post- AD SUDD.

[0026] The first proof of concept was obtained in an open label single arm feasibility study of 10 patients with post- AD SUDD who received preparations of gut-directed Cur (with no additional bio-absorption enhancers such as piperine) and Ber (Coptis chinensis') in combination via oral route under specific therapeutic doses. Therapeutic outcomes were evaluated by the DICS scoring scale, wherein a reduction of DICS score >3 between the baseline and at week 8 with the treatment was considered as significant. Analysis of the data obtained so far showed that in 7 out of 10 patients (70%) the Cur / Ber combination induced a significant reduction of the median DICS score, reflected in a significant change in individual DICS scores before and after treatment (Fig. 1), suggesting significant improvement of the severity of post- AD SUDD symptoms with the combined Cur / Ber treatment. (EXAMPLE 1)

[0027] Additional proof was obtained in a retrospective study of 33 patients with post- AD SUDD who were treated by the same protocol. Therapeutic outcomes were evaluated as above at the baseline and at week 8 with the treatment, and psychometric responses by Visual Analogue Scale (VAS) with questionnaires introduced post-treatment. This study showed that 21 out of 33 patients (64%) reported a significant improvement of symptoms (Fig. 2), and 11 out of 33 patients (33%) reported complete remission of all symptoms. (EXAMPLE 2) Urged by these findings, the inventors are now conducting a comprehensive multicenter randomized placebo-controlled study of post-AD SUDD patients who are being treated by the same therapeutic approach, and potentially incorporating additional herbal extracts. (EXAMPLE 3)

[0028] The present application provides proof of concept for the use of Cur and Ber as a combination therapy that can be effective and safe for the treatment of DD and AD, and specifically for the long-term management of post-AD SUDD. Moreover, this application provides specific guidelines for therapeutic and dosing regimens of this combination therapy to achieve maximum post-AD SUDD recovery in terms of reduction of severity of SUDD symptoms, number of symptoms, recurrence of symptoms, minimization of side effects. As proven to be essentially more effective, accessible and safer than the conventional medicines for this specific indication, such as long-term antibiotics or 5- ASA for example, it is projected that the Cur / Ber combination can be used as add-on to or even replace the conventional medicines, thereby minimizing their doses, the related side effects and costs of the treatment.

[0029] In summary, the present application provides a new therapeutic approach for the treatment of chronic bowel conditions such as post-AD SUDD, using an exceptionally safe and surprisingly effective combination of herbal extracts comprising Cur and Ber (Coptis chinensis) as the main active ingredients. It is projected that the Cur / Ber combination therapy can be used as add-on to the conventional therapies such as 5-ASA and rifaximin, with or without supplementation of specific dietary formulas and / or dietary regimens, to minimize their dosing and their related side effects or adherence issues. Based on present findings, it is further projected that the Cur and Ber combination therapy may serve as a viable therapy for DD, mild AD and post-AD SUDD and potentially other common bowel conditions. As such, it is expected to be reciprocated with a good patients’ compliance.

[0030] BRIEF DECSRIPTION OF DRAWINGS

[0031] To better understand the subject matter and to exemplify how it may be carried out in practice, certain embodiments of the invention are described by way of examples with reference to the following figures. Fig. 1 illustrates the effect of the Cur / Ber combination therapy on the improvement of post- AD SUDD symptoms as arises from the analysis of an open label single arm feasibility study of 10 patients. Figure shows individual DICS scores at the baseline and at week 8 with the treatment, with the primary outcome (clinical response) defined as a reduction of DICS score >3 achieved in 7 out of 10 patients (70%, p=0.004).

[0032] Fig. 2 illustrates the same effect as arises from the analysis of a retrospective study of 33 post-AD SUDD patients treated with the Cur / Ber combination therapy and evaluated at the baseline and at week 8 with the treatment by the DICS and VAS scores. Figure shows the proportion of patients showing improvement of the primary outcome (DICS score drop of >3 points and / or VAS score improvement of >7) in 21 out of 33 patients (64%), about half of which (33%) had complete remission of all symptoms.

[0033] DETAILED DESCRIPTION OF EMBODIMENTS

[0034] In the broadest sense, the invention can be articulated in terms of methods and compositions for use in alleviating, reducing or preventing the recurrence of symptoms of a bowel disease. The term “bowel disease’" encompasses herein a wide range of common conditions affecting the large intestine. The most prominent examples are diseases related to diverticular disease including AD and post AD-SUDD as well as those classified as Inflammatory Bowel Diseases (IBD), such as Crohn's and ulcerative colitis, irritable bowel syndrome (IBS), microscopic colitis, and celiac disease. A common feature of all these disorders is a partial or complete manifestation of the following symptoms: cramping, abdominal pain, bloating, gas, and diarrhea or constipation, which can be episodic, chronic and recurrent.

[0035] In some embodiments the compositions and methods of the invention can be used for alleviating, reducing or preventing the recurrence of symptoms of Diverticular Disease (DD) or diverticulitis. The term “Diverticular Disease” encompasses herein the entire range of DD related conditions, including diverticulosis (formation of one or more diverticula in the colon), diverticulitis (inflammation of diverticula with or without infection) and diverticular bleeding (breakage of blood vessels in diverticula). It further encompasses Type 0: asymptomatic diverticulosis, Type I: acute uncomplicated diverticulitis, Type II: acute complicated diverticulitis and Type III: chronic diverticular disease or post-AD symptomatic uncomplicated diverticular disease (SUDD). The diagnosis of these various conditions is regularly made by treating physicians (gastroenterologists), by medical examination and imaging of the large intestine by colonoscopy and / or CT, and relevant blood tests. The severity of condition is evaluated by respective clinical scoring accounting for various clinical and endoscopic variables, such as Mayo score / disease activity index (DAI) for ulcerative colitis for example. In the case of DD, the inventors have developed and published a Diverticular Clinical Score (DICS) for the assessment of patient’s specific clinical status.

[0036] In this respect the invention provides compositions and methods using a combination of Curcumin (Cur) and Berberine (Ber) or plant extracts comprising these actives. The term “Curcumin” predominantly refers herein to diferuloylmethane or betadiketone (IUPAC name: (lE,6E)-l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene- 3, 5-dione), a molecule with chemical formula C21H20O6, and molecular weight of about 368 g / mol. It further encompasses herein Cur obtained from natural sources and by synthetic processes. In terms of natural sources, it encompasses Cur extracted from plants such as Curcuma longa L., which is the basis of turmeric spice. The term “Berberine” (also Umbellatine, Berbericine), refers herein to an organic heteropentacyclic compound, i.e., quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids, a molecule with chemical structure C2OHISN04+and molecular weight of about 336 g / mol. It encompasses herein Ber obtained from various plants like Coptis chinensis, goldenseal, goldthread, Oregon grape and others.

[0037] The term “extracts” encompasses herein any preparation of Cur or Ber made by extracting any part of a raw plant material, including by solvents such as ethanol, oil or water and methods such as maceration, percolation, decoction, ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) and other methods, and simple drying and lyophilization of the source-plants. This term encompasses herein extracts provided as tinctures, absolutes or in powder form.

[0038] Important advantages of the present compositions and methods are their oral compatibility and accessibility.

[0039] In some embodiments the Cur and Ber combination can be provided in separate or the same oral composition.

[0040] In some embodiments the Cur and Ber combination can be provided by separate or the same oral administration. In some embodiments the Cur and Ber can be provided as isolated actives or plant extracts.

[0041] In some embodiments the Cur and Ber actives can be formulated in solid or liquid formulations such as tablets or encapsulated liquids or gels, including slow and controlled release components and capsule shells.

[0042] In some embodiments the plant extracts can be provided in a powder form.

[0043] In other embodiments the plant extracts can be provided in a liquid, semi-liquid or gel form.

[0044] In some embodiments the preparations or extracts of Cur and / or Ber can be devoid of a bio -absorption enhancer, such as quercetin, genistein, naringin, sinomenine, piperine or glycyrrhizin. These natural substances that are present in many plant extracts have been known to enhance the bioavailability of different drugs, either by increasing their absorption and systemic exposure or by delaying their metabolism, or by both processes. The main advantage of preparations devoid of bio-absorption enhancers is that they minimize systemic exposure to actives (Cur and Ber) and increase the concentrations of actives at the target organ (the gut).

[0045] In some embodiments the preparations or extracts of Cur and / or Ber can be devoid or substantially devoid of piperine. The terms “devoid” or “substantially devoid” imply herein deviations of up to 0.01-0.05%, 0.05-0.1%, 0.1-0.2%, 0.2-0.3%, 0.3-0.4%, 0.4-0.5%, 0.5-0.6%, 0.6-0.7%, 0.7-0.8%, 0.8-0.9%, 0.9-1%, 1-2%, 2-3%, 3-4% and 4-5% weight percent of piperine as per total weight of the preparation or plant extract (w / w).

[0046] In some embodiments the Cur extract can be obtained from Curcuma longa L.

[0047] In some embodiments the Ber extract can be obtained from Coptis chinensis.

[0048] Another important feature of the present compositions and methods is that Cur and Ber are provided in specific proportions and doses.

[0049] In some embodiments the Cur and Ber, or extracts thereof, can be provided at a weight ratio in the range between about 10:1 and about 1:10 (w / w), respectively, or more precisely at a weight ratio in the range between about 10: 1 to 1 : 10, about 9: 1 to 1:9, about 8:1 to 1:8, about 7:1 to 1:7, about 6:1 to 1:6, about 5:1 to 1:5, about 4:1 to 1:4, about 3:1 to 1:3, or about 2:1 to 1:2 (w / w), respectively. In some embodiments the Cur and Ber, or extracts thereof, can be provided at a weight ratio of about 5:1, about 4:1, about 7:3, about 3:2, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 2:3, about 3:7, about 1:4 or about 1:5 (w / w). respectively.

[0050] In some embodiments the Cur and Ber, or extracts thereof, can be provided at a weight ratio of about 3:1 or 3:2, respectively.

[0051] In some embodiments the Cur and Ber, or extracts thereof, can be provided at a weight ratio of in the range between about 2:1 and 1:1, or at a weight ratio of about 3:2, respectively

[0052] In some embodiments the Cur and Ber, or extracts thereof, can be provided at a weight ratio of about 2:1 or about 1:1, respectively.

[0053] In some embodiments said ratios apply to the situation in which the Cur and Ber combination is provided in the same oral composition or the same oral administration.

[0054] In some embodiments said ratios apply to the situation in which the Cur and Ber combination is provided in separate oral compositions and separate oral administrations.

[0055] In some embodiments the Cur and Ber combination, or extracts thereof, can be provided at a dose or amount in the range between about 100 mg to about 10,000 mg each, or more precisely, at a dose in the range between about 100 to 10,000 mg, about 200 to 9000 mg, about 300 to 8000 mg, about 400 to 7000 mg, about 500 to 6000 mg, about 500 to 5000 mg, about 500 to 4000 mg, 500 to 3000 mg, or 500 to 2000 mg each in the same or separate oral compositions.

[0056] In some embodiments the dose or amount of Cur, or an extract thereof, can be in the range of about 100-500, 500-1000, 1000-2000, 2000-3000, 3000-4000, 4000-5000, 5000-6000, 6000-7000, 7000-8000, 8000-9000 and 9000-10,000 mg, provided as a separate or the same composition with Ber, and the dose or amount of Ber, or an extract thereof, can be in the range of about 100-500, 500-1000, 1000-2000, 2000-3000, 3000- 4000, 4000-5000, 5000-6000, 6000-7000, 7000-8000, 8000-9000 or 9000-10,000 mg, provided as a separate or the same composition with Cur.

[0057] In some embodiments the dose or amount of Cur, or the extract, can be in the range of about 100-500, 500-1000, 1000-1500, 1500-2000, 2000-2500, 2500-3000, 3000- 3500, 3500-4000, 4000-4500 or 4500-5000 mg, and the dose or amount of Ber, or the extract, can be in the range of about 100-500, 500-1000, 1000-1500, 1500-2000, 2000- 2500, 2500-3000, 3000-3500, 3500-4000, 4000-4500 or 4500-5000 mg, provided in the same or separate oral compositions.

[0058] In some embodiments, the dose or amount of Cur, or the extract, can be about 10,000, 9000, 8000, 7000, 6000, 5000 mg or 4500, 4000, 3500, 3000, 2500, 2000, 1500, 1000, 500, 400, 300, 200 or 100 mg, and the dose or amount of Ber, or the extract, can be about 10,000, 9000, 8000, 7000, 6000, 5000 mg or 4500, 4000, 3500, 3000, 2500, 2000, 2500, 1000, 500, 400, 300, 200 or 100 mg, provided in the same or separate oral compositions.

[0059] In other words, in some embodiments the compositions of the invention can comprise a dose or an amount of Cur, or the extract, of about 10, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg and a dose or an amount of Ber, or the extract, of about 100, 200, 300, 300, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg provided in the same or separate oral compositions.

[0060] More specifically, in some embodiments the compositions can comprise about 500 mg Cur and about 500 mg Ber, or extracts thereof, in the same composition. Such compositions can be administered 3 times a day, for example, providing a daily dose or amount of about 1500 mg Cur and about 1500 mg Ber.

[0061] In some embodiments the compositions can comprise about 1000 mg Cur and about 1000 mg Ber or extracts thereof. When administered 2 times a day, they can provide a daily dose or amount of about 2000 mg Cur and about 2000 mg Ber.

[0062] In some embodiments the compositions can comprise about 1000 mg Cur and about 500 mg Ber or extracts thereof. When administered 2 times a day, they can provide a daily dose or amount of about 2000 mg Cur and about 1000 mg Ber, and with 3 times a day, they can provide a daily dose or amount of about 3000 mg Cur and about 1500 mg Ber.

[0063] In some embodiments the compositions can comprise about 1500 mg Cur and about 500 mg Ber or extracts thereof. When administered 2 times a day, they can provide a daily dose or amount of about 3000 mg Cur and about 1000 mg Ber.

[0064] In some embodiments the compositions can comprise about 750 mg Cur and about 500 mg Ber or extracts thereof. When administered 2 times a day, they can provide a daily dose or amount of about 1500 mg Cur and about 1000 mg Ber, and with 3 times a day, they can provide a daily dose or amount of about 2250 mg Cur and about 1500 mg Ber.

[0065] The compositions can be administered in the morning, noon, evening, depending on the needs and symptoms of a specific patient, and the rate of remission with the treatment.

[0066] More generally, in some embodiments the compositions of the invention can comprise a dose or an amount of Cur and Ber, or extracts thereof, in the range of about 500 mg to about 3000 mg each in the same oral composition.

[0067] In some embodiments the compositions of the invention can comprise a dose or an amount of Cur and Ber ort extracts thereof in the range of about 500 mg to about 2000 mg each in the same oral composition.

[0068] The methods of the invention can use preparations or extracts of Cur and Ber in the same or separate compositions which are introduced at specific ratios and therapeutic doses or amounts by a single or separate administrations. The terms “ therapeutic close" or “ therapeutically effective dose" or "therapeutically effective amount”, which herein are interchangeable, are used herein in the broadest sense to refer to a dose or an amount of active that enable to achieve an amelioration, an alleviation or a reduction of severity or recurrence of at least one symptom of a disease as evaluated by relevant clinical criteria. Therapeutically effective dose can refer to as a daily or weekly dose of the active provided in a single or successive administrations. In this context, this term is applied in the sense of daily regimens or daily therapeutic doses or amounts of Cur and Ber introduced to a patient by a single or successive oral administrations.

[0069] More specifically, in some embodiments the methods and therapeutic regimens of the invention can provide Cur and Ber, or extracts thereof, at a daily dose or amount in the range between about 100 mg to about 10,000 mg each, or more precisely, at a dose or amount in the range between about 100 to 10,000 mg, about 200 to 9000 mg, about 300 to 8000 mg, about 400 to 7000 mg, about 500 to 6000 mg, about 500 to 5000 mg, about 500 to 4000 mg, 500 to 3000 mg, or 500 to 2000 mg each, provided by the same of separate oral administrations.

[0070] In some embodiments the daily dose or amount of Cur and Ber, or extracts thereof, can be in the range between about 100-500, 500-1000, 1000-2000, 2000-3000, 3000-4000, 4000-5000, 5000-6000, 6000-7000, 7000-8000, 8000-9000 and 9000-10,000 mg each, provided by the same or separate oral administrations.

[0071] In some embodiments the daily dose or amount of Cur and Ber, or extracts thereof, can be in the range between about 100-500, 500-1000, 1000-1500, 1500-2000, 2000-2500, 2500-3000, 3000-3500, 3500-4000, 4000-4500 or 4500-5000 mg each, provided by the same or separate oral administrations.

[0072] In some embodiments, the daily dose or amount of Cur and Ber, or extracts thereof, can be about 10,000, 9000, 8000, 7000, 6000, 5000 mg or 4500, 4000, 3500, 3000, 2500, 2000, 1500, 1000 or 500 mg each, provided by the same or separate oral administrations.

[0073] In other words, in some embodiments the methods and therapeutic regimens of the invention can comprise a daily dose or amount of Cur, or extracts thereof, of about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg and a daily dose or amount of Ber, or extracts thereof, of about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg, provided by the same or separate oral administrations.

[0074] For example, in some embodiments the daily doses or amounts of Cur and Ber can be of about 1500 mg and about 1500 mg, respectively, keeping with the ratio of 1:1 therebetween.

[0075] In some embodiments the daily doses or amounts of Cur and Ber can be of about 2000 mg and about 2000 mg, respectively, keeping with the ratio of 1:1 therebetween.

[0076] In some embodiments the daily doses or amounts of Cur and Ber can be of about 2000 mg and about 1000 mg, respectively, or 3000 mg and about 1500 mg, respectively, keeping with the ratio of 2:1 therebetween.

[0077] In some embodiments the daily doses or amounts of Cur and Ber can be of about 3000 mg and about 1000 mg, respectively, keeping with the ratio of 3:1 therebetween.

[0078] In some embodiments the daily doses or amounts of Cur and Ber can be of about 750 mg and about 500 mg, respectively, or 1500 mg and about 1000 mg, respectively, or 2250 mg and about 1500, respectively, keeping with the ratio of 3:2 therebetween.

[0079] Said daily doses of Cur and Ber can be provided by a single administration of both actives, or extracts thereof, or in successive administrations at different time points during the day (e.g., morning, midday and evening). In some embodiments said daily doses can involve 1, 2, 3, 4, or 5 daily administrations of the Cur and Ber combination.

[0080] In some embodiments Cur and Ber, or extracts thereof, can be administered at least 1 to 5 times a day.

[0081] In some embodiments they can be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 months, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more, or through the entire life of a patient with a bowel disease or DD, and particularly in cases with chronic presentations such as post-AD SUDD.

[0082] The therapeutic regimens of the invention can be further articulated in terms of single or successive administrations of the compositions of the invention as above with the specific ratios of actives and doses that proved to be effective for alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease, or DD.

[0083] In some embodiments the therapeutic regimens of the invention can comprise 1, 2, 3, 4, or 5 daily administrations of the compositions of the invention to achieve the afore-mentioned therapeutic daily doses.

[0084] In some embodiments the therapeutic regimens of the invention can comprise daily or weekly administrations of said compositions in a course of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 months, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more.

[0085] These particular aspects can be further articulated in terms any of the aforementioned compositions of the invention for use in alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease, and DD in particular, wherein the composition is administered by any of the afore-mentioned dosing regimens.

[0086] The invention can be further articulated in terms of uses of the afore-mentioned compositions in the manufacture of a medicament for alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease, and DD in particular.

[0087] In some embodiments the compositions, methods and uses of the invention can be applicable to Acute Diverticulitis (AD) or post-AD Symptomatic Uncomplicated Diverticular Disease (SUDD).

[0088] In some embodiments the compositions, methods, therapeutic regimens and uses of the invention can further incorporate or comprise use of additional therapeutic agents. The term “ additional therapeutic agent" implies herein conventional medicines for treating bowel diseases and DD, such as certain analgesic, antibiotics and immunomodulatory drugs. It further implies certain dietary formulas or dietary regimens for treating bowel diseases and DD, such as high-fiber diet, rich in fruits and vegetables, lean protein and healthy fats, and supplements containing thereof.

[0089] The terms “about” or “approximately” are meant to encompass herein a deviation of up to ±15% from the specified values or ranges, and more specifically up to a deviation of about ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, ±10%, ±11%, ±12%, ±13%, ±14% or ±15% therefrom.

[0090] EXAMPLES

[0091] The invention is not limited to any specific methods and experimental conditions. The methods can vary from those detailed below, depending on the specific applications of the invention.

[0092] EXAMPLE 1: An open label single arm feasibility study

[0093] 1.1 Study group

[0094] Patients (n=10) were recruited to the study by the following parameters:

[0095] Inclusion criteria:

[0096] — Diagnosis of previous AD and ongoing abdominal symptoms of SUDD (left abdominal pain and / or change in bowel habits and bloating).

[0097] — Active SUDD (DICS score >10).

[0098] — Age 18-80 years.

[0099] Exclusion criteria:

[0100] — Patients with non-controlled renal or liver disease, hypertension, cardiovascular disease, cerebrovascular disease, chronic pancreatitis, diabetes mellitus, gallstone disease, uncontrolled migraines, or neurological disorders.

[0101] — Patients with significant laboratory abnormalities, including anemia with hemoglobin <10, leucopenia (WBC<4k / mcl), thrombocytopenia (Plt<100K / mcl), abnormal coagulation tests (INR, PTT), or elevation of liver or kidney function tests above normal

[0102] — Patient with active infection, sepsis or pneumonia

[0103] — Pregnant or nursing women — Known allergy to either Cur or Ber

[0104] Early termination criteria:

[0105] — A serious adverse event

[0106] — Recurrent AD attack

[0107] 1.2 Measured outcomes

[0108] Primary outcomes:

[0109] — Percentage of patients reaching clinical response 4 weeks after initiation of therapy (clinical response defined as a drop of DICS score >3)

[0110] Secondary outcomes:

[0111] — Percentage of patients having clinical remission at week 4 after initiation of therapy (clinical remission defined as DICS score < 5)

[0112] — Percentage of patients having rapid clinical response at day 7 after initiation of therapy

[0113] — Percentage of patients having rapid clinical response at week 4 after initiation of therapy

[0114] — Percentage of patients achieving normalization of CRP or Calprotectin (Cal) levels (calculated out of patients with baseline levels above 1.5 of normal CRP and / or Calprotectin levels)

[0115] — Percentage of patients achieving >50% improvement of CRP or Cal levels (calculated out of patients with abnormal values at baseline for these indices)

[0116] — Time-to-response defined as number of weeks to achieve a drop of DICS score >3

[0117] — Percentage of patients in clinical remission at day 28 after initiation of therapy

[0118] — Percentage of patients reaching significant clinical response at week 8 after initiation of therapy (significant clinical response defined as a drop of DICS score >5)

[0119] — Percentage of patients reaching clinical pain response at week 8 after initiation of therapy (clinical pain response defined as a drop of >3 points of the 3 pain components at DICS score) 1.3 Intervention

[0120] Patients diagnosed with active SUDD received oral Cur-Ber therapy for 8 weeks, consisting of 2 capsules of 500 mg Ber before breakfast (1000 mg Ber daily) and 3 capsules of 500 mg Cur before dinner (1500 mg Cur daily). Both Ber and Cur are administered as dry concentrated powders filled into HPMC capsules. Other ongoing medications were not altered. The study used plant extracts of Cur and Ber from Curcuma longa L. and Coptis chinensis, respectively, in a powder form (regulated under GRAS).

[0121] 1.4 Procedures

[0122] Screening and initiation:

[0123] 1) Clinical scoring (DICS)

[0124] 2) Sigmoidoscopy (for consenting patients). At sigmoidoscopy, DICA endoscopic scoring was performed (blindly by two endoscopists), biopsies were taken from sigmoid colon (above 15 cm insertion) for histopathology and for snap freezing for transcriptomic analysis, and collection of fecal wash.

[0125] 3) Fecal Cal testing

[0126] 4) Physician assessment

[0127] 5) Blood tests, including CBC, SMAC, CRP, hemoglobin, albumin, serum for proteomics, whole blood, lipids (total cholesterol, LDL, HDL)

[0128] 6) Stool cultures, O&P and C.diff Tox

[0129] 7) Stool samples for microbiome

[0130] 1.5 During study

[0131] Patient filled DICS score weekly, reported by telephone or electronically.

[0132] 1.6 Conclusion (Week 8)

[0133] Analyses 1-7 as above.

[0134] 1.7 Safety

[0135] Safety assessment was performed at baseline and week 4, using blood profiling of CBC, SMAC, ESR, CRP, hemoglobin, albumin, coagulation. Adverse events were recorded.

[0136] 1.8 Data analysis and statistics

[0137] The rates of the primary and secondary outcomes were calculated using descriptive statistics adapted for small sample size. 1.9 Time frame

[0138] 8 months

[0139] 1.10 Results and conclusions

[0140] Patients were evaluated by the DICS score at the baseline and at week 8 with the treatment. Fig. 1 shows individual DICS scores at these time points, with the primary outcome (clinical response) defined as a reduction of DICS score >3 achieved in 7 out of 10 patients (70%, p=0.004). The results obtained so far suggest a significant improvement of clinical symptoms of post-AD SUDD with the Cur / Ber combination therapy.

[0141] EXAMPLE 2: A retrospective study of patients treated with Cur and Ber combination

[0142] 2.1 Study group

[0143] Eligible patients were adults (age>18 years-old) with a self-professed previous episode / s of AD and continued symptoms compatible with post-AD SUDD who used Cur and Ber (Coptis chinensis) as a treating option. Patients filled out the DICS score before and after treatment (at week 8). Alternatively, the patients were contacted to fill questionnaires based on Visual Analogue Scale (VAS) for the evaluation of psychometric responses, an improvement with therapy was evaluated by indices of 1 - No improvement to 10 - Complete improvement and disappearance of symptoms.

[0144] 2.2 Results and conclusions

[0145] The primary outcome was clinical response at week 8 with the treatment, defined as a reduction of DICS score of >3 points and / or an improvement of VAS score of >7. Fig. 2 shows that the primary outcome was achieved in 21 out of 33 patients (64%), while about half of these patients (33%) reported complete remission of all symptoms. The results suggest that the Cur / Ber combination therapy can lead to significant improvement up to complete remission of post-AD SUDD symptoms even after termination of the treatment period.

[0146] EXAMPLE 3: A multicenter randomized placebo-controlled trial

[0147] 3.1 Study group

[0148] Screening and initiation are as in EXAMPLE 1, including the inclusion, exclusion and termination criteria, and the primary and secondary outcomes. Fifty patients have been recruited so far, including 33 patients in the treatment group and 17 patients in the placebo groups. 3.2 Intervention

[0149] Patients are being randomized into two groups (2:1 proportion):

[0150] — Treatment group receiving Cur (2g)-Ber (1.0 gr) twice daily, or

[0151] — Placebo group.

[0152] The treatment regimen includes:

[0153] — Morning: 2 capsules of Cur + 1 capsule of Ber, and

[0154] — Evening: 2 capsules of Cur + 1 capsule of Ber taken with meals. Placebo capsules include starch.

[0155] This study is currently ongoing

Claims

CLAIMS1. A method of alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease in a subject in need thereof, the method comprises oral administering to said subject a therapeutically effective amount of Curcumin (Cur) and Berberine (Ber) or a plant extract comprising thereof, the Cur and the Ber being administered separately or by the same administration.

2. A method of alleviating, reducing or preventing the recurrence of at least one symptom of Diverticular Disease (DD) in a subject suffering therefrom, the method comprises oral administering to said subject a therapeutically effective amount of Curcumin (Cur) and Berberine (Ber) or a plant extract comprising thereof, the Cur and the Ber being administered separately or by the same administration.

3. The method of claim 2, wherein the Diverticular Disease (DD) is Acute Diverticulitis (AD).

4. The method of claim 2, wherein the Diverticular Disease (DD) is post- AD Symptomatic Uncomplicated Diverticular Disease (SUDD).

5. The method of any one of claims 1 to 4, wherein the Cur and the Ber are administered at a weight ratio in the range between about 10:1 and about 1:10, respectively.

6. The method of claim 5, wherein the weight ratio of Cur to Ber is about 3:1, about 3:2, respectively.

7. The method of claim 5, wherein the weight ratio of Cur to Ber is about 2:1 or about 1:1, respectively.

8. The method of any one of claims 1 to 7, wherein the Cur and / or the Ber are in the form of a plant extract.

9. The method of claim 8, wherein the Cur and / or the Ber plant extracts are devoid or substantially devoid of piperine.

10. The method of claim 8, wherein the Cur and / or the Ber plant extracts are in a powder form.

11. The method of claim 8, wherein the Cur extract is obtained from Curcuma longa L. plant.

12. The method of claim 8, wherein the Ber extract is obtained from Coptis chinensis plant.

13. The method of any one of claims 1 to 12, wherein the Cur and the Ber are administered to the subject at a daily dose of in the range between about 100 mg to about 10,000 mg each.

14. The method of claim 13, wherein the daily dose of Cur and Ber is in the range of about 5000 mg to about 500 mg each.

15. The method of claim 14, wherein the daily dose of Cur and Ber is in the range of about 3000 mg to about 500 mg each.

16. The method of claim 15, wherein the daily dose of Cur is about 1500 mg and the daily dose of Ber is about 1000 mg.

17. The method of claim 15, wherein the daily dose of Cur is about 2000 mg and the daily dose of Ber is about 1000 mg.

18. The method of any one of claims 1 to 17, wherein the Cur and the Ber are being administered to the subject 2 or 3 times a day.

19. The method of any one of claims 1 to 18, wherein the Cur and the Ber are being administered to the subject for at least 1 month.

20. The method of any one of claims 1 to 19, further comprising administering to the subject at least one additional therapeutic agent.

21. The method of claim 20, wherein the therapeutic agent is selected from at least one of a drug for treating a bowel disease or DD, a dietary formula or a dietary regimen for treating a bowel disease or DD.

22. An oral composition for use in alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease, the composition comprises a therapeutically effective amount of Curcumin (Cur) and Berberine (Ber) or a plant extract comprising thereof.

23. An oral composition for use in alleviating, reducing or preventing the recurrence of at least one symptom of Diverticular Disease (DD), the composition comprises a therapeutically effective amount of Curcumin (Cur) and Berberine (Ber) or a plant extract comprising thereof.

24. The composition for use according to claim 23, wherein the Diverticular Disease (DD) is Acute Diverticulitis (AD).

25. The composition for use according to claim 23, wherein the Diverticular Disease (DD) is post- AD Symptomatic Uncomplicated Diverticular Disease (SUDD).

26. The composition for use according to any one of claims 22 to 25, wherein a weight ratio of Cur to Ber is in the range between about 10:1 and about 1:10, respectively.

27. The composition for use according to claim 26, wherein the weight ratio of Cur to Ber is about 3:1 or about 3:2, respectively.

28. The composition for use according to claim 26, wherein the weight ratio of Cur to Ber is about 2:1 or about 1:1, respectively.

29. The composition for use according to any one of claims 22 to 28, wherein the Cur and Ber are in the form of a plant extract.

30. The composition for use according to claim 29, wherein the Cur and / or the Ber plant extracts are devoid or substantially devoid of piperine.

31. The composition for use according to claim 29, wherein the Cur and / or the Ber plant extracts are in a powder form.

32. The composition for use according to claim 29, wherein the Cur extract of is obtained from Curcuma longa L. plant.

33. The composition for use according to claim 29, wherein the Ber extract of is obtained from Coptis chinensis plant.

34. The composition for use according to any one of claims 22 to 33, wherein the Cur and the Ber are provided at an amount in the range between about 100 mg to about 10,000 mg each.

35. The composition for use according to claim 34, wherein the Cur and Ber amount is in the range of about 5000 mg to about 500 mg each.

36. The composition for use according to claim 35, wherein the Cur and Ber amount is in the range of about 3000 mg to about 500 mg each.

37. The composition for use according to claim 36, wherein the Cur amount is in the range between about 500 mg to about 2000 mg and the Ber amount is in the range of about 500 mg to about 1000 mg.

38. The composition for use according to claim 37, wherein the Cur amount is about 500 mg and the Ber amount is about 500 mg.

39. The composition for use according to claim 37, wherein the Cur amount is about 1000 mg and the Ber amount is about 500 mg.

40. The composition for use according to claim 37, wherein the Cur amount is about 750 mg and the Ber amount is about 500 mg.

41. The composition of any one of claims 22 to 40, further comprising at least one additional therapeutic agent.

42. A therapeutic regimen for alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease, the regimen comprises oral administering of at least 1 to 3 daily doses of a composition of any one of claims 22 to 40.

43. A therapeutic regimen for alleviating, reducing or preventing the recurrence of at least one symptom of Diverticular Disease (DD), the regimen comprises oral administering of at least 1 to 3 daily doses of a composition of any one of claims 22 to 40.

44. The therapeutic regimen of claim 42 or 43, wherein said daily doses of the composition are being administered for at least 1 month.

45. Use of a therapeutically effective amount of Curcumin (Cur) and Berberine (Ber) or a plant extract comprising thereof in the manufacture of an oral medicament for alleviating, reducing or preventing the recurrence of at least one symptom of a bowel disease or Diverticular Disease (DD).

Images