EP3716961A1 - Composition for preventing and/or curing gastrointestinal disorders - Google Patents
Composition for preventing and/or curing gastrointestinal disordersInfo
- Publication number
- EP3716961A1 EP3716961A1 EP18819554.9A EP18819554A EP3716961A1 EP 3716961 A1 EP3716961 A1 EP 3716961A1 EP 18819554 A EP18819554 A EP 18819554A EP 3716961 A1 EP3716961 A1 EP 3716961A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- diarrhoea
- composition according
- berberine
- curcumin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/062—Ascomycota
- A61K36/064—Saccharomycetales, e.g. baker's yeast
Definitions
- composition for preventing and/or curing gastrointestinal disorders comprising:
- compositions for the cure and/or prevention of gastrointestinal diseases and/or disorders wherein said composition, in any form of pharmaceutically acceptable administration, comprises a mixture comprising or, alternatively, consisting of at least berberine (a) and Saccharomyces boulardii (b).
- Diarrhoea as a condition in which there are three or more watery evacuations per day or a higher number of evacuations with respect to the normal evacuations. Diarrhoea is commonly classified into acute diarrhoea (the most frequent form) and chronic diarrhoea. Acute diarrhoea is defined as an increase of the water content, volume or frequency of defecation lasting for at least 14 days.
- This disease causes the death of about 2.5 million people in the world. Just in the United States alone, diarrhoea annually causes about 128000 hospitalisations and 3000 deaths per year. Infections that cause acute diarrhoea include viruses, bacteria and less often parasites, while causes of non-infective type of acute diarrhoea may include adverse effects from drugs, abdominal, gastroenteric or endocrine diseases. There are various types of diarrhoea such as for example secretory diarrhoea where there is an increase of secretion or a reduction of the absorption of electrolytes often due to the presence of bacterial toxins, or diseases that reduce the absorption surface area in the bowel.
- osmotic diarrhoea is due to the presence of osmotically active solutes and that are poorly absorbed in the bowel lumen that hinder the normal absorption of water and electrolytes. Some laxatives such as lactulose, magnesium citrate, or poor digestion of some foods such as milk are typical causes of osmotic diarrhoea.
- Exudative diarrhoea is instead characterised by the presence of blood or pus in the faeces. It is a typical form in case of inflammatory bowel diseases such as Crohn's disease or ulcerative colitis or in case of severe E. coli infections or food poisoning.
- Types of secondary diarrhoea that could be caused by poor absorption phenomena, like in the case of steatorrhea where poor absorption of fatty acids causes the presence of large amounts of fats in the faeces, are also known.
- the start, duration, seriousness and frequency, same case applying to the characteristics of the faeces are crucial towards the diagnosis and cure of acute diarrhoea.
- Other symptoms to be taken into account or to be reported to the medical personnel include the degree of dehydration, thirst, variation of urination frequency and altered mental status.
- vomit is typical of disorders caused by viruses or particular bacterial toxins.
- Fever, tenesmus and presence of blood in the faeces are symptoms typical of bacterial proliferation and inflammation instead.
- the first required step is rehydration, preferably orally, for the replacement of fluid deficit.
- Oral rehydration solution (ORS) must contain a mixture of salts and glucose dissolved in water.
- ORS Oral rehydration solution
- the OMS approved an ORS with reduced osmolarity (250 mOsm/L with respect to the reference standard of 311 mOsm/L) which is capable of reducing defecation, events of vomit thus avoiding intravenous rehydration and hyponatremia phenomena.
- Drugs commonly used for curing diarrhoea are agents that reduce gastrointestinal motility and antibiotics. The first act increasing the bowel transit time, potentially increasing fluids and electrolytes absorption.
- the active ingredient most widely used for reducing motility is loperamide, an agonist of m, k and d receptors of the myenteric plexus. Its use alongside simethicone causes a quick action on non-specific acute diarrhoea and flatulence. Loperamide is not recommended in cases of bleeding or inflammatory diarrhoea in that it can cause severe adverse effects. Furthermore, these agents are not recommended for children in that they can cause adverse effects on the central nervous system and potentially respiratory depression too.
- antibiotic treatment of diarrhoea of infective origin treatment with loperamide is not always recommended and should be carefully weighed depending on the severity of the symptoms.
- Antibiotic treatment is particularly recommended in case of Shigella dysentery, cholera, pseudomembranous colitis caused by parasites and in case of sexually transmitted diseases.
- Antibiotics are recommended in case of some bowel infections that cause acute watery diarrhoea or in case of bowel infections that can cause sepsis.
- the most prescribed antibiotics include azithromycin, metronidazole, ciprofloxacin in case of acute diarrhoea caused by infections respectively of Campylobacter, Clostridium difficile and E. coll, enterohepatitis origin.
- Another drug used in case of acute diarrhoea is bismuth subsalicylate, which is capable of controlling the symptomatology and could also have antibiotic and anti-inflammatory properties.
- bismuth subsalicylate which is capable of controlling the symptomatology and could also have antibiotic and anti-inflammatory properties.
- it does not accurately meet the patients' compliance in that it has an about four-hour action onset, it can interfere with the absorption of other drugs such as doxycycline and above all it can cause tinnitus and darkening of the tongue.
- probiotics are also widely used for treating diarrhoea. These agents probably act stimulating the immune system and thus compete for nutrients and binding sites on the intestinal epithelial cells with pathogenic microorganisms. These agents, mainly S. boulardii e Lactobacillus acidophilus, have revealed considerable capacity to reduce the duration of diarrhoea in children and the consistency of the faeces but without acting on the other parameters (such as abdominal pain for example).
- absorbents such as diosmectite, kaolin, pectin
- diarrhoea could be used in case of diarrhoea thanks to their capacity to absorb the toxins responsible for acute diarrhoea.
- absorbents such as diosmectite, kaolin, pectin
- they are also known to cause constipation and alter the absorption of other drugs such as theophylline or digoxin.
- all clays diosmectite, kaolin are forbidden in food supplements due to their aluminium content.
- IBS Irritable Bowel Syndrome
- This disorder in the general population varies significantly. In Northern America, this disorder has a prevalence of 12% of the population. In Southern America, the prevalence is considerably higher and it reaches 21% of the population. The lowest prevalence is observed in South East Asia, with a value of 7%. The genre difference in the prevalence of this syndrome is more marked in the United States and in Canada, with a 1.5 to 2 times higher prevalence in women than men. Asia reveals a lower genre difference in the prevalence. Another genre difference lies in the type of bowel disorder, with women mainly suffering from constipation and men more frequently affected by IBS associated with diarrhoea. The prevalence of this disorder is inversely proportional to the age of the patients.
- IBS-D diarrhoea
- IBS-C constipation
- IBS-M alternation between the two disorders
- Irritable Bowel Syndrome Various comorbidities are associated to the Irritable Bowel Syndrome, including syndromes associated to chronic pain (fibromyalgia, chronic fatigue syndrome, chronic pelvic pain), other bowel disorders (gastroesophageal reflux syndrome, dyspepsia) and psychiatric disorders (depression, anxiety).
- chronic pain fibromyalgia, chronic fatigue syndrome, chronic pelvic pain
- other bowel disorders gastroesophageal reflux syndrome, dyspepsia
- psychiatric disorders depression, anxiety
- IBS is a syndrome subject to various relapses over the years.
- long term follow-ups reveal a 2 to 18% deterioration of the patients, an unaltered situation in 30 to 50% of the patients and a 12 to 38% improvement of the patients.
- a change in the type of bowel disorders related to this syndrome could occur over time: most of the patients go from IBS with prevalent diarrhoea or tympanites to an IBS with alternating constipation and diarrhoea. Patients going from IBS-C to IBS-D or vice versa is rarer.
- the pathophysiology of the irritable bowel syndrome is heterogeneous: similar symptoms may arise from causes even very different from each other. Many factors that can contribute to the pathogenesis of IBS have been discovered over the last 40 years.
- Irritable bowel syndrome etiologic factors can be classified as follows:
- the therapy can be aimed at treating abdominal symptoms, such as pain, cramps, bloating or intestinal symptoms such as diarrhoea or constipation.
- the present invention provides a composition for use according to the attached claims.
- a composition comprising or, alternatively, consisting in an effective amount of a mixture(M) comprising at least (a) berberine and (b) yeasts belonging to the Saccharomyces boulardii species is an object of the present invention.
- Said composition comprising said mixture (M) for use in preventive or curative treatment - in a subject - of at least one disease and/or disorder of the gastrointestinal tract, wherein said treatment comprises the administration of said composition to the subject, is an object of the present invention.
- a pharmaceutical composition, a food supplement or a medical device comprising the composition comprising the mixture (M) as defined above and at least one excipient acceptable for pharmaceutical or food purposes is also an object of the present invention.
- compositions comprising or, alternatively, consisting in an effective amount of a mixture(M) comprising at least (a) berberine and (b) yeasts belonging to the Saccharomyces boulardii species and, optionally, curcumin (c) with high activity in the curative or preventive treatment of gastrointestinal tract disorders and/or diseases.
- a mixture(M) comprising at least (a) berberine and (b) yeasts belonging to the Saccharomyces boulardii species and, optionally, curcumin (c) with high activity in the curative or preventive treatment of gastrointestinal tract disorders and/or diseases.
- said high activity can be due to the combined action among components a) and b), and, optionally, c) as indicated above.
- the expression "treatment” of a disease or disorder is used to indicate the therapy aimed at restoring a subject's health conditions, maintaining the current conditions and/or preventing the deterioration of said health conditions.
- prevention of a disease or disorder is used to indicate a therapy aimed at hindering the occurrence of such disease or disorder in a subject, including but not exclusively complication or effect of a pre-existing disease or disorder.
- composition/s is deemed to comprise a pharmaceutical composition, a composition for a food supplement, a composition for a food product or a composition for a medical device
- Berberinea is an isoquinoline alkaloid and it is present in the cortex and in the rhizome of various plant species of the eastern hemisphere such as Coptis chinensis Franch., Coptis japonica Makino., Beiteiis thunbergii DC., Berberis aristata L, Berberis vulgaris DC., Hydrastis canadensis L, and Thalictrum lucidum Ait. This metabolite is known to the traditional oriental medicine where it was used for treating diarrhoea and gastroenteritis. Significant analgesic, anti-inflammatory and anti-tumour effects with potential therapeutic impact on diabetes, hyperlipidaemia and cardiovascular problems have been attributed to berberine more recently.
- berberine is contained in an extract of at least one plant of the Berberis genre and it derives from said at least one plant of the Berberis genre.
- the treatment most widely used for treating dehydration caused by diarrhoea is the restoration of liquids and electrolytes by administering an oral rehydration solution.
- This type of therapy is clearly not capable of affecting the duration of diarrhoea in any manner whatsoever.
- an adjuvant therapy capable on acting on the duration of this gastrointestinal disorder too.
- Saccharomyces boulardii is a yeast that was isolated for the first time in the Garcinia mangostana fruit. Numerous pre-clinical developments, this yeast revealed to be effective at preventing and treating diarrhoea, especially antibiotic-related diarrhoea. Saccharomyces boulardii can be co-administered with antibiotics to reduce the risk of diarrhoea.
- yeasts of the Saccharomyces boulardii species belong to the strain filed at the Microbial Type Culture Collection and Gene Bank (MTCC) in Chandigarh, India, with filing number 5375 and available for sale, for example supplied by Nutraceutica S.r.l., Bologna, Italy.
- Microbial Type Culture Collection and Gene Bank MTCC
- Curcuma longa is a plant that has been used for thousands of years in the Chinese traditional medicine for treating various types of diseases. It is a perennial plant belonging to the Zingiberaceae family and grown in India and South-eastern Asia.
- Curcuma longa mainly contains 3 secondary metabolites: curcumin (diferuloylmethane), demethoxycurcumin and bisdemethoxycurcumin.
- Curcumin the main secondary metabolite, has numerous pharmacological activities, such as anti inflammatory, antioxidant, immunomodulatory, antitumoral and neuroprotective activities. It is one of the most potent anti-inflammatories of natural origin.
- the main inflammation molecular mechanisms have been extensively studied.
- Various enzymes, cytokines, chemokines and polypeptide hormones have been identified as inflammation mediators. They include COX-2, 5-lipoxygenases, the tumour necrosis factor a, interleukins (IL-1, IL-6, IL-17, IL-21, IL-23) and the MCP-1 protein.
- the tumour necrosis factor a is one of the main inflammation mediators.
- curcumin is a highly pleiotropic molecule, capable of interacting with numerous molecular targets involved in the inflammation. Curcumin has various action mechanisms, but the main one consists in modulating the expression of numerous proteins, including proinflammatory cytokines (TNF-a, IL-8, IL-1 b, IL-6), apoptotic proteins, NF-kB, COX-2, STAT3, MDA, etc... Curcumin modulates the inflammatory response by down-regulating the cyclooxygenase-2, lipoxygenase and inducible nitric oxide synthase (iNOS) activities.
- NF-kB nuclear factor kappa-B
- curcumin can inhibit the activation of NF-kB blocking the phosphorylation of the I KB kinase inhibitory factor.
- Another potential mechanism of the anti-inflammatory action of curcumin consists in regulating the AP-1 transcription factor in macrophages.
- curcumin is metabolised rapidly, conjugated in the liver and excreted with the faeces, hence it is associated with a limited systemic bioavailability.
- Data regarding the pharmacokinetics of curcumin in humans are limited and mainly derive from clinical studies carried out on cancer patients.
- a phase I clinical study carried out on 25 patients with various precancerous lesions, revealed that the doses of 4, 6 and 8 g/day of curcumin for a period of 3 months lead to serum concentrations of 0.51 ⁇ 0.11, 0.63 ⁇ 0.06 and 1.77 ⁇ 1.87 mM respectively, proving the fact that the oral bioavailability of this compound is very limited.
- the systemic clearance is also high and the biological half- life is very low.
- curcumin is also capable of inhibiting formaldehyde induced arthritis in rats at a 40 mg/kg dose, which is also associated to a ulcerogenic index that is lower than that of phenylbutazone at similar doses (0.60 vs 1.70).
- curcumin The anti-inflammatory action of curcumin was evaluated in various clinical studies. In a clinical study, carried out on 45 patients suffering from postoperative oedema. The patients were divided into 3 groups, respectively treated with 400 mg of curcumin, lactose (a placebo) or 100 mg pf phenylbutazone 3 times per day for 3 days. Curcumin proved to be superior than phenylbutazone, thanks to its capacity to reduce all inflammation parameters.
- IL-1 b interleukin-1 b
- IL-6 interleukin-6
- IL-8 tumour necrosis factor-a
- TNF tumour necrosis factor
- iNOS irritable bowel syndrome
- nitric oxide could also be involved in the inflammatory process that characterises the irritable bowel syndrome with potential direct action on the intestinal nerves and intestinal permeability.
- the present invention simultaneously and synergically allows obtaining:
- the present formulation has anti-diarrhoeal, anti-microbial and anti-inflammatory activity.
- the combination of these activities can be particularly useful for treating gastrointestinal disorders, such as diarrhoea or irritable bowel syndrome.
- the anti-diarrhoeal effect may derive from the following activities:
- Berberine has the capacity to reduce intestinal motility, acting both as an agonist of the opioid receptors at intestinal level and acting as a blocker of the calcium channels, which is indispensable for the contraction of the intestinal smooth muscle and the ensuing motility.
- berberine has the capacity of increasing the gene expression of the sodium and aquaporin channels at intestinal level: this allows increasing the intestinal water absorption, with ensuing reduction of the intestinal transit speed.
- Saccharomyces boulardii prevents the release of water and ions into the intestinal lumen which could lead to increasing intestinal motility and acts synergically with berberine to treat diarrhoea and prevent the occurrence thereof.
- the anti-microbial effect may be obtained from the combination of the following activities:
- Saccharomyces boulardii reduces bacterial proliferation.
- berberine may have synergic action with the anti-microbial compounds produced by Saccharomyces boulardii, thus contributing towards the prevention of diarrhoea caused by bacteria and other pathogenic microorganisms.
- formulation's capacity to reduce inflammation may derive from the following actions:
- Curcumin if present, has the capacity to inhibit the NF-kB transcription factor. This allows reducing the gene expression and activating numerous proteins involved in the inflammatory processes, such as the COX-2, the 5-lipoxygenase, the tumour necrosis factor a, the interleukins (IL-1, IL-6, IL-17, IL-21, IL-23) and the MCP-1 protein.
- Berberine is capable of activating the PPAR-a receptors, thus causing heterodimerisation withy the retinoic acid receptors.
- the PPAR-a/RXR complex interacts with the DNA and inhibits the transcription of the genes that encode for pro-inflammatory proteins.
- the synergic action occurs between berberine, Saccharomyces boulardii and, optionally, curcumin.
- the synergy particularly occurs when berberine, preferably extracted from plants belonging to the Beiteris genre, is present at an amount comprised between 10 mg and 5000 mg, Saccharomyces boulardii is present at an amount comprised between 1x10 7 and 1x10 12 CFU and, if present, Curcumin, preferably extracted from plants belonging to the Curcuma genre, is present at an amount comprised between 10 mg and 10000 mg per dosage unit.
- berberine (a) is contained at an amount comprised between 5 and 6000 mg, preferably between 50 mg and 1000 mg and/or yeasts (b) belonging to the Saccharomyces boulardii species are present at an amount comprised between 1 x 10 7 and 1 x 10 12 , preferably between 1 x 10 8 and 1 x 10 10 colony-forming units (CFU) and/or curcumin (c), if present, is present at an amount comprised between 5 mg and 12000 mg, preferably between 100 mg and 2000 mg.
- yeasts (b) belonging to the Saccharomyces boulardii species are present at an amount comprised between 1 x 10 7 and 1 x 10 12 , preferably between 1 x 10 8 and 1 x 10 10 colony-forming units (CFU) and/or curcumin (c), if present, is present at an amount comprised between 5 mg and 12000 mg, preferably between 100 mg and 2000 mg.
- the berberine (a) and yeasts belonging to the Saccharomyces boulaardii species (b) are at a weight ratio between 1:1 and 30:1.
- the berberine (a) the yeasts belonging to the Saccharomyces boulaardii species (b) and, if present, curcumin (c) are at a weight ratio between 1:1:1 and 30: 1 :50.
- composition according to the present invention may comprise at least one inert ingredient, such as at least one excipient from among those used commonly and known to the man skilled in the art.
- inert ingredient is used to indicate any substance, or combination of substances, auxiliary of the production of a pharmaceutical, food or nutraceutical form found in the product and finished other than the active ingredient, even though it can modify the stability, the release or other characteristics.
- Non-limiting examples of such ingredients are diluent excipients, absorbents, adsorbents, lubricants, glidants, colourants, surfactants, antioxidants, sugar substitutes, flavourings, ligands, disintegrators, plasticisers, thickeners, emulsifiers, humectants, wetting agents, preservatives, chelating agents and the like.
- the composition according to the present invention comprises, besides (a), (b) and, optionally, (c), at least one further active ingredient of natural or synthetic origin.
- a non-limiting example of said active ingredients is diosmectite.
- the present invention regards the composition comprising (a), (b) and, optionally, (c), as defined above, for use in preventive or curative treatment - in a subject - of at least one disease and/or disorder of the gastrointestinal tract, wherein said treatment comprises the administration of said composition to the subject.
- composition according to the present invention can be for use in human subjects or for veterinarian use, by way of non-limiting example, in pets such as dogs or cats, or in other mammals.
- the composition according to the present invention is for use in humans.
- the administration of the composition to the subject occurs orally, for example in form of a tablet, pill, even coated, capsule, granulate, solution, suspension, syrup, food product containing (a), (b) and, optionally, (c) or in any other form known to a man skilled in the art.
- the treatment according to the invention comprise the administration (a), (b) and, optionally, (c), said administration according to the invention may occur simultaneously, for example in a single formulation, or in rapid sequence, for example through two or more formulations taken by the subject in any order, in a close sequence over time (e.g. within 1 to 10 minutes) in two distinct compositions.
- the composition is for the treatment - in a subject - of at least one disease and/or disorder that is at least one among acute diarrhoea, chronic diarrhoea, constipation, irritable bowel syndrome (IBS), chronic inflammatory bowel diseases and their symptoms.
- IBS irritable bowel syndrome
- the present invention provides a pharmaceutical composition, a food supplement or a medical device comprising the composition according to at least one of claims 1-5 and at least one excipient acceptable for pharmaceutical and/or food purposes.
- the expression "medical device” in the context of the present invention is used according to the meaning laid down by the Italian Legislative Decree n° 46, dated 24 February 1997, and the 93/42/EEC directive dated 14 June 1993, i.e. it indicates a substance or another product, used alone or in combination, designated by the manufacturer to be used in humans for diagnosis, prevention, control, therapy or disease attenuation purposes, the product not exercising the main action, in or on the human body, for which it is designated, neither with pharmacological or immunology means nor by means of a metabolic process but the function thereof can be assisted by such means.
- the pharmaceutical composition, food supplement or medical device of the present invention can be solid, liquid or semisolid, for example as a suspension or gel, and it can be in any form known to a man skilled in the art of food products, pharmaceutical or nutraceutical formulations, by way of non-limiting example, in form of a capsule, tablet, at least partly oral-soluble or water-soluble powder, granules, pellets, micro particles, optionally contained in a sachet or in a capsule or in a tablet (mini-tablet), liquid or semi-solid preparation, gel, suspension, solution, biphasic liquid system and equivalent forms.
- Example 15 The formulation of Example 15 was prepared by mixing Berberine, Curcumin and Saccharomyces boulardii with the excipients and introducing said mixture into a capsule using a capsule filling machine.
- Example 17 The formulation of Example 17 was prepared by mixing Curcumin, Berberine and Saccharomyces boulardii with the excipients and introducing this mixture into a sachet.
- Example 19 The formulation of Example 19 was prepared by mixing Berberine, Curcumin and Saccharomyces boulardii with the excipients and compressing said mixture using a tablet press, to form a tablet. The tablet was subsequently coated using a hydroxypropyl cellulose film, Titanium Dioxide and Patent Blue V.
- Intestinal motility disorders represent a major social problem; as a matter of fact, it is known that unpleasant symptoms such as constipation, flatulence, diarrhoea, etc. affect very many people up to conditioning their lifestyle at times (Ng et al 2015). Furthermore, there is a high statistical increase of serious colon diseases (diverticulosis, polyps, cancers, etc.), related and depending on the intestinal motility condition. It has been estimated that in developed countries about 20% of the population suffers from constipation at some point of their life and that the constipation increases with age and reduces as the body weight increases (Le Pluart et a/ 2015). On the contrary, in underdeveloped countries, which lack good health conditions, diarrhoea is one of the main causes of death (de Vrese et al 2007). These problems call for studies aimed at identifying new drugs active on the gastrointestinal tract.
- the present project evaluated the effect of two formulations and their single constituents (with the aim of observing a possible synergic effect between the single components) (i) on lactose-induced (or alternatively castor oil-induced) diarrhoea and (ii) on the small intestine motility altered by administration of croton oil.
- mice Male ICR strain mice weighing 20-25 g supplied by Charles River were used. The animals, stabled in thermoregulated rooms (temperature at 23 ⁇ 2 °C, humidity at 50 ⁇ 2%, 12-hour light-dark cycles), have free access to water and food, consisting of a standard diet supplied by Mucedola Mangimi (Settimo Milanese, Italy). All experiments were carried out in compliance with the Italian Decree Law n° 116 dated 27 January 1992 and in compliance with the European Community Council Directive guidelines (86/609/ECC and 2010/63/UE).
- mice were starved for 12 hours, they were isolated in single cages provided at the bottom with a mesh arranged 5 cm above an absorbent paper sheet. This will allow to examine the excreted faeces.
- the animals receive 0.2 ml of castor oil or lactose by means of a feeding tube.
- the diarrhoea was examined 15 minutes after the administration of the cathartic agent and every 15 minutes up to the sixth hour (in case of castor oil) or every hour starting from the 12 hour up to 24 hours (in case of lactose). The results were expressed as the diarrhoea inhibition percentage.
- Intestinal transit in the small intestine is studied during an inflammatory process which induces an alteration of the motility (Izzo et al 2001).
- Chronic intestinal inflammation is induced in mice through two oral administrations of croton oil (20 pL/mouse) for 2 consecutive days.
- the motility was studied for 4 days after (maximum inflammatory response) applying the technique described by Izzo et al (2001).
- the mice - starved for one night - were placed in cages provided with a wide-mesh grid arranged 5 cm above the floor to facilitate the dropping of the faeces and prevent coprophagy.
- mice were divided into groups of 10 animals and treated using the following active ingredients: Berberis aristata extract titrated in Berberina, Saccharomyces boulardii, Curcuma longa extract titrated in Curcumin and the combinations thereof.
- active ingredients Berberis aristata extract titrated in Berberina
- Saccharomyces boulardii Saccharomyces boulardii
- three doses were used with the aim of identifying the submaximal dose (a dose that induces a significant but not maximal effect) which is used subsequently for evaluating the effect of the two formulations on gastric emptying and intestinal transit.
- the treatments were carried out orally 30 minutes before (i) oral administration of castor oil (castor oil- induced diarrhoea) and the marker used for measuring the intestinal transit (activated carbon).
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