WO2003013558A1 - Treatment of radiation-induced diarrhea with probiotics - Google Patents
Treatment of radiation-induced diarrhea with probiotics Download PDFInfo
- Publication number
- WO2003013558A1 WO2003013558A1 PCT/IT2002/000494 IT0200494W WO03013558A1 WO 2003013558 A1 WO2003013558 A1 WO 2003013558A1 IT 0200494 W IT0200494 W IT 0200494W WO 03013558 A1 WO03013558 A1 WO 03013558A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lactobacillus
- bifidobacterium
- bacteria
- protective
- colitis
- Prior art date
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- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
Definitions
- This invention relates to methods of treating inflammatory bowel diseases (IBD) and related conditions such as by the administration of pharmaceutical or dietary compositions containing significant quantities of probiotic-containing lactic acid bacteria.
- probiotic refers to products that contain live lactic bacteria (i.e., capable of reproducing) that are able to exert a beneficial effect on the host organism by improving the balance of the intestinal flora and to block the growth of any pathogenic microbes.
- IBS irritable bowel syndrome
- the present invention provides prophylaxis and treatment of intestinal l mucosa-related conditions by administration of a probiotic preparation characterized by a high concentration of protective bacteria (i.e. 450 billion per packet), mostly streptococci, lactobacilli and bifidobacteria. Daily administration of the preparation prevents the onset of the inflammatory process, thanks to the high concentrations (billions) of protective bacteria present in the intestinal lumen and in the feces.
- protective bacteria i.e. 450 billion per packet
- An object of the present invention is to treat colitis associated with gastrointestinal disorders, particularly IBD in the acute phase, and to prevent or treat weight loss associated with gastrointestinal disorders, particularly in instances of chronic, long-lasting conditions.
- the procedure of the present invention may be considered for preventing and/or treating conditions susceptible to such treatment including ulcerative colitis, Crohn's disease, pouchitis, allergic colitis, eosinophilic colitis, actinic (radiation) colitis as well as diverticulitis, diverticulosis, hepatic encephalopathy, portal hypertension, bacterial peritonitis, gastrointestinal manifestations of Behcet diseases and of other autoimmune disorders, steatohepatitis and other chronic liver diseases.
- the method of the present invention has provided relief from pain and discomfort to patients suffering from actinic colitis as a result of radiation therapy, a common occurrence for those receiving radiation therapy in the lower half of the torso.
- An additional point is that these patients, having less unwanted effects, can tolerate a higher amount of radiation and or chemotherapy.
- compositions used in the methods of the present invention comprise as essential active ingredients: (a) from 10 to 95% by weight of total composition of lyophilized lactic bacterium Streptococcus thermophilus, and (b) from 90 to 5% by weight of total composition of at least one further lyophilized lactic bacterium selected from the group consisting of Lactobacillus plantarum and Lactobacillus casei, L. Bulgaricus, L. acidophilus and one or more Bifidobacterium, i.e. B. breve, B. infantis, B. longum, B. bifidum..
- An excipient in an amount of from 1 to 10%) by weight of total components can be added.
- the composition can be used in combination with a compatible pharmaceutical in an amount of from 1 to 20% by weight based on the total weight of the composition. It is essential that the viable bacteria concentration be at least lxlO 10 for (a) and lxlO 10 for (b) per gram of the composition. Preferably, the viable bacteria concentration of both (a) and (b) should be used between 1x10 and 1 10 per gram of the composition.
- compositions of the invention can be prepared with methods well- known to those skilled in dairy technology, enabling the presence of viable bacteria at concentrations ranging between lxlO 10 and lxlO 11 bacteria per gram of the composition.
- compositions of the invention can be made in conventional pharmaceutical forms adapted for human or veterinary use, such as for example tablets, coated tablets, capsules, enteric coated tablets or capsules, packets, solutions, sachets, suspensions, emulsions, suppositories, pellets, syrups, vaginal suppositories, and are prepared in the usual manner by mixing active ingredients in the mentioned amounts, eventually adding excipients and/or carriers, adjuvants and/or dispersing agents. Water may be used as the diluent. Organic solvents can be used in the form of adjuvants.
- Adjuvants can be for example, non-toxic organic solvents such as paraffins, vegetable oils (peanut oil or sesame oil) glycerin, glycols (propylene glycol, polyethylene glycol), solid carriers such as for example natural mineral flours (kaolin, talc), synthetic mineral flours (silicates for example L), sugar (cane sugar for example), emulsifiers (alkylsulfonates or arylsulfonates and the like), dispersants (lignin, methylcellulose, starch and polyvinylpyrrolidone, for example) and lubricants (magnesium stearate, talc, stearic acid, sodium laurylsulfonate, for example).
- non-toxic organic solvents such as paraffins, vegetable oils (peanut oil or sesame oil) glycerin, glycols (propylene glycol, polyethylene glycol), solid carriers such as for example natural mineral flours (kaolin, talc), synthetic
- Preferred excipients for the composition of the invention are maltodextrin, microcrystalline cellulose, maize starch, levulose, lactose and dextrose.
- Formulations for rectal administration may take the form of a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
- Orally administrable forms can contain, in addition to usual excipients, additives such as sodium citrate, calcium carbonate, calcium dihydrogen phosphate, together with several additional substances such as starch, gelatin and the like. Rectal administration may also be used. In case of liquid compositions compatible coloring agents or flavoring substances may be added.
- the compositions may contain such compatible pharmaceuticals as anticholinergies, ant stamines, analgesics, adrenergics, anti- inflammatories, antiseptics, hepatoprotective agents or antilipemic drugs, charcoal, vitamins, antioxidants, saturated and/or unsaturated fatty acids, herbal extracts, chitosane and chitosane-like compounds, in amounts of from 1 to 20% by weight, based on the total weight of the composition.
- the individual microorganisms in the dehydrated form are mixed in appropriate proportions and the mixture is then mixed with the excipients or optionally with other pharmaceuticals.
- the protective lactic acid bacteria used in the methods of the present invention may be selected from Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus catenaforme, Lactobacillus cellobiosus, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus gasserii, Lactobacillus jensenii, Lactobacillus leichmanii, Lactobacillus minutus, Lactobacillus plantarum, Lactobacillus rogosae, Lactobacillus salivarius, Bifidobacterium adolescents, Bifidobacterium angulatum, Bifidobacteriumbifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium dentium, Bifid
- compositions used in the methods of the present invention preferably include a combination of various protective lactic acid bacteria, primarily streptococci and lactobacilli and bifidobacteria such as Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum.
- various protective lactic acid bacteria primarily streptococci and lactobacilli and bifidobacteria such as Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum.
- a preferred combination is Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei and Lacobacillus bulgaricus.
- the present invention is characterized by the administration of high doses, in the hundreds of billions, of protective lactic acid bacteria cells, calculated on a daily basis. Administration is typically divided into several doses over the day, usually three times a day, even though one single dose is equally effective and can be given to facilitate the compliance of the patient. As the weight of bacteria grown varies from batch to batch, for accuracy it is convenient to reckon the amounts administered on the basis of the number (actual or estimated) of bacteria cells administered per day.
- Daily doses may range from as low as about 100 x 10 9 cells up to about 3,600 x 10 9 or more, preferably at least 450 x 10 9 cells and desirably witi in a "core" range of from about 900 x 10 9 to about 1,800 x 10 9 bacterial cells per day. These amounts are significantly in excess of similarly measured amounts currently used to restore bacterial imbalance in the gut. The amount administered by the clinician may vary within the above ranges and will be dependent upon the patient's condition and response to therapy.
- the dietary supplements used in the methods of the present invention may include in addition to the probiotic lactic acid bacteria one or more of plant extracts, vitamins, charcoal, minerals as well as flavoring, coloring or stabilizing ingredients.
- the probiotic dietary or pharmaceutical compositions used in the method of the present invention may be administered orally or rectally. Administration may be accompanied with other active ingredients used to treat the particular clinical indication being treated.
- actives include corticosteroids, anti-TNF ⁇ antibodies, cytokines, 5ASA and its derivatives, immunosuppressants such as cyclosporin, and various antibodies and genetically modified bacteria among others as will be apparent to the skilled clinician .
- a preferred formulation designed for oral administration is the probiotic lactic acid bacteria-containing composition in starch-coated pellets or associated in a pharmaceutical presentation with substances such as carbohydrates, sugars, lipids, physiologically acceptable polymers and copolymers and the like. These materials are used to protect the bacteria's viability after ingestion and to facilitate passage of the probiotic lactic acid bacteria composition through the stomach and into the intestine such that the probiotic lactic acid bacteria composition is released or otherwise made available at the appropriate site requiring treatment in the intestinal pathway.
- a specific embodiment of the invention relates to patients who are irradiated in the pelvic area.
- a side-effect is frequently noted, which is diarrhea.
- this condition may in extreme cases mean that the x-ray treatment itself has to be suspended. Therefore, the present invention can be useful to increase the amount of x-rays and/or chemotherapy to the patient.
- diarrhea sets in approximately two weeks after the start of the treatment and is correlated with the magnitude of the dose per fraction and with the volume exposed to radiation.
- the intestinal tract which is most sensitive to x- rays, is composed of the epithelium of the small intestine.
- difficulty in absorbing fats and impermeability are noted.
- the proliferative activity of the crypt ceases (in its middle third), and cellular necroses with pyknosis, karyolysis, karyorrhexis, and an accumulation of debris in the cryptic lumen are observed.
- the initial reaction is of the precocious type and can occur during x-ray therapy. This is represented by an acute enteritic picture, whose severity is related to the portion of the small intestine that is irradiated and the dosages administered.
- the enteritic process can become more complicated, with a severe loss of fluids and electrolytes; the x-ray-induced change in the function of the mucus- lymphoid barrier owing to the interfacial lymphocytolysis which depletes the Peyer's patches and to the exfoliation of the unreplaced enterocytes, may promote the development of fatal septicemic pictures.
- these patients may be successfully treated with a preparation containing a high concentration of lyophilized live bacteria that consist of probiotic microflora arranged in a qualitatively and quantitatively optimum way to ensure a re-balancing action of the intestinal flora in order to reduce the impact of the diarrhea, thereby improving the patient's quality of life and drastically decreasing the risks of the above-mentioned x-ray therapy having to be suspended.
- Probiotic lactobacillus-containing compositions must be able to resist colonization, remove toxic substances, produce nutrients and stimulate the immune system.
- the present invention is characterized by the use of much higher concentrations of lactic bacteria that it contains, in the order of 10 10 to 10 11 bacteria per gram of product, compared to other products.
- the probiotic compositions used contain a large number of species of bacteria, seven, unlike other products.
- Group A 85 patients who underwent x-ray therapy alone;
- Group B 85 patients to whom, combined with x-ray therapy, a packet containing 450 x 10 9 cells of Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki subsp.
- Bulgaricus, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum was administered, at a dose of one packet x 3 times a day on an empty stomach, starting from the first day of x-ray therapy treatment.
- the patients in both groups were prescribed a moderately hypercaloric diet in order to compensate both for the loss of weight secondary to the surgery and the diet conditions of radiation-induced metabolic "stress".
- the diet was also hypolydic in order to reduce the secretion of biliary acids as much as possible.
- All of the patients were irradiated with an X-6 6 MV or 15 MV Linac with the "box" multi-portal technique, with the lower limit of the fields being below the sealing holes, the upper limits being at the L5-S1 passage, and the lateral limit being 1.5 cm outside of the above-mentioned line.
- the total dose administered was between 60 and 70 Gy.
- the dimensions of the irradiation fields were reduced at a dose of 45 Gy.
- Gastroenteritic toxicity was evaluated based on the WHO scale (Table 1).
- Group B 85 of 85 patients (100%) were evaluated. Toxicity was noted in 26 of 85 patients (30.5%) and was classified as follows: level 3 in 1 patient (3.8%); level 2 in 17 patients (65.3%); level 1 in 8 patients (30.7%). No change in intestinal transit was noted in the other 59 patients (69.4%) (Table 2).
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Abstract
Inflammatory conditions in the intestinal mucosa are prevented or treated with a dietary or pharmaceutical probiotic composition containing protective Streptococci, Lactobacilli and Bifidobacteria in a daily amount of from lOO to 3,600 x 109 bacteria cells.
Description
TREATMENT OF RADIATION-INDUCED DIARRHEA WITH PROBIOTICS
This invention relates to methods of treating inflammatory bowel diseases (IBD) and related conditions such as by the administration of pharmaceutical or dietary compositions containing significant quantities of probiotic-containing lactic acid bacteria. The term "probiotic" refers to products that contain live lactic bacteria (i.e., capable of reproducing) that are able to exert a beneficial effect on the host organism by improving the balance of the intestinal flora and to block the growth of any pathogenic microbes.
Background of the Invention
In the past a wide variety of products intended to correct imbalances and or restore bacteria flora to the gut have been available to treat irritable bowel syndrome (IBS). To date there are no drug or dietary products available for treatment of IBS that are also effective for treating inflammatory bowel diseases (IBD). As a matter of practice and experience, products used to treat IBS are not effective to treat IBD.
The role and composition of the intestinal bacteria flora and its relationship with the mucosa itself has been studied. It has been determined that in the terminal section of the small intestine and of the colon, there exists a large concentration of bacteria which are in close and intimate contact with the covering surface of the intestine. In normal circumstances, there is a balance between the host populations and the various defense structures of the mucosa; these bacteria are indeed useful to eliminate toxic substances, produce substances absolutely necessary to the integrity of the organism as well as increase the defense capacities of the mucosa thanks mostly to the production of immunoglobulins and mucus. This balance is preserved because the "friendly" bacteria with beneficial and protective action, prevail over toxic bacteria. Any condition altering this balance (e.g. an infectious state, abuse of some drugs, most probably an inadequate diet) can boost the growth of aggressive bacteria which damage the defenses of the intestinal mucosa. This may lead to ulcers and lesions of the intestine which are the basis of these intestinal diseases and provoke some well-know symptoms such as diarrhea, blood in the stools, weight loss, etc.
An alteration in the patrimony of the intestinal bacterial flora, and in particular the prevalence of aggressive bacteria, is at the origin of some of these symptoms. The present invention provides prophylaxis and treatment of intestinal l
mucosa-related conditions by administration of a probiotic preparation characterized by a high concentration of protective bacteria (i.e. 450 billion per packet), mostly streptococci, lactobacilli and bifidobacteria. Daily administration of the preparation prevents the onset of the inflammatory process, thanks to the high concentrations (billions) of protective bacteria present in the intestinal lumen and in the feces.
Description of the Invention
An object of the present invention is to treat colitis associated with gastrointestinal disorders, particularly IBD in the acute phase, and to prevent or treat weight loss associated with gastrointestinal disorders, particularly in instances of chronic, long-lasting conditions. The procedure of the present invention may be considered for preventing and/or treating conditions susceptible to such treatment including ulcerative colitis, Crohn's disease, pouchitis, allergic colitis, eosinophilic colitis, actinic (radiation) colitis as well as diverticulitis, diverticulosis, hepatic encephalopathy, portal hypertension, bacterial peritonitis, gastrointestinal manifestations of Behcet diseases and of other autoimmune disorders, steatohepatitis and other chronic liver diseases.
In a particular embodiment, the method of the present invention has provided relief from pain and discomfort to patients suffering from actinic colitis as a result of radiation therapy, a common occurrence for those receiving radiation therapy in the lower half of the torso. An additional point is that these patients, having less unwanted effects, can tolerate a higher amount of radiation and or chemotherapy.
The compositions used in the methods of the present invention comprise as essential active ingredients: (a) from 10 to 95% by weight of total composition of lyophilized lactic bacterium Streptococcus thermophilus, and (b) from 90 to 5% by weight of total composition of at least one further lyophilized lactic bacterium selected from the group consisting of Lactobacillus plantarum and Lactobacillus casei, L. Bulgaricus, L. acidophilus and one or more Bifidobacterium, i.e. B. breve, B. infantis, B. longum, B. bifidum.. An excipient in an amount of from 1 to 10%) by weight of total components can be added. These amounts are all based on the total weight of the composition. The composition can be used in combination with a compatible pharmaceutical in an amount of from 1 to 20% by weight based on the total weight of the composition. It is essential that the viable bacteria concentration be at least lxlO10 for (a) and lxlO10 for (b) per gram of the
composition. Preferably, the viable bacteria concentration of both (a) and (b) should be used between 1x10 and 1 10 per gram of the composition.
The compositions of the invention can be prepared with methods well- known to those skilled in dairy technology, enabling the presence of viable bacteria at concentrations ranging between lxlO10 and lxlO11 bacteria per gram of the composition.
The compositions of the invention can be made in conventional pharmaceutical forms adapted for human or veterinary use, such as for example tablets, coated tablets, capsules, enteric coated tablets or capsules, packets, solutions, sachets, suspensions, emulsions, suppositories, pellets, syrups, vaginal suppositories, and are prepared in the usual manner by mixing active ingredients in the mentioned amounts, eventually adding excipients and/or carriers, adjuvants and/or dispersing agents. Water may be used as the diluent. Organic solvents can be used in the form of adjuvants. Adjuvants can be for example, non-toxic organic solvents such as paraffins, vegetable oils (peanut oil or sesame oil) glycerin, glycols (propylene glycol, polyethylene glycol), solid carriers such as for example natural mineral flours (kaolin, talc), synthetic mineral flours (silicates for example L), sugar (cane sugar for example), emulsifiers (alkylsulfonates or arylsulfonates and the like), dispersants (lignin, methylcellulose, starch and polyvinylpyrrolidone, for example) and lubricants (magnesium stearate, talc, stearic acid, sodium laurylsulfonate, for example). Preferred excipients for the composition of the invention are maltodextrin, microcrystalline cellulose, maize starch, levulose, lactose and dextrose. Formulations for rectal administration may take the form of a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
The administration takes place in the usual manner, preferably by the oral route. Orally administrable forms can contain, in addition to usual excipients, additives such as sodium citrate, calcium carbonate, calcium dihydrogen phosphate, together with several additional substances such as starch, gelatin and the like. Rectal administration may also be used. In case of liquid compositions compatible coloring agents or flavoring substances may be added.
As an optional component, the compositions may contain such compatible pharmaceuticals as anticholinergies, ant stamines, analgesics, adrenergics, anti- inflammatories, antiseptics, hepatoprotective agents or antilipemic drugs, charcoal, vitamins, antioxidants, saturated and/or unsaturated fatty acids, herbal extracts, chitosane and chitosane-like compounds, in amounts of from 1 to 20% by weight,
based on the total weight of the composition. As mentioned above, to prepare the compositions, the individual microorganisms in the dehydrated form are mixed in appropriate proportions and the mixture is then mixed with the excipients or optionally with other pharmaceuticals.
The protective lactic acid bacteria used in the methods of the present invention may be selected from Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus catenaforme, Lactobacillus cellobiosus, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus gasserii, Lactobacillus jensenii, Lactobacillus leichmanii, Lactobacillus minutus, Lactobacillus plantarum, Lactobacillus rogosae, Lactobacillus salivarius, Bifidobacterium adolescents, Bifidobacterium angulatum, Bifidobacteriumbifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium dentium, Bifidobacterium eriksonii, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium plantarum, Bifidobacterium pseudocatenulatum, Bifidobacterium pseudolongum, Streptococcus lactis, Streptococcus rajfinolactis and Streptococcus thermophilus.
Compositions used in the methods of the present invention preferably include a combination of various protective lactic acid bacteria, primarily streptococci and lactobacilli and bifidobacteria such as Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum. A preferred combination is Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei and Lacobacillus bulgaricus.
Illustrative combinations of probiotic bacteria from various sources are:
Streptococcus thermophilus 270xl09 57%
Bifidobacterium breve 45x109 9.3%
Bifidobacterium infantis 45xl09 9.3%
Bifidobacterium longum 45xl09 9.3%
Lactobacillus acidophilus 15xl09 3%
Lactobacillus plantarum 7.5xl09 2%
Lactobacillus casei 37.5xl09 8%
Lacobacillus bulgaricus 7.5xl09 2%
Streptococcus thermophilus 257.1xl09 57.13%
Bifidobacterium breve 42.9xl09 9.53%
Bifidobacterium infantis 42.9xl09 9.53% Bifidobacterium longum 42.9x109 9.53% Lactobacillus acidophilus 14.3xl09 3.18% Lactobacillus plantarum 7.1xl09 1.58% Lactobacillus casei 35.7xl09 7.93% Lacobacillus bulgaricus 7.1xl09 1.58%
The present invention is characterized by the administration of high doses, in the hundreds of billions, of protective lactic acid bacteria cells, calculated on a daily basis. Administration is typically divided into several doses over the day, usually three times a day, even though one single dose is equally effective and can be given to facilitate the compliance of the patient. As the weight of bacteria grown varies from batch to batch, for accuracy it is convenient to reckon the amounts administered on the basis of the number (actual or estimated) of bacteria cells administered per day. Daily doses may range from as low as about 100 x 109 cells up to about 3,600 x 109 or more, preferably at least 450 x 109 cells and desirably witi in a "core" range of from about 900 x 109 to about 1,800 x 109 bacterial cells per day. These amounts are significantly in excess of similarly measured amounts currently used to restore bacterial imbalance in the gut. The amount administered by the clinician may vary within the above ranges and will be dependent upon the patient's condition and response to therapy.
The dietary supplements used in the methods of the present invention may include in addition to the probiotic lactic acid bacteria one or more of plant extracts, vitamins, charcoal, minerals as well as flavoring, coloring or stabilizing ingredients.
Doses in these amounts quickly develop high concentrations of protective bacteria in the intestinal lumen and the feces. The probiotic dietary or pharmaceutical compositions used in the method of the present invention may be administered orally or rectally. Administration may be accompanied with other active ingredients used to treat the particular clinical indication being treated. Illustrative actives include corticosteroids, anti-TNFα antibodies, cytokines, 5ASA and its derivatives, immunosuppressants such as cyclosporin, and various antibodies and genetically modified bacteria among others as will be apparent to the skilled clinician .
A preferred formulation designed for oral administration is the probiotic lactic acid bacteria-containing composition in starch-coated pellets or associated in a pharmaceutical presentation with substances such as carbohydrates, sugars,
lipids, physiologically acceptable polymers and copolymers and the like. These materials are used to protect the bacteria's viability after ingestion and to facilitate passage of the probiotic lactic acid bacteria composition through the stomach and into the intestine such that the probiotic lactic acid bacteria composition is released or otherwise made available at the appropriate site requiring treatment in the intestinal pathway.
A specific embodiment of the invention relates to patients who are irradiated in the pelvic area. In these patients a side-effect is frequently noted, which is diarrhea. In addition to having a negative effect on the quality of life of the patient subjected to x-ray therapy treatment, this condition may in extreme cases mean that the x-ray treatment itself has to be suspended. Therefore, the present invention can be useful to increase the amount of x-rays and/or chemotherapy to the patient.
As a rule, diarrhea sets in approximately two weeks after the start of the treatment and is correlated with the magnitude of the dose per fraction and with the volume exposed to radiation. The intestinal tract, which is most sensitive to x- rays, is composed of the epithelium of the small intestine. As a matter of fact, even at moderate doses of x-ray therapy, difficulty in absorbing fats and impermeability are noted. Within a few hours after the radiation is completed, the proliferative activity of the crypt ceases (in its middle third), and cellular necroses with pyknosis, karyolysis, karyorrhexis, and an accumulation of debris in the cryptic lumen are observed.
The initial reaction is of the precocious type and can occur during x-ray therapy. This is represented by an acute enteritic picture, whose severity is related to the portion of the small intestine that is irradiated and the dosages administered.
The enteritic process can become more complicated, with a severe loss of fluids and electrolytes; the x-ray-induced change in the function of the mucus- lymphoid barrier owing to the interfacial lymphocytolysis which depletes the Peyer's patches and to the exfoliation of the unreplaced enterocytes, may promote the development of fatal septicemic pictures.
The literature reports various dietetic and pharmacological means to be helpful in preventing the diarrheal syndrome that sets in patients exposed to x-ray therapy treatment in the pelvic region. Previously used medical treatments are based on the use of sucralfate, smectite, milk enzymes, and acetylsalicylic acid.
In addition to an appropriate dietetic regime, it has been found these patients may be successfully treated with a preparation containing a high
concentration of lyophilized live bacteria that consist of probiotic microflora arranged in a qualitatively and quantitatively optimum way to ensure a re-balancing action of the intestinal flora in order to reduce the impact of the diarrhea, thereby improving the patient's quality of life and drastically decreasing the risks of the above-mentioned x-ray therapy having to be suspended.
Probiotic lactobacillus-containing compositions must be able to resist colonization, remove toxic substances, produce nutrients and stimulate the immune system.
The present invention is characterized by the use of much higher concentrations of lactic bacteria that it contains, in the order of 1010 to 1011 bacteria per gram of product, compared to other products. In addition the probiotic compositions used contain a large number of species of bacteria, seven, unlike other products.
These bacteria are able to attach and survive stably in the intestine and able to compete effectively, when necessary, with the bacterial population of the intestine under various pathologic conditions in order to bring the intestinal micro-environment back into balance.
Example
170 patients, 88 of them male and 82 female, ranging in age between 45 and 65, Performance Status superior to 70; all previously having received irradiation in the pelvic area were recorded. The following pathologies were noted: 90 had colorectal cancer and had already undergone anterior resection surgery, and 80 had cervical-uterine cancer and had already undergone hysteroadenectomy.
The patients were divided into two groups: Group A = 85 patients who underwent x-ray therapy alone; Group B = 85 patients to whom, combined with x-ray therapy, a packet containing 450 x 109 cells of Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki subsp. Bulgaricus, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum was administered, at a dose of one packet x 3 times a day on an empty stomach, starting from the first day of x-ray therapy treatment.
From the start of the x-ray therapy treatment, the patients in both groups were prescribed a moderately hypercaloric diet in order to compensate both for the loss of weight secondary to the surgery and the diet conditions of radiation-induced metabolic "stress". The diet was also hypolydic in order to reduce the secretion of biliary acids as much as possible.
All of the patients were irradiated with an X-6 6 MV or 15 MV Linac with the "box" multi-portal technique, with the lower limit of the fields being below the sealing holes, the upper limits being at the L5-S1 passage, and the lateral limit being 1.5 cm outside of the above-mentioned line. The patients suffering from colorectal cancer were irradiated in the prone position, while those with uterine cancer were treated in the supine position; both treatments were carried out on patients with full bladders in order to displace the intestinal loops upward and forward; finally, for all of the patients personalized protection was used which, considering only the target volume, tended to protect as much of the intestinal loops as possible
The total dose administered was between 60 and 70 Gy. The dimensions of the irradiation fields were reduced at a dose of 45 Gy.
Gastroenteritic toxicity was evaluated based on the WHO scale (Table 1).
Table 1 Evaluation of Toxicity
In the patients of Group A, 83 of 85 (97.6%) of the patients were evaluated treatment had to be suspended because they developed acute enteritis that was resistant to the usual pharmacological treatments. Toxicity was noted in 42 (50.6%) patients, broken down as follows: level 4 diarrhea in 9 patients (21.4%); level 3 diarrhea in 14 patients (33.3%); level 2 diarrhea in 10 patients (23.8%); level 1 diarrhea in 6 patients (14.2%); level 0 diarrhea in 3 (7.1%).
In Group B 85 of 85 patients (100%) were evaluated. Toxicity was noted in 26 of 85 patients (30.5%) and was classified as follows: level 3 in 1 patient (3.8%); level 2 in 17 patients (65.3%); level 1 in 8 patients (30.7%). No change in intestinal transit was noted in the other 59 patients (69.4%) (Table 2).
In all of the patients in Group A the appearance of side-effects was noted such as: asthenia, tenesmus, and episodes of colitis, but especially weight loss, all attributable to the x-ray therapy treatment. In the patients of Group B, however, only asthenia was noted, while colitis and weight loss did not occur in any of the patients in the group.
The data demonstrate that 1) prophylactic treatment with lactic acid bacteria proved to be effective in preventing the development of diarrhea in patients who had undergone x-ray-therapy treatment, allowing them to complete the radiation treatment with both direct and indirect beneficial effects on their quality of life and with good tolerability for the patients. In addition, the use of the high doses of lactobacilli, in these case histories, brought about a reduction in the incidence of other side-effects such as, for example, colitis compared to the patients in the group treated only with x-ray therapy.
Claims
1. A method of preventing or treating an inflammatory condition in the intestinal mucosa comprising administering to a person in need of same an effective amount of a dietary or phaπnaceutical probiotic composition comprising protective Streptococci, Lactobacilli and bifidobacteria in a daily amount of from
100 to 3,600 x 109 bacteria cells.
2. The method of claim 1 wherein the protective bacteria are selected from the group consisting of Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus catenaforme, Lactobacillus cellobiosus, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus gasserii, Lactobacillus jensenii, Lactobacillus leichmanii, Lactobacillus minutus, Lactobacillus plantarum, Lactobacillus rogosae, Lactobacillus salivarius, Bifidobacterium adolescents, Bifidobacterium angulatum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium dentium, Bifidobacterium eriksonii, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium plantarum, Bifidobacterium pseudocatenulatum, Bifidobacterium pseudolongum, Streptococcus lactis, Streptococcus rqffinolactis and Streptococcus thermophilus.
3. The method of claim 1 wherein the protective bacteria are selected from the group consisting of Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium bifidum and Bifidobacterium breve.
4. The method of claim 3 wherein the protective bacteria are selected from Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei and Lacobacillus bulgaricus.
5. The method of claim 1 wherein the composition is aαtoinistered orally.
6. The method of claim 1 wherein the composition is administered rectally.
7. The method of claim 1 wherein the daily amount administered is at least 100 x 109 bacteria cells per day.
8. The method of claim 1 wherein the daily amount administered is from about 450 to about 1,800 x 109 bacteria cells.
9. A method of treating inflammatory bowel diseases as manifested by a condition selected from the group consisting of weight loss associated with gastrointestinal disorders, ulcerative colitis, Crohn's disease, pouchitis, allergic colitis, eosinophilic colitis, actinic (radiation) colitis as well as diverticulitis, diverticulosis, hepatic encephalopathy, portal hypertension, bacterial peritonitis, gastrointestinal manifestations of Behcet diseases and of other autoimmune disorders, steatohepatitis and other chronic liver diseases said method comprising administering to a person in need of same an effective amount of a probiotic dietary or pharmaceutical composition comprising protective streptococci, lactobacilli and bifidobacteria selected from the group consisting of Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum. in a daily amount of from at least lOOxlO9 to 3,600xl09 bacteria cells.
10. A method of treating pain and discomfort of actinic colitis resulting from radiation therapy, said method comprising administering to a person in need of same said method comprising administering to a person in need of same an effective amount of a probiotic dietary or pharmaceutical composition comprising protective streptococci, lactobacilli and bifidobacteria selected from the group consisting of Streptococcus thermophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbruecki, Bifidobacterium longum, Bifidobacterium infantis and Bifidobacterium bifidum. in a daily amount of from at least lOOxlO9 to 3,600xl09 bacteria cells.
11. A method of increasing the tolerance of a patient to increased amounts of irradiation and/or chemotherapy and/or immunomodulating agents that can be given to a patient, said method comprising administering to the patient an effective amount of protective Streptococci, Lactobacilli and ifidobacteria in a daily amount of from 100 to 3,600 x 109 bacteria cells, at a concentration of lOOxlO9 to 3,600xl09 bacterial cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002329043A AU2002329043A1 (en) | 2001-07-30 | 2002-07-26 | Treatment of radiation-induced diarrhea with probiotics |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30811701P | 2001-07-30 | 2001-07-30 | |
| US60/308,117 | 2001-07-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2003013558A1 true WO2003013558A1 (en) | 2003-02-20 |
| WO2003013558A8 WO2003013558A8 (en) | 2003-08-14 |
Family
ID=23192625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IT2002/000494 WO2003013558A1 (en) | 2001-07-30 | 2002-07-26 | Treatment of radiation-induced diarrhea with probiotics |
Country Status (3)
| Country | Link |
|---|---|
| AR (1) | AR034920A1 (en) |
| AU (1) | AU2002329043A1 (en) |
| WO (1) | WO2003013558A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1481681A1 (en) * | 2003-05-30 | 2004-12-01 | Claudio De Simone | Lactic acid bacteria combination and compositions thereof |
| FR2875406A1 (en) * | 2004-09-21 | 2006-03-24 | Danisco | STRAIN OF LACTOBACILLUS ACIDOPHILUS HAVING ANALGESIC PROPERTIES AT THE GASTROINTESTINAL SYSTEM LEVEL |
| WO2008064521A1 (en) * | 2006-11-30 | 2008-06-05 | Pharmapep Research & Development (Shenzhen) Co., Ltd. | Lactobacillus fermentum cms-h002 and use thereof |
| EP2228067A1 (en) * | 2010-02-22 | 2010-09-15 | LR Health & Beauty Systems GmbH | Probiotic compound and use of same |
| US20100291051A1 (en) * | 2008-01-15 | 2010-11-18 | Sapporo Breweries Limited | Agent for prevention of alcoholic hepatopathy |
| WO2011080395A3 (en) * | 2009-12-28 | 2011-09-15 | Suomen Punainen Risti Veripalvelu | Probiotic bifidobacterial composition in accordance with secretor blood group status |
| CN104398538A (en) * | 2014-10-28 | 2015-03-11 | 大连医科大学 | Composite probiotics preparation for mitigating chemotherapy side effect |
| CN105797145A (en) * | 2010-07-26 | 2016-07-27 | Qu生物制药公司 | Immunogenic anti-inflammatory compositions |
| CN111248443A (en) * | 2020-03-10 | 2020-06-09 | 安徽大学 | A kind of synbiotic composition with improving ulcerative colitis and its preparation and application |
| CN112236154A (en) * | 2018-05-31 | 2021-01-15 | 深圳华大生命科学研究院 | A composition and its application |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018112739A1 (en) * | 2016-12-20 | 2018-06-28 | 深圳华大基因研究院 | Bifidobacterium pseudocatenulatum, culture method therefor and application thereof |
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| US5716615A (en) * | 1992-02-10 | 1998-02-10 | Renata Maria Anna Cavaliere Vesely | Dietary and pharmaceutical compositions containing lyophilized lactic bacteria, their preparation and use |
| WO2000054788A1 (en) * | 1999-03-15 | 2000-09-21 | Italmed S.N.C. Di Galli G. E Pacini G. | Pharmaceutical composition for medical and veterinary use for regenerating intestinal flora in diarrhoea or dyspeptic syndrome |
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- 2002-07-26 AU AU2002329043A patent/AU2002329043A1/en not_active Abandoned
- 2002-07-26 WO PCT/IT2002/000494 patent/WO2003013558A1/en not_active Application Discontinuation
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| US5716615A (en) * | 1992-02-10 | 1998-02-10 | Renata Maria Anna Cavaliere Vesely | Dietary and pharmaceutical compositions containing lyophilized lactic bacteria, their preparation and use |
| WO2000054788A1 (en) * | 1999-03-15 | 2000-09-21 | Italmed S.N.C. Di Galli G. E Pacini G. | Pharmaceutical composition for medical and veterinary use for regenerating intestinal flora in diarrhoea or dyspeptic syndrome |
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Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1481681A1 (en) * | 2003-05-30 | 2004-12-01 | Claudio De Simone | Lactic acid bacteria combination and compositions thereof |
| JP2012246300A (en) * | 2004-09-21 | 2012-12-13 | Dupont Nutrition Biosciences Aps | Strain of lactobacillus acidophilus having analgesic property in gastrointestinal system |
| JP2008513411A (en) * | 2004-09-21 | 2008-05-01 | ダニスコ エー／エス | Lactobacillus acidophilus strain with gastrointestinal analgesic activity |
| WO2006032542A1 (en) * | 2004-09-21 | 2006-03-30 | Danisco A/S | Strain of lactobacillus acidophilus having analgesic properties in the gastrointestinal system |
| AU2005287482B2 (en) * | 2004-09-21 | 2011-08-25 | Dupont Nutrition Biosciences Aps | Strain of Lactobacillus acidophilus having analgesic properties in the gastrointestinal system |
| FR2875406A1 (en) * | 2004-09-21 | 2006-03-24 | Danisco | STRAIN OF LACTOBACILLUS ACIDOPHILUS HAVING ANALGESIC PROPERTIES AT THE GASTROINTESTINAL SYSTEM LEVEL |
| WO2008064521A1 (en) * | 2006-11-30 | 2008-06-05 | Pharmapep Research & Development (Shenzhen) Co., Ltd. | Lactobacillus fermentum cms-h002 and use thereof |
| US8747836B2 (en) * | 2008-01-15 | 2014-06-10 | Sapporo Breweries Limited | Agent for prevention of alcoholic hepatopathy |
| US20100291051A1 (en) * | 2008-01-15 | 2010-11-18 | Sapporo Breweries Limited | Agent for prevention of alcoholic hepatopathy |
| WO2011080395A3 (en) * | 2009-12-28 | 2011-09-15 | Suomen Punainen Risti Veripalvelu | Probiotic bifidobacterial composition in accordance with secretor blood group status |
| EP2228067A1 (en) * | 2010-02-22 | 2010-09-15 | LR Health & Beauty Systems GmbH | Probiotic compound and use of same |
| CN105797145A (en) * | 2010-07-26 | 2016-07-27 | Qu生物制药公司 | Immunogenic anti-inflammatory compositions |
| CN104398538A (en) * | 2014-10-28 | 2015-03-11 | 大连医科大学 | Composite probiotics preparation for mitigating chemotherapy side effect |
| CN112236154A (en) * | 2018-05-31 | 2021-01-15 | 深圳华大生命科学研究院 | A composition and its application |
| CN111248443A (en) * | 2020-03-10 | 2020-06-09 | 安徽大学 | A kind of synbiotic composition with improving ulcerative colitis and its preparation and application |
Also Published As
| Publication number | Publication date |
|---|---|
| AR034920A1 (en) | 2004-03-24 |
| WO2003013558A8 (en) | 2003-08-14 |
| AU2002329043A1 (en) | 2003-02-24 |
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