CN107050065B - New application of bifidobacterium tetragenous live bacteria composition - Google Patents
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- CN107050065B CN107050065B CN201710205213.1A CN201710205213A CN107050065B CN 107050065 B CN107050065 B CN 107050065B CN 201710205213 A CN201710205213 A CN 201710205213A CN 107050065 B CN107050065 B CN 107050065B
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- bifidobacterium
- bacillus cereus
- lactobacillus acidophilus
- enterococcus faecalis
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- A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a new application of a bifidobacterium tetragenous viable bacteria composition, belonging to the technical field of medicines. The invention discloses an application of a bifidus tetragenous viable bacteria composition in preparing an auxiliary hypoglycemic medicament or health food or food, an application of the bifidus tetragenous viable bacteria composition in preparing an auxiliary glycated albumin-reducing medicament or health food or food, and an application of the bifidus tetragenous viable bacteria composition in preparing an auxiliary hypoglycemic medicament or health food or food suitable for patients with type II diabetes and patients with combined insulin. The invention discovers a new application of the bifidobacterium tetragenous viable bacteria composition, expands the application range of the bifidobacterium tetragenous viable bacteria composition, expands the clinical application range of the bifidobacterium tetragenous viable bacteria composition from a digestive department to a new diabetes endocrine department, belongs to a probiotic micro-ecological preparation, has harmless components and has no side effect on human bodies.
Description
Technical Field
The invention relates to a new application of a bifidobacterium tetragenous viable bacteria composition, belonging to the technical field of medicines.
Background
According to IDF (International diabetes Federation) statistics, the total population number of the diabetics is 9840 million, the neurological diseases become 70%, wherein the incidence rate of the diabetes is 60%, namely the total population number of constipation of the diabetics nationwide is 4100 million, and the total population number of constipation of the diabetics in urban population is 2200 million. Most of the hypoglycemic drugs for clinically treating diabetes mellitus are sulfonylurea insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinedione insulin sensitizers, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogues and the like, and the drugs can generate side effects such as hypoglycemia, digestive tract reactions (abdominal distension and diarrhea), allergy, abnormal liver function, rash and the like.
Diabetes is a series of metabolic syndromes such as sugar, protein, fat, water and electrolytes caused by absolute or relative insufficiency of insulin in a body. Diabetes patients develop constipation along with the imbalance of intestinal flora and inflammatory reaction. The imbalance of intestinal flora causes the increase of G-ratio in a host, the increase of intestinal permeability or the shift of intestinal flora, the organism activates low-degree chronic inflammatory reaction of pancreatic islets by generating and absorbing more toxins, and the inflammation can cause the structural damage and dysfunction of pancreatic beta cells through various ways, promote the apoptosis of the beta cells and cause the insufficient secretion of insulin; inflammation can also cause endothelial cell structural and functional abnormalities, leading to insulin transport disorder in human tissue cells and insulin resistance caused by failure to play normal roles.
At present, the lactobacillus casei has the efficacy of reducing blood sugar in literature report, and the probiotics which is reported in the literature and can achieve the efficacy of reducing blood sugar needs to be taken 10 times8An9Individual live bacteria, even higher.
Chinese patent CN 01108353.0 discloses a "Bifidobacterium quadruple viable bacteria tablet", which is composed of four strains of Bifidobacterium infantis, Lactobacillus acidophilus, enterococcus faecalis and Bacillus cereus.
The content of each bacterial powder in each gram of tablet is respectively as follows: bifidobacterium infantis 5.0 × 106A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
The four kinds of bacteria are preserved in China general biological center of the Committee for culture Collection of microorganisms, and the addresses are as follows: west road No. 1 hospital No. 3, north jing, chaoyang district, preservation date: year 2000, 6, 20 days, deposit number: bifidobacterium infantis 0460.1, lactobacillus acidophilus 0460.2, enterococcus faecalis 0460.3, bacillus cereus 0460.4.
This patent describes: the "Bifidobacterium quadruple viable tablet" can supplement normal physiological bacteria in intestinal tract of human body, and restore microecological balance in vivo. Clinical research shows that the bifidobacterium tetragenous viable bacteria tablet has good curative effect on adult acute diarrhea, chronic diarrhea, adult constipation, infantile acute diarrhea and the like.
However, none of the patents and related documents mentioned above has any mention about the effect of reducing blood sugar level, glycated hemoglobin and glycated albumin in diabetic patients.
Disclosure of Invention
The invention provides a new application of a bifidobacterium tetragenous viable bacteria composition, in particular to an application of the bifidobacterium tetragenous viable bacteria composition in preparing medicines or health-care foods or foods for assisting in reducing blood sugar, reducing blood hemoglobin and reducing albumin.
Application of a live bifidobacterium tetragonococcus composition in preparing an auxiliary hypoglycemic medicament or health food or food, wherein the live bifidobacterium tetragonococcus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
Use of a live bifidotetragenous composition comprising bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus in the manufacture of a medicament or health food or food for the adjuvant treatment of diabetes mellitus type II patients.
Use of a live bifidotetragenous composition comprising bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus in the manufacture of an adjunctive hypoglycemic medicament or health food or food suitable for patients with combined insulin.
Application of a bifidobacterium tetragenous live bacterium composition in preparing a medicament or health-care food or food for assisting in reducing glycated albumin, wherein the bifidobacterium tetragenous live bacterium composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
Application of a living bifidobacterium tetragonococcus composition in preparing a medicament or health-care food or food for assisting in reducing glycated hemoglobin, wherein the living bifidobacterium tetragonococcus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
Preferably, in the above-mentioned use, each gram of the live bifidobacterium tetragonoloba composition comprises bifidobacterium infantis at 1.0 x 1061.0 x 108Lactobacillus acidophilus is 1.0 × 1061.0 x 108Enterococcus faecalis 1.0 × 1061.0 x 108Bacillus cereus 1.0X 1051.0 x 107And (4) respectively.
More preferably, in the above-mentioned use, said live bifidobacterium tetragonolobal composition comprises bifidobacterium infantis 5.0 x 10 per gram6A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
The strain preservation number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
In the application, the formulation of the live bifidobacterium tetranectum composition is any one of tablets, capsules, granules, powder and liquid preparations.
The invention also provides an auxiliary hypoglycemic medicament or health food containing the bifidobacterium tetragenous viable composite, wherein the bifidobacterium tetragenous viable composite comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus; the dosage form of the auxiliary hypoglycemic drug or the health food is any one of tablets, capsules, granules, powder and liquid preparations.
Preferably, in the above application, the composition comprises 1.0 × 10 Bifidobacterium infantis per gram of the live Bifidobacterium tetranectum composition61.0 x 108Lactobacillus acidophilus is 1.0 × 1061.0 x 108Enterococcus faecalis 1.0 × 1061.0 x 108Bacillus cereus 1.0X 1051.0 x 107And (4) respectively.
More preferably, in the above-mentioned use, said live bifidobacterium tetragonolobal composition comprises bifidobacterium infantis 5.0 x 10 per gram6A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
The invention also provides an auxiliary hypoglycemic food containing the bifidobacterium tetragenous viable bacteria composition, wherein the bifidobacterium tetragenous viable bacteria composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
Preferably, said composition of viable bifidobacterium tetragonoides comprises bifidobacterium infantis 1.0 x 10 per gram61.0 x 108Lactobacillus acidophilus is 1.0 × 1061.0 x 108Enterococcus faecalis 1.0 × 1061.0 x 108Bacillus cereus 1.0X 1051.0 x 107And (4) respectively.
More preferably, said live bifidobacteria tetranection composition comprises bifidobacterium infantis 5.0 x 10 per gram6A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
The bifidobacterium tetragenous viable bacteria composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
The content of each bacterial powder in each gram of the composition is respectively as follows: bifidobacterium infantis 5.0 × 106A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
Wherein, four kinds of bacteria are preserved in China general biological center of microorganism preservation management Committee, address: west road No. 1 hospital No. 3, north jing, chaoyang district, preservation date: year 2000, 6, 20 days, deposit number: bifidobacterium infantis 0460.1, lactobacillus acidophilus 0460.2, enterococcus faecalis 0460.3, bacillus cereus 0460.4.
The strain preservation number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the enterococcus faecalis has a strain preservation number of enterococcus faecalis 0460.3; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the strain preservation number of the bacillus cereus is bacillus cereus 0460.4; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days.
The commonly used hypoglycemic drugs at present comprise sulfonylurea insulin secretagogues, non-sulfonylurea insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinedione insulin sensitizers, peptidylpeptidase-4 inhibitors, glucagon-like peptide-1 analogues and the like. When the diabetes mellitus patients take the medicines, adverse reaction symptoms such as hypoglycemia, digestive tract reaction, anaphylactic reaction and the like can occur.
The mechanism for the bifidobacterium tetragenous viable bacteria composition to exert the auxiliary blood sugar reduction is as follows: after the bifidobacterium tetrad composition enters the intestinal tract of a human body, the enterococcus faecalis and the bacillus cereus consume oxygen in the intestinal tract, provide an anaerobic environment for the bifidobacterium infantis and the lactobacillus acidophilus and promote the growth of the bifidobacterium infantis and the lactobacillus acidophilus, so that the bifidobacterium infantis can enable the intestinal tract group to reach a balanced state, the intestinal tract flora balance is quickly restored, the intestinal tract flora balance enables the intestinal tract permeability to be reduced, the organism inflammation is reduced, the abnormal sugar tolerance is relieved, and the functions of reducing the blood sugar level, the glycosylated hemoglobin and the glycosylated albumin level are achieved.
The invention has the beneficial effects that:
the live bifidobacterium tetranectum composition is mainly used in the digestive department in clinical application at present, and the product indications are used for treating diarrhea, constipation and functional dyspepsia related to the imbalance of intestinal flora. The invention finds a new application of the bifidobacterium tetragenous viable bacteria composition, gradually expands the application of the bifidobacterium-containing four-strain composition from a digestive department to an endocrine department, has the effect of assisting in reducing the blood sugar, the glycosylated hemoglobin and the glycosylated albumin of a diabetic patient, and can be used for preparing an assistant blood sugar reducing medicament or health food or food suitable for treating the type II diabetic patient and the patient with combined insulin. The live bifidobacterium tetragenous composition is used for preparing an auxiliary hypoglycemic medicament, has harmless components and has no side effect on human body.
The invention uses four bacterial powders of bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus to prepare a composition, wherein the bifidobacterium infantis is 1.0 multiplied by 1061.0 x 108Lactobacillus acidophilus is 1.0 × 1061.0 x 108Enterococcus faecalis 1.0 × 1061.0 x 108Bacillus cereus 1.0X 1051.0 x 107The invention not only finds that the composition prepared from four bacteria powders of bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus can achieve the effects of reducing blood sugar, glycosylated hemoglobin and glycosylated albumin, but also finds that the composition of the four bacteria with lower orders of magnitude can achieve the effects of reducing blood sugar, glycosylated hemoglobin and glycosylated albumin.
Drawings
FIG. 1 shows the change of glycated albumin before and after two groups of treatments.
Detailed Description
In order to illustrate the effects of the viable bifidobacterium tetragonolobal composition on blood sugar, blood hemoglobin and albumin, the present invention is further illustrated by animal experiments and clinical experiments, but the present invention is not limited by the examples.
The bifidobacterium tetragenous viable bacteria composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus.
Each gram of the bifidobacterium tetradentate live bacteria composition contains bifidobacterium infantis of 5.0 x 106A plurality of; lactobacillus acidophilus is 2.5 × 106A plurality of; enterococcus faecalis 2.5X 106A plurality of; bacillus cereus 2.5X 105And (4) respectively.
Wherein, four kinds of bacteria are preserved in China general biological center of microorganism preservation management Committee, address: west road No. 1 hospital No. 3, north jing, chaoyang district, preservation date: year 2000, 6, 20 days, deposit number: bifidobacterium infantis 0460.1, lactobacillus acidophilus 0460.2, enterococcus faecalis 0460.3, bacillus cereus 0460.4.
The strain preservation number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the enterococcus faecalis has a strain preservation number of enterococcus faecalis 0460.3; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days;
the strain preservation number of the bacillus cereus is bacillus cereus 0460.4; the preservation place is the common microorganism center of the institute of microbiology of China academy of sciences, No. 3 of Xilu No. 1 of Beijing, Chaoyang, and the preservation date is 2000 years, 6 months and 20 days.
The bifidobacterium tetragenous viable bacteria composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and one or more auxiliary materials conforming to the specification of pharmacopoeia can be added into the composition, the active components in the bifidobacterium tetragenous viable bacteria composition are bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, the active ingredients of the four viable bacteria can be prepared into any dosage form such as tablets, granules, capsules, powder and the like, and the specific dosage form of the prepared composition can not influence the auxiliary blood sugar reducing effect, in the animal experiment of the embodiment, in order to facilitate the gavage of a mouse, the mixed bacteria powder of the four bacteria is prepared into a solution to carry out the following animal experiment, and the following clinical experiments by taking the bifidobacterium tetragenous viable bacteria tablet as an example prove that the bifidobacterium tetragenous viable bacteria composition can play a role in assisting in reducing blood sugar.
The preparation method of the bifidobacterium tetragenous viable bacteria composition comprises the following steps:
(1) the preparation method of the powder comprises the following steps: fermenting, culturing and freeze-drying the four strains to prepare bacterial powder, and sieving the four bacterial powders with a 60-mesh sieve; weighing the auxiliary materials according to a certain proportion and then sieving; adding the screened auxiliary materials into a batch mixer for batch mixing, and then adding the mixed bacterial powder. Mixing the four kinds of lyophilized powder and adjuvants in a mixing machine, discharging, and packaging with a packaging machine to obtain the final product.
(2) The preparation method of the granules comprises the following steps: fermenting, culturing and freeze-drying the four strains to prepare bacterial powder, and sieving the four bacterial powders with a 60-mesh sieve; weighing the auxiliary materials according to a certain proportion and then sieving; and adding the sieved auxiliary materials and the bacterial powder into a granulator for granulation. And packaging by using a packaging machine after granulation is finished to obtain a finished product.
(3) The preparation method of the capsule comprises the following steps: fermenting, culturing and freeze-drying the four strains to prepare bacterial powder, and sieving the four bacterial powders with a 60-mesh sieve; weighing the auxiliary materials according to a certain proportion and then sieving; adding the screened auxiliary materials into a batch mixer for batch mixing, and then adding the mixed bacterial powder. Mixing the four lyophilized powders and adjuvants in a mixer, discharging, filling the mixed adjuvants into capsule by a capsule filling machine, and packaging to obtain the final product.
(4) The preparation method of the tablet comprises the following steps: fermenting, culturing and freeze-drying the four strains to prepare bacterial powder, and sieving the four bacterial powders with a 60-mesh sieve; weighing the auxiliary materials according to a certain proportion and then sieving; adding the screened auxiliary materials into a batch mixer for batch mixing, and then adding the mixed bacterial powder. And mixing the four freeze-dried powders and the auxiliary materials in a mixing machine, discharging, and tabletting by using a tabletting machine to obtain a finished product.
1 animal test design and method
TABLE 1 animal test design and methods
2 human body experiment overall design and method
The abbreviations involved in the following examples are explained as follows:
akp (alkali phosphatase) alkaline phosphatase; ALT (alanine aminotransferase) alanine aminotransferase; AST (aspartate aminotransferase) aspartate aminotransferase; cr (Creatinine) creatinine; CRF (case Report form) medical record Report form; fas (full Analysis set) full Analysis dataset; hb (hemoglobin) hemoglobin; plt (platelet) platelets; PPS (Per-Protocol Set) compliant with the recipe dataset; rbc (red Blood cell) red Blood cells; SS (Security set) security dataset; WBC (white Blood cell) leukocytes; tbil (total bilirubin) total bilirubin; GGT (γ -glutamyl transpeptidase) glutamyltranspeptidase; bun (urea nitrogen); BFI (Bowel Function index) bowel Function index; PAC-SYM (patient Association of compliance system) Constipation patient symptom self-rating Scale; CSBMs (complete discrete people Bowell movements) complete Spontaneous defecation; SBMs (spinal feces Bowel movements) spontaneous defecation conditions; PGIC (Patient-reported Global Impression of Change) patients' Global Impression scale for changes.
2.1 design of the experiment
Randomized, double-blind, placebo-controlled, multicenter clinical studies were used.
2.2 case number and grouping
The total number of cases was selected to be 240; 6 centers. The patient is a patient with type II diabetes and has constipation symptoms.
2.3 random methods
A hierarchical block random approach was used.
(1) The block randomization procedure, by means of the SAS9.4 statistical software package PROC PLAN procedure, was used to generate a random schedule, i.e., a random code table, of treatments (test and control) received by each subject for the indication.
(2) Case number assignment: the numbers of the medicines of the testees distributed by the centers are random, the test has 6 centers, each center ranks according to a set rule, namely a group leader unit, each center of the participating units is ranked according to the initial of Chinese pinyin, and an SAS software package is used for generating a central code random number table to obtain the random codes of each center. Each center dispenses the medication in sequence as it is dispensed.
3 case selection criteria
3.1 Inclusion case criteria
None of the following were included in the test:
(1) the medicine accords with the diabetes diagnosis standard, belongs to type 2 diabetes patients, and has the course of disease more than or equal to 1 year;
(2) during screening, the content of the glycosylated hemoglobin (HbA1c) is more than or equal to 7 percent and less than or equal to 12 percent;
(3) the diagnosis standard of chronic constipation is met, and the course of disease is more than or equal to 6 months;
(4) 18-70 years old (including 18 and 70 years old), male and female are unlimited;
(5) voluntarily signs a written informed consent.
3.2 exclusion criteria
Any one of the following was included, and was not included:
(1) type I diabetes, gestational diabetes and other special diabetes patients; or unstable glycemic control in diabetes (fasting plasma glucose >11.1 mmol/L);
(2) patients with diabetic ketoacidosis or hyperosmolar non-ketotic diabetic coma;
(3) organic constipation such as intestinal diseases, endocrine and metabolic diseases (except diabetes); constipation caused by nervous system diseases, muscle diseases, etc.;
(4) drug-induced constipation, such as constipation caused by antidepressants, calcium antagonists, diuretics, sympathomimetics, aluminum or calcium containing antacids, calcium agents, iron agents, antidiarrheal agents, and the like;
(5) gastrointestinal diseases, such as colitis, mesenteric lymphadenitis, with a history of intestinal surgery;
(6) drugs or methods that may affect the assessment of clinical outcome have been used within the last 2 weeks, such as: antibiotics (β -lactams, aminoglycosides, macrolides, etc.); micro-ecological viable bacteria preparation (Bacillus subtilis dual viable bacteria enteric-coated capsule, Bacillus bifidus Lactobacillus dual viable bacteria tablet, Clostridium butyricum enterococcus dual viable bacteria tablet, etc.); osmotic purgative (magnesium sulfate, lactulose, etc.); anthraquinones (rheum officinale, aloe vera, senna leaf, etc.); gastrointestinal motility promoting drugs (metoclopramide, morpholine, cisapride), etc.;
(7) patients with myocardial infarction or stroke in the brain within the past 6 months or with serious cardiovascular diseases and risks, including unstable angina, heart failure or life-threatening arrhythmia, etc.;
(8) patients with abnormal liver and kidney functions (i.e. ALT or AST is 1.5 times higher than the upper limit of normal value; creatinine is higher than the normal value), or patients receiving dialysis treatment;
(9) patients with severe hypertension disease with systolic pressure more than 160mmHg, diastolic pressure more than 90mmHg or hypotension (resting sitting blood pressure) < 90/50mmHg after drug control;
(10) psychotic, alcohol dependence or history of drug abuse;
(11) lactating women, pregnant women, and people ready for birth within 3 months during or after administration is stopped;
(12) allergic constitution or those who have been allergic to various drugs or those who are allergic to the pharmaceutical ingredients used in the test;
(13) other clinical investigators were enrolled 3 months prior to the trial;
(14) the investigator considered inappropriate for other patients participating in the study.
4 study drug and treatment method
4.1 test drugs
(1) Test drugs: bifidobacterium tetragenous viable tablet, national standard for medicine S20060010. The main components are as follows: bifidobacterium infantis, Lactobacillus acidophilus, enterococcus faecalis, Bacillus cereus, specification: 0.5 g/tablet, storage: and (3) keeping away from light and transporting at 2-8 ℃, wherein the effective period is as follows: and (4)18 months.
(2) Control drug: the bifidobacterium tetrad viable bacteria tablet simulator is completely consistent with the bifidobacterium tetrad viable bacteria tablet in appearance, color and the like but does not contain medicinal components. The main components are as follows: pharmaceutical excipients, storage: and (3) keeping away from light and transporting at 2-8 ℃, wherein the effective period is as follows: and (4)18 months.
The bifidobacterium tetragenous viable bacteria tablet medicament is produced by Hangzhou Dada biopharmaceutical limited company.
4.2 dosing regimen
(1) Test group (abbreviated as group a): basic therapy and bifidobacterium tetragenous viable bacteria tablets are orally taken 3 times a day, 3 tablets are taken each time, and are taken after meals by warm boiled water, and the basic therapy and basic therapy medicaments need to be taken separately at intervals of 15 minutes. The administration is continued for 8 weeks.
(2) Control group (abbreviated as group B): the basic therapy plus bifidobacterium tetragenous viable bacteria tablet simulating agent is orally taken 3 times a day, 3 tablets are taken each time, and is taken after meal with warm boiled water, and the basic therapy medicine need to be taken separately at an interval of 15 minutes. The administration is continued for 8 weeks.
4.3 study period
The treatment period was 4 weeks, and the follow-up period was 8 weeks.
4.4 basic treatment
The conventional treatment of diabetes is adopted, the blood sugar is controlled by taking medicines or injecting insulin orally, and an individual treatment scheme can be adopted according to actual conditions, and health education and life style adjustment (including knowledge education, psychological dispersion, diet control, proper amount of exercise and the like of diabetes are performed at the same time. The fasting blood sugar is controlled to be less than or equal to 7mmol/L and the blood sugar is controlled to be less than or equal to 10mmol/L after 2h, and the basic treatment scheme and dosage are not changed in the research.
5 evaluation of therapeutic Effect
5.1 evaluation of therapeutic index
Glycated albumin and glycated hemoglobin
5.2 evaluation of safety
(1) General physical examination items: vital signs (heart rate, respiration, body temperature, blood pressure) and physical examination (including general examination, abdominal examination and anorectal digital examination, and special attention should be paid to the presence or absence of abdominal tenderness, abdominal mass, etc.) during abdominal examination;
(2) laboratory indexes are as follows: blood routine (RBC, HB, WBC, PLT), liver function (ALT, AST, AKP, TBIL, GGT), kidney function (Cr, BUN), urinary routine, glycated albumin, glycated hemoglobin, electrocardiogram;
(3) adverse events: adverse events, severe adverse events and adverse event incidence.
6 criteria for evaluation of therapeutic effects
6.1 Main therapeutic index
Glycated albumin and glycated hemoglobin: the numerical difference between the test group and the control group, within the group and between the groups was compared.
6.2 Secondary efficacy index
Change in glycated albumin; subgroup analysis (taking change value of glycosylated hemoglobin at 12 weeks as curative effect index, adopting a layered analysis method to explore BMI, and performing layered analysis at 25kg/m2, 8 years of diabetic course and 8mmol/L of baseline fasting glucose); stability analysis of the hypoglycemic effect: stability of lowering blood glucose is the standard deviation of blood glucose test values for 2 weeks, 4 weeks, and 8 weeks.
6.3 evaluation criteria for safety
None: safe and has no adverse reaction;
mild: is safe, if adverse reaction exists, the medicine can be continuously taken without any treatment;
medium: has safety problem and moderate adverse reaction, and can continue to administer drug after being treated;
and (3) severe degree: the test was terminated due to severe adverse reactions.
7 results of animal experiments
7.1 fasting blood glucose changes in different groups
TABLE 2 comparison of fasting plasma glucose changes (mean. + -. standard deviation, mmol/L) for different experimental groups
As can be seen from Table 2, when the mice are gazed with the bacterial suspension containing the four bacterial powders, the fasting blood glucose value of the mice in the experimental group is in a descending trend along with the prolongation of the gavage time, and by the fifth week, the fasting blood glucose value of the mice in the normal dose group in the experimental group is reduced from 14.36 +/-0.12 mmmol/L to 6.67 +/-0.09 mmmol/L; the fasting blood glucose value of the mice in the high-dose group in the experimental group is reduced from 14.26 +/-0.05 mmmol/L to 6.73 +/-0.09 mmmol/L; the fasting blood glucose value of the mice in the low-dose group in the experimental group is reduced from 14.30 +/-0.14 mmmol/L to 6.63 +/-0.05 mmmol/L. Therefore, the four bacterium powder compositions of the bifidobacterium infantis, the lactobacillus acidophilus, the enterococcus faecalis and the bacillus cereus have the function of reducing the fasting blood glucose of diabetic mice.
7.2 comparison of glycated hemoglobin changes in different groups
TABLE 3 comparison of the change in glycated hemoglobin for the different experimental groups (mean. + -. standard deviation,%)
As can be seen from Table 3, when the mice are gazed with the bacterial suspension containing the four bacterial powders, the glycosylated hemoglobin value of the mice in the experimental group is in a descending trend along with the prolongation of the gavage time, and the glycosylated hemoglobin value of the mice in the normal dosage group in the experimental group is reduced from 5.33 +/-0.09 to 3.86 +/-0.05 by the fifth week; the value of the glycosylated hemoglobin of the mice in the high-dose group in the experimental group is reduced from 5.26 +/-0.05 to 3.83 +/-0.05; the value of the glycosylated hemoglobin of the low-dose group in the experimental group is reduced from 5.23 +/-0.05 to 4.03 +/-0.05. Therefore, the four bacterium powder compositions of the bifidobacterium infantis, the lactobacillus acidophilus, the enterococcus faecalis and the bacillus cereus have the function of reducing the glycosylated hemoglobin of diabetic mice.
7.3 comparison of glycated Albumin changes in different groups
TABLE 4 comparison of glycated Albumin changes in different groups (mean. + -. standard deviation,%)
As can be seen from Table 4, when the mice are gazed with the bacterial suspension containing the four bacterial powders, the glycated albumin value of the mice in the experimental group is in a descending trend along with the prolongation of the gavage time, and the glycated albumin value of the mice in the normal dose group in the experimental group is reduced from 11.27 +/-0.09 to 9.17 +/-0.05 by the fifth week; the value of the glycated albumin of the mice in the high-dose group in the experimental group is reduced from 11.23 +/-0.05 to 9.20 +/-0.05; the value of the glycated albumin in the low-dose group in the experimental group is reduced from 11.23 +/-0.05 to 9.23 +/-0.05. Therefore, the four bacterium powder compositions of the bifidobacterium infantis, the lactobacillus acidophilus, the enterococcus faecalis and the bacillus cereus have the function of reducing the glycated albumin of the diabetic mice.
7.4 comparison of insulin level changes in different groups
TABLE 5 comparison of insulin changes (mean. + -. standard deviation, mIU/L) for different experimental groups
As can be seen from Table 5, the mice are gavaged with the bacterial suspension containing the four bacterial powders, the insulin level values of the mice in the experimental group are in an ascending trend along with the prolongation of the gavage time, and the insulin level values of the mice in the normal dose group in the experimental group are increased from 1.23 +/-0.05 to 3.37 +/-0.05 by the fifth week; the value of the insulin level of the mice in the high-dose group in the experimental group is increased from 1.23 +/-0.05 to 3.47 +/-0.05; the insulin level value of mice in the low dose group in the experimental group is increased from 1.27 +/-0.05 to 3.27 +/-0.05. Therefore, the four bacterium powder compositions of the bifidobacterium infantis, the lactobacillus acidophilus, the enterococcus faecalis and the bacillus cereus have the function of promoting the insulin secretion of the diabetic mice, thereby achieving the effect of reducing the blood sugar of the diabetic mice.
8 results of clinical trials
8.1 grouping and completion
TABLE 6 two groups of patients baseline data (mean. + -. standard deviation)
TABLE 7 two groups of patients baseline data
8.2 Main therapeutic index-glycated hemoglobin and glycated Albumin index
TABLE 8 glycated Albumin Change before and after treatment (FAS)
From the results in Table 8, it can be seen that the amount of glycated albumin in the patients decreased with time from the baseline level in the experimental group compared to the control group when the viable Bifidobacterium quadruple tablets were administered during the treatment period. The amount of glycated albumin decreased in the experimental group was much greater than that in the control group. Therefore, the bifidus tetrad viable bacteria tablet can be used for the level of glycated albumin of the diabetic patients.
TABLE 9 glycated Albumin Change before and after treatment (PPS)
From the results in Table 9, it can be seen that the amount of glycated albumin in the patients decreased with time from the baseline level in the experimental group compared to the control group when the viable Bifidobacterium quadruple tablets were administered during the treatment period. The amount of glycated albumin decreased in the experimental group was much greater than that in the control group. Therefore, the bifidus tetrad viable bacteria tablet can be used for the level of glycated albumin of the diabetic patients.
The results in tables 8 and 9 show that the statistical results of the FAS set and the PPS set are approximately the same for the change in glycated albumin, and it can be verified that the bifidobacterium quadruple viable cell tablets have a good effect of reducing the level of glycated albumin in diabetic patients.
TABLE 10 Change in glycated hemoglobin before and after treatment (FAS)
From the results in Table 10, it can be seen that the amount of glycated hemoglobin in the patients decreased with time from the baseline level in the experimental group compared to the control group when the viable bifidobacterium tetragonolobum tablets were administered during the treatment period. Therefore, the bifidus tetrad viable bacteria tablet can reduce the level of glycosylated hemoglobin of a diabetic patient.
TABLE 11 Change in glycated hemoglobin before and after treatment (PPS)
From the results in Table 11, it can be seen that the amount of glycated hemoglobin in the patients decreased from the baseline level with time in the experimental group compared to the control group when the viable Bifidobacterium quadruple tablets were administered during the treatment period. Therefore, the bifidus tetrad viable bacteria tablet can reduce the level of glycosylated hemoglobin of a diabetic patient.
The results in tables 10 and 11 were combined to show that the FAS set and the PPS set were approximately the same in terms of the change in glycated hemoglobin, and that the bifidobacterium tetranectum tablets had a good effect of reducing the glycated albumin level in diabetic patients.
8.3 Secondary efficacy index
(1) Change of glycated Albumin: the FAS analysis result shows that the values of the glycated albumin in the baseline period of the test group and the control group are respectively as follows: 21.38 +/-5.74 percent and 21.93 +/-6.51 percent; 4 weeks after treatment, 20.08 +/-6.05% and 20.58 +/-7.30% respectively; the concentration of the drug is respectively 19.07 +/-5.56% and 20.83 +/-8.74% 8 weeks after treatment, and the change trend of the experimental group is most obvious after 8 weeks of drug administration; 12 weeks after treatment, 19.03 + -5.19% and 19.36 + -6.14% for both groups, respectively. Therefore, the bifidobacterium tetragenous viable tablet has a reducing effect on the glycosylated hemoglobin, and has an auxiliary effect on reducing the blood sugar of the diabetic. (see FIG. 1)
(2) Subgroup analysis: as can be seen from Table 12, the BMI was 25kg/m or more during the baseline period2The course of diabetes is shortIn 8 years, in subjects with fasting blood glucose less than 8mmol/L and insulin treatment at baseline, the test group has a more obvious trend of lowering glycosylated hemoglobin from baseline at 12 weeks than the control group, thereby indicating that the bifidobacterium tetragenous viable tablet has the efficacy of assisting in lowering blood glucose.
TABLE 12 subgroup analysis of glycated hemoglobin Change before and after treatment
(3) Stability analysis of the hypoglycemic effect (stability of lowering blood sugar ═ standard deviation of blood sugar test values at 2 weeks, 4 weeks, and 8 weeks): the results show that the glucose reduction stability of the test group (2.02 +/-2.77 mmol/L) is more discrete than that of the control group (2.77 +/-5.51 mmol/L). Therefore, the bifidobacterium tetragenous viable bacteria tablet has the effect of assisting in reducing blood sugar.
8.4 safety index
The vital signs change before and after treatment, including body temperature, heart rate, respiration, systolic pressure, diastolic pressure and laboratory examination indexes, including normal indexes such as red blood cells, white blood cells, red blood cells, platelets, urine white blood cells, urine red blood cells, urine proteins, ALT, AST, ALP, TBiL, GGT, BUN, Cr and the like.
The clinical research shows that the bifidobacterium tetragenous viable tablet can assist in reducing the blood sugar of the diabetic patients, especially the patients with type II diabetes or/and the patients with combined insulin, and the bifidobacterium tetragenous viable tablet can assist in reducing the blood sugar, reducing the blood glucose hemoglobin and reducing the blood glucose albumin.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Use of a live bifidobacterium tetragonoide composition comprising bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, wherein the bifidobacterium infantis has a strain deposit number of bifidobacterium infantis 0460.1, in the manufacture of a medicament for adjunctively lowering blood glucose for use in insulin therapy by injection; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
2. The application of a bifidobacterium tetragonolobus composition in preparing a medicament for assisting in reducing blood sugar of type II diabetes by insulin injection therapy, wherein the bifidobacterium tetragonolobus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
3. The application of a bifidobacterium tetragonolobus composition in preparing a medicament for assisting in reducing glycated albumin in insulin injection therapy, wherein the bifidobacterium tetragonolobus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
4. Use of a live bifidobacterium tetragonolobal composition comprising bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, said bifidobacterium infantis having a strain deposit number of bifidobacterium infantis 0460.1, in the manufacture of a medicament for the adjuvant reduction of glycated hemoglobin in an injectable insulin therapy; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
5. The use according to any one of claims 1 to 4, wherein the viable Bifidobacterium tetranectum composition comprises Bifidobacterium infantis at 1 x 10/g61 x 10 of8Lactobacillus acidophilus is 1 × 1061 x 10 of8Enterococcus faecalis 1 × 1061 x 10 of8Bacillus cereus 1X 1051 x 10 of7And (4) respectively.
6. The use according to any one of claims 1 to 4, wherein the viable bifidobacterium tetragonolobal composition is in the form of any one of tablets, capsules, granules, powder and liquid preparations.
7. The application of the bifidobacterium tetragonolobal live bacterium composition in preparing an auxiliary hypoglycemic health-care product or food combined with an insulin injection therapy, wherein the bifidobacterium tetragonolobal live bacterium composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
8. The application of a bifidobacterium tetragonolobus composition in preparing a health-care product or food for assisting in reducing glycosylated hemoglobin in combination with an insulin injection therapy, wherein the bifidobacterium tetragonolobus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
9. The application of a bifidobacterium tetragonolobus composition in preparing health care products or food for assisting in reducing glycated albumin in combination with insulin injection therapy, wherein the bifidobacterium tetragonolobus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
10. The application of a bifidobacterium tetragonolobus composition in preparing a health-care product or food for assisting in reducing blood sugar in combination with insulin injection therapy for treating type II diabetes mellitus, wherein the bifidobacterium tetragonolobus composition comprises bifidobacterium infantis, lactobacillus acidophilus, enterococcus faecalis and bacillus cereus, and the strain deposit number of the bifidobacterium infantis is bifidobacterium infantis 0460.1; the lactobacillus acidophilus has a strain preservation number of lactobacillus acidophilus 0460.2; the strain preservation number of the enterococcus faecalis is 0460.3; the strain preservation number of the bacillus cereus is bacillus cereus 0460.4.
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