CN1747727A - Inhibitor for perioperative blood sugar elevation - Google Patents
Inhibitor for perioperative blood sugar elevation Download PDFInfo
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- CN1747727A CN1747727A CN 200480003625 CN200480003625A CN1747727A CN 1747727 A CN1747727 A CN 1747727A CN 200480003625 CN200480003625 CN 200480003625 CN 200480003625 A CN200480003625 A CN 200480003625A CN 1747727 A CN1747727 A CN 1747727A
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Abstract
An inhibitor for perioperative blood sugar elevation characterized by containing a branched amino acid, a compound which can be converted into a branched amino acid in vivo or a compound to which an amino group has been transferred from a branched amino acid. This inhibitor for perioperative blood sugar elevation is useful as a drug which is safe to the living body, inhibits abnormal elevation in the blood glucose level caused by anesthesia, surgery, etc. and enables proper blood sugar control, when administered to a perioperative patient.
Description
Technical field
The medicine that the blood glucose value that the present invention relates to suppress stress to be caused by perioperative anesthesia, operation etc. rises is characterized by and comprises branched-chain amino acid.
Background technology
The invasion and attack that the known factor of accepting to influence in vivo dynamic equilibrium when the live body that comprises the patient is for example anaesthetized, operation etc. produces stress the time, live body is secreted multiple insulin resistance hormone (catecholamine, glucagon, corticoid etc.), promote sugared new life and sugar decomposition in the liver, and deposit into blood-glucose (hereinafter by autonomic nervous system/hormonal system, be also referred to as blood glucose) rise, so that the function of keeping living cells (for example, referring to MAYUMI etc., " IGAKU NOAYUMI ", 168 volumes, 418-423 page or leaf, 1994).
Especially, owing to significantly hyperglycemia or osmotic diuresis among the patient who suffers from diabetes in abnormal carbohydrate metabolism illness such as the perioperative, may dewater because by anesthesia or operation etc. cause to produce insulin action near invasion and attack stress such as fasted conditions or anesthesia or operation etc. insufficient.If these state continuances are seriously insufficient because sugar utilizes, some kinds of severe complications for example Developmental and Metabolic Disorder, stupor and multiple organ dysfunction syndrome may appear in the patient sometimes.Under these patient's situations, when the patient who is in perioperative did not give sugar, body protein and steatolysis appearred, and free fatty acid and ketoboidies increase in the blood, cause ketoacidosis.This not only can occur having among the patient of abnormal carbohydrate metabolism, and appears at experience similarly and need among the patient of height invasion and attack degree operation of longer operating time, or appears at ICU and concentrate among the patient who suffers from serious symptom who treats, etc.
Therefore, the blood glucose value of control perioperative is the important topic of control general anesthesia.Blood glucose value not only shortens the cycle that aftertreatment needs in the known control perioperative in suitable scope, and increases operation back patient's survival probability.
At present, by replenishing saccharide, being generally glucose, under the hyperglycemia situation, control blood glucose value in the perioperative with the insulin administration method.The insulin administration method is to use the continuous intravenous administration insulin of infusion pump, and simultaneously if desired, the method for insulin concentration in monitoring patient's blood glucose value and patient's the blood after operation is so that blood sugar level is in suitable scope when keeping operation.
Yet controlling the used correct insulin dose of patient continuously needs advanced technology.When giving insulin excessively mistakenly, the patient becomes, and hypoglycemia and having causes going into a coma or the risk of several heavy damages of central nervous system.In order to keep body protein and fat and to prevent ketoacidosis, the saccharide of for example infusing is given the patient in normal operation, and this insulin dose depends on the saccharide of these supplies, thereby needs more advanced control.In addition, the patient for insulin sensitivity reduces usually observes noninsulindependent diabetes in older or overweight people, with above-mentioned insulin administration the influence that blood glucose value reduces is expected sometimes inadequately.
Therefore, the technology by insulin administration blood sugar control value is not the method for inevitable safety for the patient, and is difficult to control/management.
Therefore, as blood glucose value rising inhibitor of the present invention, blood glucose value rising inhibitor is the safe and also unknown now constituent this point that comprises branched-chain amino acid for the patient.In addition, we can say that the present invention is excellent invention, because be different from the insulin administration method, the dosage of the unnecessary strict control insulin of the present invention, and can easily in perioperative, replenish sugar.
Disclosure of the Invention
The object of the invention provides and is suppressed at the medicine that observed blood glucose value rises in the perioperative, more particularly provide blood glucose value rising inhibitor, it is safe for the live body that comprises human patients, and by under anesthesia to patient's administration, be suppressed at that observed abnormal plasma glucose value rises in the perioperative.
The inventor concentrates on attention as influencing in vivo dynamic equilibrium and being on the aminoacid of safe chemical compound for live body.In order to address the above problem, the present inventor has had been found that the present invention by research and the non-narcotic amino acid whose physiological function that influences homeostasis under anesthesia of comparing.Particularly, the inventor has been found that the anesthesia blood glucose value of rat down is lower than the non-narcotic blood glucose value of rat down when under anesthesia the rat of having an operation being comprised the amino acid transfusion of essential, accurate essential and non essential amino acid.In addition, the inventor has furtherd investigate in these aminoacid that comprise in the concurrent present amino acid transfusion, have and suppress in the above-mentioned live body branched-chain amino acid of ascending effect on the blood glucose value, and in perioperative, particularly under anesthesia, suppressing effect increases, that is, the amino acid whose effective dose that plays a role also is lower than under non-narcotic.The inventor have been found that when glucose and these aminoacid under the anesthesia medicament during administration simultaneously, than the non-narcotic insulin secretion that promotes more down.The inventor finishes the present invention by the broad research based on these discoveries.
That is to say, the present invention relates to:
(1) inhibitor for perioperative blood sugar elevation is characterized by and comprises branched-chain amino acid, be transformed into the chemical compound of branched-chain amino acid or shift amino chemical compound from branched-chain amino acid in can body,
(2) the blood glucose value rising inhibitor of above-mentioned (1), wherein branched-chain amino acid is leucine and/or isoleucine,
(3) the blood glucose value rising inhibitor of above-mentioned (1) or (2), the chemical compound that is transformed into branched-chain amino acid in wherein can body is salt, ester or the amide of branched-chain amino acid, or comprises the oligopeptide of branched-chain amino acid,
(4) the blood glucose value rising inhibitor of above-mentioned (1), wherein shifting amino chemical compound from branched-chain amino acid is α-Tong Yijisuan or α-ketone-Beta-methyl valeric acid,
(5) the blood glucose value rising inhibitor of any one in above-mentioned (1)-(4), it comprises, and 0.25 to 2.5 Grams Per Minute rises leucine and/or 0.25 to 3.5 Grams Per Minute rises isoleucine,
(6) the blood glucose value rising inhibitor of any one in above-mentioned (1)-(4), it comprises, and 1 to 10 Grams Per Minute rises glucose and 0.25 to 2.5 Grams Per Minute rises leucine and/or 0.25 to 3.5 Grams Per Minute rises isoleucine,
(7) the blood glucose value rising inhibitor of any one in above-mentioned (1)-(6), wherein the blood glucose value rising is caused by anesthetics,
(8) the blood glucose value rising inhibitor of any one in above-mentioned (1)-(6), it is used for the treatment of and/or prevents the blood glucose value under the anesthesia to rise,
(9) the blood glucose value rising inhibitor of any one in above-mentioned (1)-(6), it is used for and anesthetics and usefulness,
(10) the inhibition method that rises of blood glucose value, it comprises any one blood glucose value rising inhibitor in patient's administration of perioperative above-mentioned (1)-(6),
(11) anesthesia, it comprises any one blood glucose value rising inhibitor and usefulness in anesthetics and above-mentioned (1)-(6),
(12) branched-chain amino acid, be transformed into the chemical compound of branched-chain amino acid in can body or shift amino chemical compound and be used for suppressing the application of the medicine that perioperative patient's blood glucose value rises in preparation from branched-chain amino acid,
(13) branched-chain amino acid, be transformed into the chemical compound of branched-chain amino acid in can body or shift the application of the medicine that blood glucose value that amino chemical compound is used for suppressing to be caused by anesthetics in preparation rises from branched-chain amino acid.
In the present invention, " perioperative " be meant before the operation, in the time of in the art under the operation invasion and attack condition that is caused by operation/anesthesia and postoperative period.
The accompanying drawing summary
Fig. 1 shows the result of the test that blood glucose value is influenced by to non-narcotic aminoacid following or the following parallel administration of rat of anesthesia.
Fig. 2 shows blood glucose value risen has the identification and detection result of the amino acid whose kind that suppresses effect.
Fig. 3 shows BCAA, and (3 kinds of mixture Leu+Ile+Val) rise to suppress the affirmation result of the test of effect to blood glucose value.
Fig. 4 shows the rise identification and detection result of kind with the BCAA that suppresses effect of blood glucose value.
Fig. 5 shows under the situation of parallel administration liquid glucose, BCAA (3 kinds of mixture, Leu+Ile+Val) result of the test of the inhibition effect that blood glucose value is risen.
Fig. 6 shows the anesthesia branched-chain amino acid effect of continuous input glucose down.
Fig. 7 shows non-narcotic time and the effect of leucine to blood glucose value descended in anesthesia.
Isoleucine was to the influence of AUC when Fig. 8 showed sugar tolerance.
Implement best mode of the present invention
Above-mentioned aminoacid (hereinafter, be abbreviated as BCAA) be not particularly limited, as long as they satisfy the standard of describing in the Japanese Pharmacopoeia, comprise any aminoacid for example L-aminoacid, D-aminoacid, L-aminoacid, a-amino acid, beta-amino acids, gamma-amino acid, natural amino acid, synthesizing amino acid etc., preferred natural L-aminoacid or a-amino acid.In addition, can be by deriving from plant by means of protease hydrolysis or derive from the protein of animal, or prepare above-mentioned aminoacid with microbe fermentation method, maybe can be by in organic acid, introducing the synthesizing amino acid of preparation such as amino.
BCAA is leucine, isoleucine or valine preferably.
These aminoacid can use separately or and use.Particularly, example is the mixture or (f) mixture of leucine, isoleucine and valine of mixture, (e) isoleucine and valine of mixture, (d) leucine and the valine of (a) independent leucine, (b) independent isoleucine, (c) leucine and isoleucine.
The chemical compound that changes above-mentioned BCAA in can body into can be the pharmaceutically acceptable salt of itself and acid or alkali, particularly, the acid-addition salts of BCAA or base addition salts (for example sodium salt, potassium salt, hydrochlorate, acetate etc.), its ester (for example methyl ester, ethyl ester, propyl ester etc.) or its amide (for example amide, monomethyl amide, single buserelin, dimethylformamide, diethylamide etc.).
In addition, the chemical compound that changes above-mentioned BCAA in can body into can be the analog of BCAA, and it is the precursor of BCAA, for example comprises that BCAA is as the oligopeptide of element etc.As for this oligopeptide, for example, example is for example L-isoleucyl--L-leucine, L-leucyl-L-alanine etc. of dipeptides.These analog can use separately or use with its form of mixtures.
To shift amino chemical compound can be the amino that shifts BCAA with the transaminase to the amino acceptor chemical compound of α-Tong Wuersuan (2-oxoglutaric acid) preparation for example from BCAA.For example, from each leucine, isoleucine or valine shift amino chemical compound be respectively for example, α-Tong Yijisuan, α-ketone-Beta-methyl valeric acid or KIV.
BCAA, transform in can body BCAA chemical compound and from BCAA shift amino chemical compound can be crystalline maybe can be amorphous.
Be included in the blood glucose value rising inhibitor BCAA or can body in transform into the chemical compound of BCAA combined amount do not have special restriction, do not have crystal settling as long as above-mentioned inhibitor keeps stable, even under the long term storage situation, preferably in following scope.
For example, when above-mentioned inhibitor is liquid preparation and only comprises BCAA, for example, in (a) independent leucine or (b) independent following time of isoleucine situation, preferably about 0.5 to the 4.0 Grams Per Minute liter of each BCAA concentration is more preferably about 0.7 to 3.0 Grams Per Minute liter.When the BCAA that comprises in the above-mentioned inhibitor is mixture, the mixture of (c) leucine and isoleucine for example, (d) mixture of leucine and valine, (e) mixture of isoleucine and valine, or (f) leucine, the mixture of isoleucine and valine, each mixed weight ratio is (c) leucine: isoleucine=about 1: about 0.25 to 4, (d) or (e) leucine or isoleucine: valine=about 1: about 0.25 to 4, or (f) leucine: isoleucine: valine=about 1: about 0.25 to 4: about 0.25 to 1, preferably each BCAA concentration is in above-mentioned scope.
Because preferably in perioperative, be administered to live body (patient) with the blood glucose value rising inhibitor of the present invention of infusing continuously by direct intravenouss such as intravenous drops, its dosage form preferably liquid preparation for example is used for the Injectable solution of intravenous drop, and can be to use the time by it being dissolved in the granular preparation or the powder formulation of the lyophilisation product that administration is used in the distilled water for injection etc.In addition, can be before operation oral formulations, and effect continues in the operation process of patient under anesthesia.
Preparation method can be the technology of known preparation amino acid transfusion or amino acid preparation.Finish this preparation usually by with above-mentioned constituent dissolving and be blended in the distilled water for injection, if desired, to wherein adding additive etc.Then, with filter etc. or the aqueous solution degerming from obtaining such as sterilization under heating, and prepare and become liquid preparation.
As required, blood glucose value rising inhibitor of the present invention can mix with multiple additives as required, to stablize above-mentioned inhibitor etc.The instantiation of this additive comprises pH regulator agent for example hydrochloric acid, acetic acid, malic acid, citric acid, sodium hydroxide and potassium hydroxide, osmotic pressure regulator for example Conclyte-sodium to adjust the osmotic pressure of above-mentioned inhibitor.
Blood glucose value rising inhibitor of the present invention can comprise and knownly joins usually and become to grade with blended other of amino acid transfusion, comprises for example basic amino acid (for example lysine, arginine etc.) and be different from the ArAA (for example tryptophan, phenylalanine etc.) of BCAA or its salt, lipid, vitamins, electrolyte, trace element etc. of free amino acid for example.The addition of these compositions without limits in the object of the invention scope.
When perioperative live body (patient) is given in blood glucose value rising inhibitor of the present invention administration, can avoid observed blood glucose value rising in perioperative, thereby replenish the sugar that needs parallel use insulin usually, suppress the abnormal ascending of blood glucose value simultaneously.
Perioperative live body (patient) is in anesthesia down usually, can advantageously use blood glucose value rising inhibitor of the present invention under general anesthesia and local anesthesia.The anesthesia that is used for the patient under the narcotism normally is used for the method for medical field.For example, this method is to suck anesthesia, intravenous anesthesia, spinal anesthesia, epidural anesthesia etc.In addition, operable anesthetics in blood glucose value rising inhibitor uses is not had special restriction, inhalational anesthetic example is laughing gas, anesthetic ether, isoflurane, enflurane, sevoflurane and halothane etc.; The example of intravenous anesthesia medicament is amobarbital sodium, sodium thiamylal, penthiobarbital, nembutal calcium, propofol, benzene phenodiazine , stable, midazolam, hydroxyzine, Droperidol, flumazenil, ketamine etc.; The example of local anesthetic is that quinocaine, Mepivacaine Hydrochloride, procaine hydrochloride, Ropivacaine HCL, benzocaine, benzocaine, lignocaine, oxetacaine, tetracaine hydrochloride, Oxybuprocaine, carbostesin etc. are (with reference to the therapeutic agent classification of describing in the Japanese Pharmacopoeia, the 14 edition, etc.)
Preferably under the situation of liquid preparation and under the situation at lyophilisation product, when using, be dissolved in sterile distilled water after continuously intravenous administration blood glucose value rising of the present invention inhibitor give live body (patient).For medicine-feeding rate, the concentration of BCAA etc. is adopted iptimum speed in body weight by considering administration live body (patient) and the above-mentioned inhibitor under each situation, monitor blood glucose value by the doctor in the preferred in addition operative cycle and come regulations speed in time, so that suitable suggested rate.Usually, total BCAA amount is about 2 to 200 milligrams/body weight-kilogram/time, preferred 5 to 500 milligrams/body weight-kilogram/time.Under the medicinal preparation for oral administration situation, 5 to 300 milligrams/body weight-kilogram of oral administration before the administration anesthesia medicament.
Embodiment
In the present invention, followingly illustrate preferred for preparation example and experimental example, yet the invention is not restricted to following preparation example etc.
Each abbreviation in illustrated such as this description and accompanying drawings is as described below.In addition, unless specify in addition, aminoacid is considered to L-aminoacid when optical isomer.
BCAA: branched-chain amino acid
EAA: essential and accurate essential amino acid
Leu: leucine
Ile: isoleucine
Val: valine
Lys: lysine
Thr: threonine
Trp: tryptophan
Met: methionine
Phe: phenylalanine
Cys: cysteine
Tyr: tyrosine
Arg: arginine
His: histidine
Ala: alanine
Pro: proline
Ser: serine
Asp: aspartic acid
Glu: glutamic acid
Glucose: glucose
Reference example
Amino acid solution (reference table 1) described in the preparation reference example 2 to 6.In addition, reference example 1 relates to amino acid transfusion " Amiparen " (10% common amino acid transfusion), and by OTSUKAPHARMACEUTICAL FACTORY, Inc. makes.Reference example 2 relates to the Freamine that only comprises the essential and accurate essential amino acids (EAA) in reference example 1 aminoacid.Reference example 3,4,5 or 6 relates to comprising removes BCAA, basic amino acid, ArAA or other amino acid whose residual amino acid whose Freamine respectively.
As for each aminoacid, use cryodesiccated product (by manufacturings such as AJINOMOTO Co.Ltd., KYOWA HAKKO KOGYO Co.Ltd.).Add each aminoacid to the 450mL distilled water for injection to table 1 described concentration, and use the agitator stirring and dissolving.In addition, when the osmotic pressure ratio of normal saline is lower than 1, add Conclyte-sodium, make solution and blood isoosmotic pressure to proofread and correct osmotic pressure.In 6.5 to 7.4 scopes, measure aqueous solution 500mL with the pH of glacial acetic acid regulator solution, solution is by heat sterilization (106 ℃, 32 minutes), with each Freamine in the preparation reference example 2 to 6.
Table 1
| Reference example | ||||||
| 1 | 2 | 3 | 4 | 5 | 6 | |
| Common | EAA | -BCAA | -base | -fragrance | -other | |
| L-Leu | 1.40 | 1.40 | 1.40 | 1.40 | 1.40 | |
| L-Ile | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | |
| L-Val | 0.8 | 0.8 | 0.8 | 0.8 | 0.8 | |
| Acetic acid L-Lys | 1.05 | 1.05 | 1.05 | 1.05 | 1.05 | |
| L-Thr | 0.57 | 0.57 | 0.57 | 0.57 | 0.57 | |
| L-Trp | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
| L-Met | 0.39 | 0.39 | 0.39 | 0.39 | 0.39 | |
| L-Phe | 0.7 | 0.7 | 0.7 | 0.7 | 0.7 | |
| L-Cys | 0.1 | |||||
| L-Tyr | 0.05 | |||||
| L-Arg | 1.05 | 1.05 | 1.05 | 1.05 | 1.05 | |
| L-His | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | |
| L-Ala | 0.8 | |||||
| L-Pro | 0.5 | |||||
| L-Ser | 0.3 | |||||
| Glycine | 0.59 | |||||
| L-Asp | 0.1 | |||||
| L-Glu | 0.1 | |||||
| Amount to | 10.00 | 7.46 | 4.46 | 4.86 | 6.56 | 6.5 |
(g/100ml)
Preparation example
Prepare Freamine in the preparation example 1 to 5 in the table 2 with the method for similar reference example.
Table 2
| Preparation example (g/100mL) | |||||
| 1 | 2 | 3 | 4 | 5 | |
| L-Leu | 1.40 | 2.00 | 1.00 | ||
| L-Ile | 0.8 | 2.00 | 1.00 | ||
| L-Val | 0.8 | 2.00 | |||
| Amount to | 3.00 | 2.00 | 2.00 | 2.00 | 2.00 |
Test example 1
The influence of rat administration aminoacid to blood glucose value descended in non-narcotic or anesthesia
In the previous day of test, under etherization cut rat neck, in right external jugular vein, keep each catheter of anesthesia medicament administrable and amino acid solution administrable.After rat was fixed on harness, subcutaneous another end that connects catheter exposed from rat back, and was connected on the swivel bearing through fixing harness.Continuously with the speed of 1 milliliter/hour/health via the catheter administration normal saline (Saline) that is used for the amino acid solution administration before lucky test.Thereafter, the rat of feeding under fasting state is allowed rat drinking water freely.
On the same day of test, shift rat to sound insulation and anti-electric chamber.Then, connect each catheter to the cable of multiple fluctuation monitor be used for administration anesthesia medicament or be used for syringe pump (the anesthesia medicament: microsyringe pump type EP32 of administration amino acid solution through branch joint, make amino acid solution: JMS syringe pump model SP100s) by EICOM Corp..After pre-determining rat bioelectric potential (EEG, EMG, body temperature, biological vibration) and stablizing 1 hour, further write down 30 minutes bioelectric potentials before lucky anesthesia begins.This method is considered to pretreatment so far, and carries out following test example.
(Diprivan 1% for intravenous administration 15 mg/kg propofol, Zeneca S.p.A., Italy) pill is given anesthetics administration group (n=16), and continuous 30 minutes 45 mg/kg/hour (i.v.) propofol of intravenous administration, intravenous administration 22.5 mg/kg/hour propofol (i.v.) 2.5 hours continuously then.
Intravenous administration 1.5 ml/kg (i.v.) Intralipos (infatmul agent, by OTSUKA PHARMACEUTICAL FACTORY, Inc makes) pill give the non-administration group of anesthetics (n=16), be similar to then anesthetics administration group continuously intravenous administration Intralipos amount to 3 hours.
With 14 ml/kg/hour speed via the amino acid solution administration catheter parallel with propofol administration or Intralipos administration, continuously the reference example of describing in the intravenous administration table 11 " Amiparen " (n=8) (by OTSUKA PHARMACEUTICAL FACTORY, Inc. makes) give two groups of rats.
After the solution of administration reference example 1 is ended, to two groups of rat administration anesthesia medicament pentobarbital sodiums (50 mg/kg), collect blood from ventral aorta via the catheter that is used for amino acid solution administration group.Measure blood glucose value with enzymatic method (Glucose-DH method).In addition, by in the difference that differs between two-way analysis (t check) back measurement normal saline administration group and the amino acid solution administration group, contrast two groups.
Test the Fig. 1 that the results are shown in of example 1.For anesthetics administration group, observe that blood glucose value is starkly lower than parallel administration group among the Amiparen (reference example 1), the aminoacid administration blood glucose value rising that invasion and attack stress cause that effectively suppresses to perform the operation be described under anesthesia.
Test example 2
Evaluation with amino acid whose kind of blood glucose value rising inhibition effect
Aminoacid with blood glucose value rising inhibition effect is tested the aminoacid of aminoacid for comprising in the reference example (Amiparen) that uses in the test example 1.
To carrying out administration 15 mg/kg propofol pellet (bolus) in the pretreated rat vein, then according to test example 1 intravenous administration propofol 3 hours continuously in the mode that is similar to test example 1.With 14 ml/kg/hour speed intravenous administration reference example 2 to 6 (each administration group n=8) or each amino acid solution of normal saline (matched group n=8) give above-mentioned rat, be parallel to the propofol administration.After administration finishes, collect blood from ventral aorta, measure insulin value in blood glucose value and the blood then according to test example 1.
Measure insulin value in the blood with ELISA method (making) by Mevcodia Co..
Test the Fig. 2 that the results are shown in of example 2.As a result, for the amino acid solution administration group of reference example 4 to 6, (A) observe blood glucose value and be starkly lower than normal saline administration (matched group), level is similar to the administration group (reference example 2) of the amino acid solution that comprises essential and accurate essential amino acids separately.By contrast, the amino acid solution administration group (reference example 3) that does not comprise BCAA demonstrates the hyperglycemia value that is similar to matched group.This result shows that BCAA effectively suppresses blood glucose value and rises.
In addition, for reference example 2 administration groups, (B) observe insulin level rising, blood glucose value minimizing, for reference example 4 to 6 administration groups, wherein demonstrate blood glucose value similarly and reduce, the insulin level increase a bit.By contrast, for reference example 3 administration groups, insulin level demonstrates and is similar to the low-level of reference example 4 to 6 administration groups.
Test example 3
BCAA (3 kinds of mixture, Leu+Ile+Val) the affirmation test that blood glucose value is risen and suppresses effect
Result according to test example 2 obtains carries out validation test to the inhibition effect that the blood glucose value that is brought by BCAA rises.
Test the Fig. 3 that the results are shown in of example 3.Comprise the group of the amino acid solution (preparation example 1) of 3 seed amino acid Leu, Ile and Val for administration, compare with matched group and suppress blood glucose value significantly.According to this result as can be known, proved that the blood glucose value of BCAA administration under effectively suppressing to anaesthetize rises.
Test example 4
Has the evaluation that suppresses the kind of the BCAA of ascending effect on the blood glucose value
In addition, the aminoacid among the BCAA with blood glucose value rising inhibition effect is studied.
Be similar to test example 1 pretreatment rat, except catheter remains on right outside tail vein.Replace used propofol in the previous test, the administration pentobarbital sodium (30 mg/kg, i.v., Somnopentyl) after, similarly with 25 ml/kg/hour constant rate of speed through intravenous route successive administration pentobarbital sodium 3 hours.With 14 ml/kg/hour speed intravenous administration preparation example 2 to 4 each amino acidic aqueous solution (each administration group n=5) or normal saline (matched group n=5).After administration finishes, collect blood, and measure blood glucose value from ventral aorta.
Test the Fig. 4 that the results are shown in of example 4.For each independent Leu or independent Ile amino acid solution (preparation example 2 or 3) group or Leu and Ile (preparation example 4) mixture, blood glucose value is starkly lower than normal saline administration group (matched group), and this is on close level and equals the group of 3 kinds of BCAA in the reception test example 3.The mixture administration of the Leu that this presentation of results anesthesia is independent down or independent Ile or Leu and Ile also obtains significant blood glucose value rising and suppresses effect.In addition, because pentobarbital sodium is used as the anesthesia medicament in this test example 4, illustrate that the blood glucose value rising that obtains BCAA under the occasion of using any anesthetics significantly suppresses effect.
Test example 5
Under the occasion of parallel administration liquid glucose, (3 kinds mixture, blood glucose value Leu+Ile+Val) rise and suppress effect test BCAA
Make blood glucose value rising model to live body and in above-mentioned model, check the effect of parallel administration BCAA by the intravenous administration glucose.
The intravenous administration propofol is to carrying out pretreated rat to be similar to test example 1, according to the administration 3 hours continuously of test example 1.With 14 ml/kg/hour speed intravenous administration ratio be that 1: 9 50wt% glucose and the mixed solution of 3 kinds of BCAA (5wt% glucose+2.7wt%BCAA administration group n=6) or individually dosed 5wt% D/W (matched group n=6) are given each above-mentioned rat.Collected (100 μ L) blood via being used for the amino acid solution catheter respectively in 30 minutes, 90 minutes and 180 minutes before the beginning administration, after the beginning administration.Then, measure blood glucose value according to test example 1.
Test the Fig. 5 that the results are shown in of example 5.In two groups, to compare before with the beginning administration, 30 minutes blood glucose values obviously increase after the beginning administration, and the level between two groups does not have difference.Yet after that, in the matched group of administration 5% D/W, blood glucose value continues to remain on high level (about 280 milligrams/deciliter).By contrast, in the parallel administration group of the mixed solution of administration 5% D/W and 3 kinds of BCAA, 90 minutes blood glucose values reduce (about 210 milligrams/deciliter) after the administration, and it compares the obviously low level that fades to matched group afterwards.This presentation of results, in perioperative owing to replenish glucose in case the blood glucose value that rises by concentration with administration after the BCAA that increases of the increase of time be controlled in the suitable blood glucose value scope, obtained blood glucose value and risen and suppress effect.
Test example 6
Branched-chain amino acid is to because the effect of the blood glucose value rising model that causes of glucose
Produce blood glucose value rising model by the intravenous administration glucose to live body, and check effect by parallel administration leucine in above-mentioned model, isoleucine and valine.
With the mode pretreatment rat of similar test example 4,, keep rat narcotism 3 hours by mode intravenous successive administration pentobarbital with similar test example 4.With 14 ml/kg/hour speed intravenous administration ratio be 1: 9 (each aminoacid of 5wt% glucose-1.8wt%; The mixed solution of the aqueous solution of 50wt% glucose n=5) and preparation example 2,3 or 5, or 5wt% D/W (n=5) is given each above-mentioned rat, parallel administration pentobarbital.Collected (100 μ L) blood via being used for the amino acid solution catheter respectively in 30 minutes, 90 minutes and 180 minutes before the beginning administration, after the beginning administration.Then, measure insulin value in blood glucose value and the blood according to test example 1.
Test the Fig. 6 that the results are shown in of example 6.Beginning to test the blood glucose value of all organizing in back 30 minutes approximately is 300 milligrams/deciliter.The blood glucose value of glucose administration group increases continuously in the mensuration process.The blood glucose value of 30 minutes parallel leucine administration groups reaches maximum after on-test, and level reduces afterwards, compares the obvious step-down of its level with 90 and 180 minutes glucose administration groups after on-test.The blood glucose value of 30 minutes parallel isoleucine administration groups also reaches peak value after on-test, does not see blood glucose value and raises continuously, and begins to test the back 180 minutes glucose administration group levels of comparing and has notable difference.
The insulin value is shown in table 3 in the blood of parallel administration leucine (glucose+leucine) group in the test example 6.
Table 3
| Insulin value (ng/mL) in the |
|||||
| 0 |
30 |
90 |
180 minutes | ||
| Anesthesia | Glucose+leucine | 137±72 | 1717±319 | 3826±807 | 5731±2471 |
| Non-narcotic | Glucose+leucine | 32±26 | 1020±229 | 386±111 | 353±100 |
Each value is represented with mean+/-standard error.
Observe and keeping under the narcotism, the insulin value increases in time in the blood of parallel administration leucine group under anesthesia, compares with non-narcotic down parallel administration leucine group, and the insulin value increased by 1.7 times at 30 minutes in the blood, increased by 9.9 times at 90 minutes, increased by 16.2 times at 180 minutes.
This presentation of results when the administration glucose, observe the branched-chain amino acid administration and blood glucose value is risen have the inhibition effect, compare with non-narcotic state down and strengthened the secretion of insulin promotion.
Test example 7
Oral leucine is to the effect-narcotism of blood glucose value reduction and the comparison-test method of non-narcotization
Non-narcotic group: under the overnight fasted state, rat is divided into groups, and collect blood (Pre value) from tail vein according to body weight.Soon afterwards, oral 10 ml/kg distilled water are given matched group, and 0.3 gram/10 ml/kg leucine suspensions are to the sample liquid group.Behind administration distilled water and sample solution, collected blood (90 minutes values) from the tail vein in 90 minutes.
Anesthesia group: under the overnight fasted condition, rat is divided into groups, and collect blood (Pre value) from the tail vein according to body weight.After collecting blood, oral 10 ml/kg distilled water are given matched group, and 0.3 gram/10 ml/kg leucine suspensions are to the sample liquid group.Kept the Saflow remaining needle to be retained in the tail vein in 30 minutes after the administration sample liquid.Afterwards, by quick intravenous administration 30 mg/kg pentobarbital sodium induced anesthesias., by extension the gastight syringe in microsyringe pump placed with remaining needle be connected, by continuous intravenous administration 30 mg/kg/hour maintenance anesthesia thereafter.From with introduce the anesthesia back keep somewhere needle keep 60 minutes lateral tail vein is collected blood (90 minutes values).
In addition, in measuring with pipe, hematocrit collects blood.Behind the centrifugal collection blood, reclaim the blood plasma part and measure blood glucose value according to test example 1.
Calculate the change value of blood glucose value by the Pre value that deducts each Mus blood plasma from 90 minutes values of each Mus blood plasma.
Test the Fig. 7 that the results are shown in of example 7.Compare before the administration with beginning, non-narcotic and anaesthetize matched group between two groups and after administration, do not observe blood glucose in 30 minutes and obviously rise.With respect to non-narcotic and anaesthetize sample liquid group between two groups, in two groups, all to observe blood glucose value and reduce, the reduction degree of blood glucose value is non-narcotic group 2.7 times in the anesthesia group.Under anesthesia, promptly in perioperative, having shown that branched-chain amino acid is compared with non-narcotization more can the blood sugar lowering value.
Test example 8
The comparison of blood glucose value rising damping effect of oral isoleucine during the anti-sugar-non-narcotic and anesthesia-
Test method
Non-narcotic group: according to body weight rat is divided into groups under the condition whole night in fasting, and collect blood (Pre value) from the tail vein.To matched group and oral respectively 0.5 gram of sample liquid group/10 ml/kg OTSUKA distilled water (waters for injection; By OTSUKA PHAMACEUTICALFACTORY, INC. produces) and the 0.5 isoleucine aqueous solution that restrains/10 ml/kg.Oral 50%OTSUKA liquid glucose (glucose injection (/ 200 milliliters of glucose 100 grams); By OTSUKAPHAMACEUTICAL FACTORY, INC. produces; Only be called liquid glucose hereinafter), make after the sample solution administration 30 minutes be 3 gram glucose/kilograms.Blood is collected from the tail vein in 30 minutes, 60 minutes, 90 minutes and 120 minutes after the beginning administration liquid glucose, and the measuring blood value.Each blood glucose value is considered to 30 minutes values, 60 minutes values, 90 minutes values and 120 minutes values respectively in non-narcotic group.
Anesthesia group: according to body weight rat is divided into groups under the condition whole night in fasting, and collect blood (Pre value) from the tail vein.Isoleucine aqueous solution to matched group and oral respectively 0.5 gram/10 ml/kg OTSUKA distilled water of isoleucine administration group and 0.5 gram/10 ml/kg.Oral 50%OTSUKA liquid glucose, make after the sample solution administration 30 minutes be 3 gram glucose/kilograms.After the administration liquid glucose 10 minutes from abdominal cavity intraperitoneal administration 0.5 gram/1 ml/kg pentobarbital sodium to the anesthesia group.Measured the blood glucose value that picks up from tail venous blood after the beginning administration liquid glucose in 30 minutes, 60 minutes, 90 minutes and 120 minutes.
In addition, in measuring with pipe, hematocrit collects blood.Centrifugal collection blood is to reclaim blood plasma.Blood plasma after the classification is used to measure blood glucose value.By under 0 minute value (it is the Pre value), 30 minutes, 60 minutes values, 90 minutes values and 120 minutes values 5 to the time (minute) and blood glucose value (milligram/decilitre) curvilinear integral obtained the blood glucose value area under curve (0-120 minute; Be abbreviated as AUC hereinafter).
Test the Fig. 8 that the results are shown in of example 8.About matched group, the AUC of anesthesia group compares obvious increase with non-narcotic group.About isoleucine administration group, compare all with matched group with the AUC of anesthesia group for non-narcotic group and reduce, reduce obviously in the anesthesia group.The blood glucose value that this presentation of results is caused by anti-sugar rises and obviously increases, because the obvious interaction between anesthetics and the isoleucine, oral isoleucine obviously strengthens the damping effect that blood glucose value rises.
Industrial applicibility
The blood glucose value rising of blood glucose value rising inhibitor of the present invention by suppressing patient's administration to be caused by operation and anesthesia. In addition, by making the patient under anesthesia, can strengthen damping effect. About above-mentioned inhibitor, its constituent is branched-chain amino acid, and this inhibitor does not cause the risk of hypoglycemia, and this risk is that the insulin regular medication that is used for the control blood glucose value in the perioperative is worried. In addition, when operation, replenish easily sugar to the patient who suffers abnormal carbohydrate metabolism, and this inhibitor is safe to the live body that comprises the people.
Claims (13)
1. inhibitor for perioperative blood sugar elevation is characterized by and comprises branched-chain amino acid, can be transformed into the chemical compound of branched-chain amino acid or shift amino chemical compound from branched-chain amino acid in the body.
2. the blood glucose value rising inhibitor of claim 1, wherein branched-chain amino acid is leucine and/or isoleucine.
3. claim 1 or 2 blood glucose value rising inhibitor, the chemical compound that is transformed into branched-chain amino acid in wherein can body is salt, ester or the amide of branched-chain amino acid, or comprises the oligopeptide of branched-chain amino acid.
4. the blood glucose value rising inhibitor of claim 1 is α-Tong Yijisuan or α-ketone-Beta-methyl valeric acid from the amino chemical compound of branched-chain amino acid transfer wherein.
5. the blood glucose value rising inhibitor of any one in the claim 1 to 4, it comprises, and 0.25 to 2.5 Grams Per Minute rises leucine and/or 0.25 to 3.5 Grams Per Minute rises isoleucine.
6. the blood glucose value rising inhibitor of any one in the claim 1 to 4, it comprises, and 1 to 10 Grams Per Minute rises glucose and 0.25 to 2.5 Grams Per Minute rises leucine and/or 0.25 to 3.5 Grams Per Minute rises isoleucine.
7. the blood glucose value rising inhibitor of any one in the claim 1 to 6, wherein blood glucose value rises and is caused by anesthetics.
8. the blood glucose value rising inhibitor of any one in the claim 1 to 6, it is used for the treatment of and/or prevents anesthesia blood glucose value rising down.
9. the blood glucose value rising inhibitor of any one in the claim 1 to 6, it is used for and anesthetics and using.
10. the inhibition method that rises of blood glucose value, it comprises any one blood glucose value rising inhibitor in patient's administration claim 1 to 6 of perioperative.
11. anesthesia, it comprises also uses the blood glucose value rising inhibitor of any one in anesthetics and the claim 1 to 6.
12. branched-chain amino acid, be transformed into the chemical compound of branched-chain amino acid in can body or shift amino chemical compound is used for suppressing the medicine that perioperative patient's blood glucose value rises in preparation application from branched-chain amino acid.
13. branched-chain amino acid, be transformed into the chemical compound of branched-chain amino acid in can body or shift the application of the medicine that blood glucose value that amino chemical compound is used for suppressing to be caused by anesthetics in preparation rises from branched-chain amino acid.
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| US8343531B2 (en) | 2006-04-21 | 2013-01-01 | Meiji Co., Ltd. | Composition containing peptide as active ingredient |
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| JPS61501569A (en) * | 1984-03-01 | 1986-07-31 | ア−ク，バ−ノン | Methods of lowering blood sugar levels in vertebrates and other organisms |
| JPS60255722A (en) * | 1984-05-30 | 1985-12-17 | Otsuka Pharmaceut Factory Inc | Amino acid transfusion for diabetes |
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| US8343531B2 (en) | 2006-04-21 | 2013-01-01 | Meiji Co., Ltd. | Composition containing peptide as active ingredient |
| CN101426513B (en) * | 2006-04-21 | 2013-05-01 | 株式会社明治 | Composition containing peptide as active ingredient |
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