CN110859307A - Composition containing sodium pyruvate and use thereof - Google Patents
Composition containing sodium pyruvate and use thereof Download PDFInfo
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- CN110859307A CN110859307A CN201911261211.XA CN201911261211A CN110859307A CN 110859307 A CN110859307 A CN 110859307A CN 201911261211 A CN201911261211 A CN 201911261211A CN 110859307 A CN110859307 A CN 110859307A
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Abstract
The invention discloses a composition containing sodium pyruvate for oral administration and application thereof, wherein the composition comprises the following necessary components: (a)2.0-25.0 parts by weight of sodium pyruvate; and (b)5.0 to 100.0 parts by weight of anhydrous glucose or other carbohydrates. The composition can be used for treating diabetes and its organ complications, or for improving Pyruvate Dehydrogenase (PDH) activity.
Description
Technical Field
The invention relates to the field of drug therapy, in particular to an effect of orally taking a composition containing sodium pyruvate on treating diabetes and organ complications thereof and related diseases of reduced Pyruvate Dehydrogenase (PDH) activity caused by non-diabetes.
Background
Diabetes is a common disease at home and abroad. According to the statistics of the international diabetes union, about 4.15 hundred million patients are treated in 2015 worldwide; the incidence in adults in China has been about 10.9% [1,2] in 2013; at present, more than 1.14 hundred million people have diabetes mellitus in adults in China, and the incidence rate of the diabetes mellitus is on an increasing trend. Although there are a number of specific therapeutic agents, there is a lack of ideal agents that act on multiple links in pathogenesis; effective prevention measures are lacking in large-area populations. Diabetes is a disorder of systemic sugar oxidation metabolism, which causes hyperglycemia and long-term stimulation of hyperglycemia in tissue cells, and causes microvascular lesions of the whole body, and although the lesions of each organ have different characteristics, the basic pathophysiological changes are similar: the traditional Chinese medicine composition is accompanied by hypoxia, acidosis, oxidative stress and inflammatory reaction, mitochondrial damage and apoptosis, has characteristic generation and tissue deposition of glycosylation end products (AGEs), and further promotes inflammatory reaction, so that malignant circulation is caused, lesions develop irreversibly, and organ insufficiency or failure is caused; wherein, diabetic kidney disease accounts for about 30-40% [3 ].
Pyruvate/propionate is traditionally not a stimulator of insulin secretion, but rather its derivative Methyl Pyruvate. At the beginning of the last century, reports about the effects of relieving the generation of eye lens glycosylation end products caused by high sugar in vivo, relieving cataract caused by diabetes, relieving and protecting diabetic retinopathy and the like of rodents in drinking water are available; in vitro experiments also show that pyruvate has the function of protecting transplanted pancreatic tissues [4,5], but until 2007, europe reports for the first time that human oral administration of large doses of sodium pyruvate (about 1.0g/kg, divided by meal) is effective in alleviating the conditions of 6 patients with type I (insulin-dependent) diabetes: even hypoglycemia occurs requiring a reduction in insulin dosage [6 ]; since then, it was reported that oral pyruvate (0.5g/kg x three times a day) had the effect of directly stimulating insulin secretion from islet cells for half a year, and the amount of insulin used was reduced by about 1/3.
However, human bodies take large doses of pyruvate (>10-15g) orally at one time with obvious symptoms of gastrointestinal irritation: abdominal pain, diarrhea, etc., which cannot be tolerated for a long time, and thus cannot be used clinically. At the same time, the literature has demonstrated that human oral administration of pyruvate at relatively low doses, e.g. 7g/d x for one week, does not have any significant physiological effects [7 ]; even larger doses, such as 25g of pyruvate taken orally in a single dose, also only temporarily alleviate the acidosis phenomenon during exercise and do not have the effect of improving exercise tolerance [8 ].
Therefore, the technical scheme that the oral administration (gastrointestinal tract) of the pyruvate can play a role in relieving diabetes and similar abnormal glucose metabolism (the common point of the two is that the PDH activity is reduced), can also make the gastrointestinal tract of a human body tolerant, and is suitable for clinical popularization to play the pyruvate function is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a composition containing sodium pyruvate, which can be orally taken for preventing and treating diabetes or organ complications thereof and related diseases caused by the reduction of PDH activity.
In a first aspect of the present invention, there is provided a composition comprising the following essential components:
(a)2.0-25.0 parts by weight of sodium pyruvate; and
(b)5.0-100.0 parts by weight of anhydrous glucose or other carbohydrates;
and the weight of the essential components accounts for 30-100% of the weight of the composition.
In another preferred embodiment, the composition further has additional components, the additional components comprising: sodium chloride, potassium chloride or potassium citrate, vitamin B, and vitamin C.
In another preferred embodiment, the composition contains the following components:
(i)2.0-25.0 parts by weight of sodium pyruvate;
(ii)0-10.0 parts by weight of sodium chloride;
(iii)0-2.0 parts by weight of potassium chloride or potassium citrate of corresponding equivalent; and
(iv)5.0-100.0 parts by weight of anhydrous glucose or other carbohydrates;
and the weight of the components (i) + (ii) + (iii) + (iv) is 80-100% of the total weight of the composition.
In another preferred embodiment, the molar ratio of sodium ions to glucose in the composition is 0.5-1: 1; more preferably close to 1: 1.
in a second aspect of the invention, there is provided a use of a composition provided by the invention as described above in the manufacture of a medicament, food or health product for the treatment or prevention of a disease or condition associated with inhibition of pyruvate dehydrogenase activity.
In another preferred embodiment, the disease is diabetes and its organ complications.
In another preferred embodiment, the diabetes is type II diabetes, and/or type I diabetes.
In another preferred embodiment, the pharmaceutical, food or health product is in the form of a solution; preferably, the solution has an osmotic pressure of 200-1200mOsm/L, and more preferably, the solution has an osmotic pressure of 220-280mOsm/L or 600-1000 mOsm/L.
In another preferred embodiment, the disease or condition further comprises sugar metabolism disorder manifestations caused by decreased pyruvate dehydrogenase activity in vivo, such as partial critical illness, tumor and senile disease; such as but not limited to shock of various etiologies, burns or colon and pancreatic tumors, and senile dementia.
Therefore, the invention provides a technical scheme which can play a role of relieving diabetes and similar abnormal glucose metabolism diseases (the common point of the functions is PDH activity reduction) by oral administration (gastrointestinal tract), can also enable the gastrointestinal tract of a human body to tolerate, and is suitable for clinical popularization to play a role of pyruvate.
Drawings
FIG. 1 shows the respective effects of oral administration of two aqueous sodium pyruvate solutions on the activity of each enzyme in renal tissue of diabetic mice; wherein,
a represents the effect on AR, aldose reductase;
b represents the effect on PDH, i.e.pyruvate dehydrogenase;
c represents the effect on PDHA1, the non-phosphorylated active moiety of pyruvate dehydrogenase;
d represents the effect on PDK, i.e., pyruvate dehydrogenase kinase;
nor means normal mouse control group;
con means no treatment control group of diabetic mice;
pyr represents the treatment group of mice with diabetes by oral administration of an aqueous solution containing only 1 w/v% of sodium pyruvate;
Pyr-ORS denotes an oral sodium pyruvate composition (0.35 w/v% NaPyr,0.2 w/v% NaCl,0.15 w/v% KCl,1.35 w/v% Glucose diabetic mouse treatment group;
indicates that there was a significant statistical difference between the two treated groups and the control group of untreated mice.
The figure shows that: oral administration of two sodium pyruvate solutions to diabetic mice also effectively inhibited the increased AR and PDK activities in vivo (kidney tissue) stimulated by high sugar, and promoted complete recovery of PDH activity inhibited by PDK.
Detailed Description
The inventor's research shows that the oral administration of the composition containing sodium pyruvate and glucose can treat diabetes and its organ complications in human diabetes (type II) animal models (db/db mice), and the therapeutically effective amount of sodium pyruvate is a sufficient tolerable amount for human use, thereby being capable of being popularized in clinic and/or human populations. Further, the inventors have also demonstrated for the first time that such a composition, orally administered, can significantly increase the PDH activity of one of the key enzymes of inhibited carbohydrate oxidation metabolism in diabetic animals (this is first demonstrated in this experiment globally), while in animals it is first demonstrated: oral sodium pyruvate compositions also simultaneously restore Pyruvate Kinase (PK) activity, one of the key glycolytic enzymes inhibited by hyperglycemia, and improve oxidation/reduction potential in organ tissues and significantly increase insulin levels in animal plasma; in vitro and in vivo experiments show that pyruvate can inhibit Aldose Reductase (AR) activity abnormally enhanced by high sugar stimulation, thereby possibly reversing sorbitol branch of glycolysis abnormally enhanced under hyperglycemia [9], effectively recovering the approximately normal glycolysis process and sugar oxidative metabolism of diabetic animals (namely reversing Warburg phenomenon of abnormal sugar metabolism of diabetes [10]), reducing fasting hyperglycemia level, reducing weight and improving the diabetic state of the animals; inhibit/reduce oxidative stress and the production of glycosylation end products (AGEs) in renal tissue. Oxidative stress/inflammatory reaction and glycosylation end product generation/accumulation in organs and tissues around the body of diabetes are two key factors except hyperglycemia in the occurrence and development of diabetes/organ complications, leading to the vicious circle of disease [3 ]. Thus, oral administration of the compositions provided by the present invention improves the function and pathological changes of organ complications (kidneys). The experiment proves that the composition containing small-dose sodium pyruvate can effectively reverse the reduced PDH activity and Warburg phenomenon, and the experimental result is consistent with the clinical curative effect, thereby completing the invention. The invention solves the problems that the large dose of sodium pyruvate which is clinically unacceptable can be used for preventing and treating diabetes and organ complications by applying the small dose of tolerable sodium pyruvate composition, and the invention is popularized in large-scale crowds to achieve the purposes of preventing and treating diabetes and other related diseases accompanied with PDH inhibition.
Composition comprising a metal oxide and a metal oxide
The invention provides a composition, wherein sodium pyruvate and anhydrous glucose or other carbohydrates are necessary components, and the composition can also contain sodium chloride, potassium chloride or potassium citrate, vitamin B, vitamin C and other additional components.
The essential components of the composition provided by the invention can be (a)2.0-25.0 parts by weight of sodium pyruvate; and (b)5.0 to 100.0 parts by weight of anhydrous glucose or other carbohydrates;
wherein the amount of sodium pyruvate is 2.0-6.0 weight parts, 2.0-10.0 weight parts, 3.5-15.0 weight parts, 5.0-20.0 weight parts, etc.;
the amount of the anhydrous glucose or other carbohydrates may be 7.0-50.0 parts by weight, 20.0-90.0 parts by weight, 40.0-75.0 parts by weight, 12.0-20.0 parts by weight, 30.0-80.0 parts by weight, etc.
In certain embodiments, the present invention provides compositions comprising: (i)2.0-25.0 parts by weight of sodium pyruvate; (ii)0-10.0 parts by weight of sodium chloride; (iii)0-2.0 parts by weight of potassium chloride or potassium citrate of corresponding equivalent; and (iv)5.0 to 100.0 parts by weight of anhydrous glucose or other carbohydrates; sodium citrate may also be present in the composition, but the composition in principle does not contain sodium bicarbonate.
Wherein the amount of sodium pyruvate is 2.0-6.0 weight parts, 3.0-4.0 weight parts, 2.0-10.0 weight parts, 3.5-15.0 weight parts, 5.0-20.0 weight parts, etc.;
the amount of sodium chloride may be 0-5.0 parts by weight, 2.0-3.5 parts by weight, 4.0-8.0 parts by weight, etc.;
the dosage of potassium chloride or potassium citrate can be 0-1.8 weight parts, 1.5-2.0 weight parts, etc.;
the amount of the anhydrous glucose or other carbohydrates may be 7.0-50.0 parts by weight, 20.0-90.0 parts by weight, 13.5-50.0 parts by weight, 40.0-75.0 parts by weight, 12.0-20.0 parts by weight, 30.0-80.0 parts by weight, etc.
In certain embodiments, the present invention provides compositions wherein the molar ratio of sodium ions to glucose is 0.5-1: 1, such as 0.6-0.8: 1 and 0.7-0.9: 1, and the like. In a preferred embodiment, the present invention provides compositions in which the molar ratio of sodium ions to glucose is close to (about) 1: 1, e.g., 0.6-0.99: 1; usually not more than 1: 1.
the compositions provided herein may be in solid form, such as, but not limited to, a powder; it may also be in liquid form, such as, but not limited to, a potable aqueous solution.
If the composition provided by the invention is to be stored in a liquid form at normal temperature, the problem of the stability of the aqueous solution of sodium pyruvate needs to be considered, and the pH of the solution is 3.5-4.9.
As used herein, "other carbohydrates" include aqueous glucose, fructose, sucrose, starch, and cereals. The cereals include rice, millet, corn, sorghum, wheat, etc. The cereal used in the present invention may be a powdered food product such as, but not limited to, rice flour, corn flour, sorghum flour, and the like. The amount of rice flour or the like to replace or partially replace 20 g of anhydrous glucose in practical use is usually 50 to 80 g.
Use of
The composition provided by the invention can be used for treating or preventing diabetes and organ complications thereof, and generally the provided composition is prepared into a medicament, food or health-care product, and then an effective amount of the composition provided by the invention is administered to an individual when needed.
The compositions provided herein can also be used to increase PDH activity orally (including by gastrointestinal administration) for conditions related to diabetes. Similarly, the provided compositions are generally prepared as a pharmaceutical, food or nutraceutical, and an effective amount of the provided compositions is administered to an individual as needed.
The composition provided by the invention has the optimum effective dose of 5-10 (no more than 15) g/day (calculated by sodium pyruvate contained in the composition) for adults when treating or preventing diabetes and organ complications thereof or increasing PDH activity.
In certain embodiments, the diabetes is type II diabetes, and/or type I diabetes; the diabetic organ complications include, but are not limited to, diabetic nephropathy, diabetic eye complications, diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, and the like.
Inhibition of PDH activity in tissue cells is an acute and chronic organ injury caused by a number of causative factors, including diabetes and diabetic ketoacidosis, and organ injury thereof [11,12 ]; sugar metabolism abnormality caused by low PDH activity exists in various critical diseases caused by non-diabetes, such as heavy bleeding, trauma or infection and shock caused by the heavy bleeding, the trauma or the infection, even tumors, brain congenital hypoplasia, senile degeneration and the like: i.e., metabolic changes characterized by the Warburg phenomenon, which is one of their common features and important factors in the molecular mechanisms of cellular metabolism [10,13,14 ]. The formation and accumulation of AGEs are not only an organ complication of diabetes, but also an important causative factor of senile neurodegeneration such as Alzheimer's Dis. The compositions provided herein ameliorate the progression of various diseases by increasing PDH activity, e.g., diabetic ketoacidosis is a critical condition with less PDH activity in vivo than in diabetic patients with non-ketoacidosis [12 ]; also, since pyruvate itself is a potent antacid preparation that effectively corrects lethal hypoxic lactic acidosis [15] whether administered intravenously or orally, it is also indicated for diabetic ketoacidosis and other conditions related to non-diabetic conditions as described above. Therefore, if intravenous administration conditions are not available, the composition provided by the invention is more suitable for oral administration of the obtained medicine, food or health care product.
The inventor adopts an aqueous solution containing 2.0 to 6.0 g of sodium pyruvate, 1.5 to 2.0 g of sodium chloride, 0 to 1.5 g of potassium chloride or corresponding equivalent of potassium citrate and 5.0 to 50.0 g of anhydrous Glucose or other corresponding amount of carbohydrate in 1000 ml of water, wherein an aqueous solution of 0.35 w/v% of a sodium pyruvate composition (0.35% NaPyr, 0.2% NaCl, 0.15% KCl, 1.35% Glucose, osmotic pressure of about 247mOsm /) is used for feeding a diabetic mouse experimental model, and an aqueous solution containing 1 w/v% of sodium pyruvate alone is used as a positive control and is simultaneously used for the diabetic mouse experimental model, and the result shows that the aqueous solution formed by the composition provided by the invention can effectively pre-treat the development of mouse diabetes and also effectively improve the pyruvate dehydrogenase activity as compared with the positive control (1% sodium pyruvate) aqueous solution, all were statistically significant.
In view of a reasonable daily water intake in humans, in some embodiments, 1000 ml of water containing 20-25 g of sodium pyruvate and 60.0-100.0 g of anhydrous glucose or other corresponding amounts of carbohydrates, which may be free of sodium chloride and potassium chloride, or further containing 0-2.0 g of sodium chloride and 0-2.0 g of potassium chloride or the corresponding equivalent of potassium citrate, is used, and the osmolality is less than 1000 mOsm/L. Can also effectively treat and prevent diabetes and organ complications thereof, can also effectively improve the activity of pyruvate dehydrogenase, and is suitable for human body/gastrointestinal tract tolerance without side effect. When a human body orally takes 250-500ml of the hypertonic formula solution every day, the oral administration is equivalent to the oral administration of 5-10g/d of sodium pyruvate. While the intake of such a volume of solution is only about equivalent to the volume of a one-bottle beverage can, when the composition provided by the present invention is mixed with a dietetically acceptable carrier, the resulting functional beverage can be administered to a population to more broadly and effectively treat and prevent diabetes and related conditions.
In certain embodiments, the compositions provided herein can also be contacted with the PDH that is inhibited by the hyperglycemia or other agent, thereby reversing/restoring the activity of the inhibited PDH. This approach can obviously be carried out in vitro experimental studies for different purposes, which have also been demonstrated in the in vitro cell experiments in the high sugar environment of the present invention.
The composition provided by the invention has another application of being used in-vitro screening experiments for screening and verifying components for treating or preventing diabetes and organ complications thereof; or using amount to screen and verify the components for improving PDH activity.
The compositions provided herein are used in screening assays, and in particular, the compositions provided herein are used in screening assays to identify candidate compounds that are useful for treating or preventing one or more of diabetes and its organ complications. Alternatively, the compositions provided herein can be used to confirm the ability of a candidate compound to increase PDH activity.
The method for preparing the medicine (preparation), the food or the health care product by the composition provided by the invention comprises the following steps: the composition provided by the invention is used as an active ingredient, and is mixed with a pharmaceutically or dietetically acceptable carrier to form a product.
Taking the example of preparing a drug (formulation) from the compositions provided by the present invention, suitable routes of administration of the drug (sterile formulation) include, but are not limited to, oral, gastrointestinal tract via gastric tube or surgery, intravenous injection, rectal and parenteral/i.e. intravaginal administration. For example, but not limited to, oral drugs are formulated by mixing 5-10g of sodium pyruvate with 20-40g of glucose or corresponding starch, and the mixture can be made into oral powders, or other solid preparations such as tablets or capsules suitable for oral administration.
When the pharmaceutical preparation is an aqueous solution, the osmotic pressure of the solution is 200-1200mOsm/L, such as 200-280mOsm/L, 240-800mOsm/L, 400-900mOsm/L or 600-1000 mOsm/L. The aqueous solution is stored at normal temperature in a liquid form, the problem of the stability of the aqueous solution of sodium pyruvate needs to be considered, and the pH of the general solution is 4.0-5.0.
In the treatment or prevention of diabetes or its organ complications or in the elevation of inhibited PDH levels in vivo, the compositions provided herein are administered to a human or mammal at a dosage of typically 5-10 g/day (or 7-9 g/day, 6-8 g/day, etc.) on a sodium pyruvate basis for a period of 1-8 weeks or more. In some embodiments, multiple administrations of an effective amount of a composition provided herein are included. Examples of these include in particular: i) administering a composition provided herein in a single dose; ii) multiple administrations over a time interval of 6-8 hours. In a further or alternative preferred embodiment, the method has a drug holiday, in particular a temporary delay in the administration of the composition provided by the invention or a temporary reduction in the dosage of the composition provided by the invention; at the end of the drug holiday, the dosage of the composition provided by the present invention is restored. The time of drug holidays varies from two days to one year.
Term(s) for
The term "an effective amount" is intended to mean an amount which, after a suitable period of administration, achieves the desired effect of lowering blood glucose and/or reducing the amount of insulin used for the purpose of treating diabetes.
The term "acceptable" means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic or prophylactic target.
As used herein, the term "prevention" refers to the ability to delay, halt, or even partially reverse the progression of a diabetic-prone (pre-stage) or diabetic person and its organ complications and associated conditions with decreased PDH activity.
As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, including various excipients and diluents. The term refers to such pharmaceutical carriers: they are not essential active ingredients per se and are not unduly toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A thorough discussion of pharmaceutically acceptable excipients can be found in Remington's pharmaceutical Sciences (Mack pub. co., n.j.1991). Pharmaceutically acceptable carriers in the composition may include liquids such as water and saline. In addition, auxiliary substances such as disintegrants, emulsifiers, pH buffering substances and the like may also be present in these carriers. Other additional components are also included in the definition of pharmaceutically acceptable carrier, for example, the compositions of the present invention may also include, but are not limited to, vitamin B, vitamin C, organic acids: such as acetate, malate, amino acids such as arginine, alanine and taurine, edible coloring matter, flavoring agent, etc.
The terms "subject" or "patient" are used interchangeably herein to refer to an animal (including a human) that can be treated with the compounds and/or methods. "individual" or "patient" herein encompasses both the male and female sex unless specifically stated otherwise. Thus, a "subject" or "patient" includes any mammal, including, but not limited to, humans, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cows, etc., which would benefit from treatment with the compounds. Preferably, the animal suitable for treatment with the compounds and/or methods of the invention is a human. In general, the terms "patient" and "individual" are used interchangeably herein.
Although numerical ranges and parameters setting forth the broad scope of the invention are approximate, the values set forth in the specific examples are presented as precisely as possible. Any numerical value, however, inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean, as considered by those skilled in the art. Except in the experimental examples, or where otherwise expressly indicated, it is to be understood that all ranges, amounts, values and percentages herein used (e.g., to describe amounts of materials, length of time, temperature, operating conditions, quantitative ratios, and the like) are to be modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning the number of significant digits recited and the number resulting from applying ordinary carry notation.
Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as is commonly understood and used by one of ordinary skill in the art. Furthermore, as used herein, the singular tense of a noun, unless otherwise conflicting with context, encompasses the plural form of that noun; the use of plural nouns also covers the singular form of such nouns.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are:
1. the method for treating the diabetes and the organ complications thereof by using the sodium pyruvate which can be clinically popularized and used by oral administration besides the existing diabetes treatment medicines is provided for the first time;
2. because the pyruvate is a powerful antacid preparation and a stimulator of PDH, the pyruvate is very suitable for preventing and treating diabetic ketoacidosis and even can be only taken orally without insulin;
3. in patients with clinical diabetes tendency, the health-care food is popularized and applied without special dietary restriction, and achieves the effects of preventing and treating diabetes and organ complications;
4. the method provides a simple specific method which can be popularized and applied in large-scale population for the first time and can prevent and treat diabetes and organ complications;
5. besides being developed as an innovative medicine, the health-care beverage can also be popularized in the population as a physiological liquid supplement or a health-care functional beverage, and the possibility and the specific method for preventing and treating diabetes and organ complications in large-scale population are exerted.
6. The oral administration is also only suitable for the diseases of PDH inhibition in vivo caused by other causes other than diabetes, such as multi-cause shock, chronic organ insufficiency, even tumors and senile lesions under certain conditions, and can also play a certain degree of prevention and treatment effects in people.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100 ml solution.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Examples
Preparing a reagent:
drug group: 0.35% sodium pyruvate, 0.2% sodium chloride, 0.15% potassium chloride and 1.35% glucose, replacing conventional animal laboratory drinking water;
normal group: conventional laboratory animal drinking water;
control group: 1.0% sodium pyruvate aqueous solution instead of drinking water for routine animal laboratories.
Experimental example 1
Experimental animals:
normal group: c57BLKS/J Normal untreated mice: drinking conventional laboratory drinking water;
control group: c57BLKS/J diabetic db/db untreated mice (conventional human type II diabetic animal experimental model): drinking conventional laboratory drinking water;
1% Pyr: drinking db/db mice containing pure 1% sodium pyruvate distilled water to replace conventional laboratory drinking water;
drug group: the db/db mice, which contained the aqueous solution containing the sodium pyruvate composition according to the invention, instead of the conventional laboratory drinking water, contained 0.35% sodium pyruvate, 0.2% sodium chloride, 0.15% potassium chloride and 1.35% glucose.
The experimental method comprises the following steps:
the randomly selected diabetic mice (week old 10 weeks) are divided into three groups, and the groups and the same normal mice respectively drink different experimental water, and the weight, the drinking water amount (about 10ml per day on average, no difference between groups) and the urine amount are observed and recorded under the same experimental conditions. Experimental observations were completed at 8 to 18 weeks of age, blood was taken for testing after sacrifice, and kidneys were taken for further examination. The following are the main experimental results and illustrations observed by routine or currently commonly used laboratory testing methods.
The statistical method comprises the following steps:
*P<0.05 and**P<0.01 is compared to the normal group;
#P<0.05 and##P<0.01 is compared to the control group;
values for diabetic db/db mice at baseline (10 weeks of age) and 8 weeks (18 weeks of age) are mean ± sd, with n-6 per group.
Result data:
1. effect of different treatment methods on body weight, blood glucose and plasma insulin levels in diabetic mice
TABLE 1
Note: glucose refers to fasting blood glucose; insulin refers to fasting plasma insulin.
The results show that the oral administration of two different sodium pyruvate drinking water can effectively control the weight gain of experimental animals, maintain the fasting blood glucose level not to rise any more and the plasma insulin level to rise in multiples; it is clearly shown that both sodium pyruvate solutions provide effective control of the diabetic state.
2. Change in serum cystatin C, 24 hr urine protein and NGAL after different treatments
TABLE 2
Note: NAGL, neutrophil gelatinase-associated lipoprotein in urine.
The results show that the drinking water orally taking two different sodium pyruvate can also obviously reduce the 24-hour urine protein amount; reduce cystatin C level in serum and NAGL content in urine. The latter two assays are early sensitive indicators of renal function impairment. Both sodium pyruvate solutions were shown to be equally effective in protecting/reducing diabetic kidney injury.
3. Changes in ROS, SOD, CAT, MDA and GSH-PX in Kidney homogenate following different treatments
TABLE 3
Note: ROS is reactive oxygen species; SOD, superoxide dismutase; CAT is catalase; MDA, i.e. malondialdehyde; GSH-PX is glutathione peroxidase.
The results show that the indexes reflecting the in vivo oxidative stress all show that the oral administration of two different sodium pyruvate drinking water can also obviously inhibit the indexes ROS and MAD promoting the oxidative stress; improving the activity of antioxidant enzymes such as SOD, CAT, GSH-PX, etc. The oxidative stress reaction and the inflammatory reaction promoted by the oxidative stress reaction are important internal links for the development of the diabetic condition, and the oral administration of the sodium pyruvate effectively inhibits the in-vivo oxidative stress reaction of diabetic mice and is beneficial to the control of diabetes and nephropathy.
4. Changes in LDH, PK and PDHa/PDHt in Kidney homogenates following different treatments
TABLE 4
Note: LDH, i.e. lactate dehydrogenase; PK, pyruvate kinase; PDHa/PDHt is the pyruvate dehydrogenase activity fraction/total pyruvate dehydrogenase.
The results show that the activities of PK which is one of the inhibited glycolytic key enzymes and PDH which is a key enzyme for the oxidative metabolism of sugar in a diabetic mouse are obviously increased by orally taking sodium pyruvate, so that the hyperglycemia is promoted to enter the normal oxidative metabolism process, and the metabolism and the function of the blood sugar and the organs of the whole body are effectively controlled; at the same time, the AR and LDH responses stimulated by high sugars are inhibited, and as a result, abnormal sugar metabolism characteristics under diabetes are driven: reversal of the Warburg phenomenon (Warburg Effect) [10 ].
5. AGEs and NAD in Kidney homogenate after different treatments+Changes in NADH
TABLE 5
Note: AGEs, advanced glycosylation endproducts; NAD (nicotinamide adenine dinucleotide)+NADH is nicotinamide adenine dinucleotide (oxidized/reduced).
The results show that the diabetic miceTwo sodium pyruvate aqueous solutions taken orally can equally effectively increase the important redox potential in vivo (kidney): NAD (nicotinamide adenine dinucleotide)+The ratio of NADH, which is beneficial to restoring antioxidant stress and inhibiting inflammatory reaction of the body, and remarkably reduces the generation and accumulation of glycosylation end products in the body/tissue, wherein the glycosylation end products are key factors for worsening the disease course of microvascular and organ complications in the whole body of diabetes mellitus and causing malignant cycle.
The results of the Western Blot assay for the determination of multiple enzyme activities in kidney tissue are shown in FIG. 1. The results in figure 1 show that oral administration of both aqueous sodium pyruvate solutions to diabetic mice was equally effective in restoring PDH and PDHA1 activity in vivo (renal tissue) due to inhibition of PDK hyperabnormalities at high sugar; both sodium pyruvate-containing solutions also significantly reduced the AR activity enhanced by high sugars.
In this regard, the results of the above experiments demonstrate that oral administration of a sodium pyruvate composition containing only 0.35% glucose and an aqueous solution containing only 1.0% sodium pyruvate in diabetic mice has the same therapeutic effect on diabetes and renal complications; also comprehensively improve the abnormal return of multiple pathways of the carbohydrate metabolism to normal under the condition of hyperglycemia, promote the secretion of insulin and improve the generation of AGEs.
Discussion:
oral administration of pure sodium pyruvate in rodents, which is virtually always accompanied by feeding, is equivalent to oral administration of sodium pyruvate containing glucose, essentially equivalent to oral administration of sodium pyruvate containing sugars, and thus shows similar efficacy in experiments. However, only 0.35% sodium pyruvate, not necessarily 1.0%, is sufficient to achieve the same therapeutic effect; however, in humans, oral administration of sodium pyruvate alone (7-25 g/day) is generally ineffective, does not increase blood levels, and is not tolerated and generalized by gastrointestinal irritation unless large doses are used due to intestinal malabsorption. The intestinal epithelial cells possess sodium-sugar cotransporter (Na)+-Glucose Co-transporter)[15]The composition of the invention containing glucose is absorbed well by the co-transporter effect when a small amount of sodium pyruvate is taken orally, so that the same effect can be achieved only by taking a large amount of oral administration. This is the gist of the present invention.
Experimental example 2
Cell experiments
Human renal tubular epithelial cell line: HK-2 cells were incubated for 3 days at high (30mmol/L) and normal (5mmol/L) levels with 0.5mmol/L sodium pyruvate (5-fold concentration of normal serum levels: previously shown by experiment that oral administration of the sodium pyruvate composition increased pyruvate levels in the plasma of animals by more than 5-fold [15]), as determined by conventional experimental methods: the cell AR PDH/PDHA1 (the major active component in PDH) and Pyruvate Dehydrogenase Kinase (PDK) activities were measured by Western Blot method, and the results were consistent with the above in vivo experimental results: inhibition of enhanced AR and PDK restored PDH and PDHA1 activity.
It is worth noting that PDK in human cells is stimulated to be enhanced under many other pathogenic factors besides high sugar, such as hypoxia, oxidative stress, tumor or aging; PDK is a kinase of PDH, and inhibits the activity of PDH by spontaneously phosphorylating it (PDH loses its activity by phosphorylating it, PDHa/PDHt ratio decreases, as shown by the above results), leading to sugar metabolism disorder: expression characterized by the Warburg phenomenon. In animal body experiments, sodium pyruvate is proved to play a role in inhibiting AR and PDK activities enhanced by abnormal stimulation so as to recover PDH activity. The above results are consistent with the consensus that pyruvate-activated PDH is the result of PDK inhibition (PDH is directly regulated by PDK phosphorylation inactivation) [16], demonstrating that oral administration of the sodium pyruvate composition provided by the present invention is effective in enhancing the activity of inhibited PDH in vivo.
Discussion:
pyruvate is a 'PDH stimulator' typified by dichloroacetic acid (DCA) belonging to the same genus [16-18 ]. The above description: oral administration of the sodium pyruvate composition of the invention restores inhibited PDH activity in renal tissues because absorbed pyruvate directly inhibits abnormally elevated PDK with sugar [16 ]. Although pyruvate can improve the inhibited PDH activity no matter in vivo systemic administration or in vitro, the experiment of the invention proves that the sodium pyruvate composition with only limited oral dose can effectively stimulate and recover the PDH activity of key enzyme inhibited by PDK enhanced in vivo, thereby improving abnormal sugar metabolism in the whole body. Thus, oral administration is also suitable for non-diabetic conditions in which PDH activity is reduced, such as in patients with shock, trauma, tumors and the elderly: they all show a decrease in PDH activity in tissues due to PDK phosphorylation, whereas previous experiments have shown that intravenous/intraperitoneal administration of large doses of sodium pyruvate has a comparable therapeutic efficacy [19-22 ]. Therefore, the intended effect can be achieved by oral administration of the sodium pyruvate composition of the present invention.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Reference documents:
1,Ogurtsova K,et al.IDF Diabetes Atlas:Global estimates for theprevalence of diabetes for 2015 and 2040.Diabetes Res Clin Pract.2017 Jun；128:40-50.
2,Wang L,et al.Prevalence and Ethnic Pattern of Diabetes andPrediabetes in China in 2013.JAMA.2017 Jun 27；317(24):2515-2523.
3,Alicic RZ,et al.Diabetic Kidney Disease:Challenges,Progress,andPossibilities.Clin J Am Soc Nephrol.2017 Dec 7；12(12):2032-2045.
4,Devamanoharan PS,et al.Non-enzymatic glycation of lens proteins andhaemoglobin-inhibition by pyruvate:an in-vivo study.Diabetes Obes Metab.1999May；1(3):159-64.
5,Brown M,et al.Pyruvate improves pancreatic islet engraftment andfunctionality.Transplant Proc.2001 Nov-Dec；33(7-8):3523.
6,Petkova I,et al.Oral application of sodium pyruvate in healthypersons and patients with diabetes mellitus type 1.Comptes rendus de l'Acad_emie bulgare des Sciences.2007；60:579-84.
7,Morrison MA,et al.Pyruvate ingestion for 7 days does not improveaerobic performance in well-trained individuals.J Appl Physiol(1985).2000Aug；89(2):549-56.
8,Olek RA,et al.Single pyruvate intake induces blood alkalization andmodification of resting metabolism in humans.Nutrition.2015 Mar；31(3):466-74.
9,Yan LJ.Redox imbalance stress in diabetes mellitus:Role of thepolyol pathway.Animal Model Exp Med.2018 Mar；1(1):7-13.
10，Zhang G,et al.The Warburg effect in diabetic kidney disease.SeminNephrol.2018；38(2):111-120.
11,Mostert M,et al.Derangements of pyruvate dehydrogenase incirculating lymphocytes of NIDDM patients and their healthy offspring.JEndocrinol Invest.1999；22(7):519-26.
12,Andersen LW,et al.Pyruvate dehydrogenase activity is decreased inemergency department patients with diabetic ketoacidosis.Acad Emerg Med.2016；23(6):685-9.
13,Luo F,et al.Hexokinase II promotes the Warburg effect byphosphorylating alpha subunit of pyruvate dehydrogenase.Chin J CancerRes.2019 Jun；31(3):521-532.
14,Burns JS,et al.Metabolic pathways of the Warburg effect in healthand disease:Perspectives of choice,chain or chance.Int J Mol Sci.2017 Dec 19；18(12).pii:E2755.
15,Liu,R,et al.Pyruvate in reduced osmolarity oral rehydration saltcorrected lactic acidosis in sever scald rats.J.Surg.Res.2018；226:173-180.
16,Priestman DA,et al.Pyruvate inhibition of pyruvate dehydrogenasekinase.FEBS Lett.1996 Sep 16；393(2-3):174-8.
17,Whitehouse S,et al.Mechanism of activation of pyruvatedehydrogenase by dichloroacetate and other halogenated carboxylicacids.Biochem J.1974 Sep；141(3):761-74.
18,Jaimes R 3rd,et al.Functional response of the isolated,perfusednormoxic heart to pyruvate dehydrogenase activation by dichloroacetate andpyruvate.Pflugers Arch.2016 Jan；468(1):131-142.
19,Sharma P,et al.Pyruvate modulates hepatic mitochondrial functionsand reduces apoptosis indicators during hemorrhagic shock inrats.Anesthesiology.2005 Jul；103(1):65-73.
20，Sharma P,et al.Role of pyruvate dehydrogenase complex in traumaticbrain injury and measurement of pyruvate dehydrogenase enzyme by dipsticktest.J Emerg Trauma Shock.2009 May；2(2):67-72.
21，Takakusagi Y,et al.Pyruvate induces transient tumor hypoxia byenhancing mitochondrial oxygen consumption and potentiates the anti-tumoreffect of a hypoxia-activated prodrug TH-302.PLoS One.2014 Sep 25；9(9):e107995.
22, wang xiao nan et al, influence of pyruvate on learning and memory of alzheimer rats, journal of neuropsychiatric disease in china 2014; 40(0):87-90.
Claims (10)
1. A composition characterized in that it comprises the following essential components:
(a)2.0-25.0 parts by weight of sodium pyruvate; and
(b)5.0-100.0 parts by weight of anhydrous glucose or other carbohydrates;
and the weight of the essential components accounts for 30-100% of the weight of the composition.
2. The composition of claim 1, wherein the composition further comprises additional components comprising: sodium chloride, potassium chloride or potassium citrate, vitamin B, and vitamin C.
3. The composition of claim 2, wherein the composition comprises the following components:
(i)2.0-25.0 parts by weight of sodium pyruvate;
(ii)0-10.0 parts by weight of sodium chloride;
(iii)0-2.0 parts by weight of potassium chloride or potassium citrate of corresponding equivalent; and
(iv)5.0-100.0 parts by weight of anhydrous glucose or other carbohydrates;
and the weight of the components (i) + (ii) + (iii) + (iv) is 80-100% of the total weight of the composition.
4. The composition of any one of claims 1 to 3, wherein the molar ratio of sodium ions to glucose in the composition is from 0.5 to 1: 1; preferably close to 1: 1.
5. use of a composition according to any one of claims 1 to 4 in the manufacture of a medicament, food or health product for the treatment or prevention of a disease or condition associated with inhibition of pyruvate dehydrogenase activity.
6. The use according to claim 5, wherein the disease is diabetes and its organic complications.
7. Use according to claim 5, wherein the diabetes is type II diabetes, and/or type I diabetes.
8. Use according to any one of claims 5 to 7, wherein the medicament, food or nutraceutical is in the form of a solution.
9. The use according to claim 8, wherein the osmolality of the solution is 200-1200mOsm/L, preferably the osmolality of the solution is 220-280mOsm/L, or 600-1000 mOsm/L.
10. The use of claim 5, wherein the disease or condition further comprises manifestations of disturbances of sugar metabolism due to decreased pyruvate dehydrogenase activity in vivo, such as in part of critical illness, tumors, and age-related conditions.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040204356A1 (en) * | 2002-12-06 | 2004-10-14 | Volkmar Guenzler-Pukall | Treatment of diabetes |
| CN103316038A (en) * | 2012-03-20 | 2013-09-25 | 胡森 | Pyruvate oral rehydration salt composition for curing circulation hypovolemia or water-losing with salt-losing |
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|---|---|---|---|---|
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| CN103263383A (en) * | 2013-05-10 | 2013-08-28 | 胡森 | Two-chamber-bag aqueous sodium pyruvate solution kit and use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN103316038A (en) * | 2012-03-20 | 2013-09-25 | 胡森 | Pyruvate oral rehydration salt composition for curing circulation hypovolemia or water-losing with salt-losing |
Non-Patent Citations (4)
| Title |
|---|
| TANAKA MASASHI等: ""Therapeutic potential of pyruvate therapy for mitochondrial diseases"", 《MITOCHONDRION》 * |
| 周方强等: "丙酮酸钠在危重病液体治疗中的潜在应用", 《中华损伤与修复杂志(电子版)》 * |
| 季敏等: "丙酮酸盐用于防治糖尿病视网膜病变", 《中国眼耳鼻喉科杂志》 * |
| 符俊达等: "不同剂量丙酮酸钠对糖尿病大鼠视网膜组织保护作用的研究", 《临床医药文献电子杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021115156A1 (en) * | 2019-12-10 | 2021-06-17 | 周方强 | Composition containing sodium pyruvate and use thereof |
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