CN1279898C - Application of glycine in preparing medicine - Google Patents

Abstract

The present invention relates to an application of glycine in medicine preparation. The glycine in medicine preparation can obviously reduce an enterogenous endotoxin level of plasma. Thus, the secretion of cytokines TNFa and IL-6 is reduced, the activity of plasma transaminase is obviously reduced, hepatic injury is obviously lightened and liver functions are obviously improved. By molecular biology method research at home and abroad, the glycine can obviously regulate down hepatic tissue LBP (lipopolysaccharide binding protein) mRNA, CD14 (endotoxin acceptor) genes and albuminous expression. By experimental confirmation, the glycine is the retarder of a mononuclear macrophage (such as kupffer cells and liver sinusoidal endothelial cells in the liver) film endotoxin acceptor (CD14). Thus, a signal transduction system in cells is blocked, and the biological effect of endotoxin is difficultly exerted. By clinical observation, the glycine can obviously reduce hepatopaths' plasma endotoxin levels; simultaneously, the liver functions are obviously improved. The glycine is an effective drug for patients with various kinds of hepatitis, fatty liver, liver cirrhosis and shocks, and has no any adverse reaction.

Description

The application of glycine in the property endotoxin medicine of preparation reduction blood plasma intestinal source

One, technical field

The present invention relates to the purposes of glycine, relate in particular to the purposes in pharmaceutical field.

Two, background technology

Glycine is a kind of chemical compound that discloses, and this product is propylhomoserin acetic acid, and its structural formula is

Molecular formula is C ₂H ₅NO ₂, white crystalline powder; Odorless, the flavor sweet.Molecular weight is 75.07.In water, dissolve, almost insoluble in ethanol or ether.

This chemical compound is known can to mix amino acid injection (as 11 kinds, 14 kinds or 17 seed amino acid injection) with several amino acids.Be used for perioperatively, wound, burn, fracture and acute hypoproteinemia patient; The histone that causes because of hepatopathy synthetic and utilize disorderly patient; The outer patients that supplement the nutrients of intestinal such as malnutrition patient and infectious disease convalescent period due to the protein uptake deficiency that gastrointestinal function imbalance causes (see: height is washed wind etc. and is write. nutritional drugs. and clinical medicine is practical complete works of. Beijing: Chinese Medicine science and technology publishing house, front page, 1996,722～725).

Three, summary of the invention

Technical problem to be solved by this invention provides the new purposes of glycine, i.e. new application in pharmacy.

Technical scheme: the present invention relates to glycine as the application for preparing in the medicine for the treatment of acute and chronic hepatitis.Relate to glycine as the application in the medicine of preparation treatment alcohol fatty hepatopathy.Relate to glycine and reduce application in the endotoxic medicine of blood plasma intestinal source property that various hepatitis, hepatopathy accompany as preparation treatment.Relate to glycine and prevent hepatitis chronicity, i.e. hepatitis the---application in the medicine of fatty liver---hepatic fibrosis---liver cirrhosis in preparation.Relate to the application in the blood plasma intestinal source property endotoxin medicine that glycine accompanies as the various shock patients of preparation treatment.

1, glycine is to the influence of Rats with Acute Liver Injury intestinal endotoxemia due to the thioacetamide (TAA).Observed glycine (irritating stomach dosage is 500mg/100g/d) to the influence (table 1) of rat plasma transaminase (ALT), endotoxin and TNF alpha levels and made histological observation with conventional pharmacological testing.Find the hepatocyte large tracts of land necrosis on every side of TAA group rat liver central veins of hepatic lobules, and a large amount of cell infiltration are arranged, and near glycine treatment rat central veins of hepatic lobules, a small amount of hepatic necrosis and inflammatory infiltration are only arranged.

Table 1 glycine group and TAA group result are relatively

Group	ALT(μ/L)	Endotoxin (EU/ml)	TNFα(μg/L)
				The glycine group	968.10±226.30	0.36±0.13	2.34±0.34
The TAA group	1318.20±69.70	0.76±0.40	2.82±0.30
				The P value	P＜0.05	P＜0.05	P＜0.05

The above results shows that the property level of endotoxin obviously reduces through glycine control thioacetamide (TAA) Rats with Acute Liver Injury blood plasma intestinal source.

2, glycine is to the influence of intestinal mucosa and intestinal vascular permeability during the rats'liver damage due to the TAA.Having observed through the blue content of glycine control rear intestinal Evans with conventional pharmacological testing is 0.96 ± 0.47, and the TAA group is 2.14 ± 0.64ug/ml, P＜0.05; Intestinal mucosal permeability (6) is 1.23 ± 0.47, and the TAA group is 1.78 ± 0.51, P＜0.05.This presentation of results TAA simultaneously also makes intestinal mucosal barrier impaired at the damage hepatic tissue, causes intestinal mucosal permeability to increase, and the intestinal mucosal permeability that glycine can suppress due to the TAA increases.

In observing glycine control group intestinal tube and blood during histamine content, find to be respectively 4.59 ± 1.47 and 3.0 ± 0.55ug/g, and the TAA group is respectively 9.39 ± 3.38 and 6.95 ± 1.96 (ug/g), learns processing P＜0.05 by statistics.Histamine content suppresses intestinal mucosal permeability to this results suggest glycine in blood and the intestinal tissue by reducing, thereby toxin can not be absorbed into blood within the enteral.

3, glycine is to hepatocyte coup injury effect due to endotoxin and the TAA.Carry out hepatocyte separation and cultivation routinely.Found that: 1. endotoxin (LPS) has the coup injury effect to hepatic parenchymal cells, can make formerly to be commissioned to train foster hepatocyte injury and to spill ALT.Glycine then can alleviate LPS to hepatocellular coup injury effect; 2. TAA has the coup injury effect to hepatic parenchymal cells, can make formerly to be commissioned to train foster hepatocyte injury and to spill ALT, and glycine does not have effect to the coup injury due to the TAA.The above results prompting glycine may combine by direct destruction endotoxin structure or with endotoxin and make the endotoxin inactivation alleviate it to hepatocellular damage.

4, glycine is to the effect of alcoholic liver injury rat intestinal endotoxemia.Irritate stomach with high lipid diet+ethanol and give rat one month, active endotoxin of plasma A LT and TNF alpha levels obviously raise, and hepatic tissue and plasma triglyceride content increase, and prevent and treat all obviously descend (table 2) through glycine

The every index result's comparison of table 2 glycine group and ethanol group blood plasma (x ± s)

Group	ALTu/l	Endotoxin (Eu/ml)	TNFα(ug/L)	Triglyceride (mg%)
					Glycine	101.0±32.1	0.0715±0.027	0.68±0.26	26.7±8.3
High lipid diet+ethanol	144.2±30.3	0.128±0.011	3.14±1.56	62.0±25.3
					The P value	P＜0.05	P＜0.05	P＜0.05	P＜0.05

Above result shows, glycine can significantly alleviate high lipid diet+ethanol and the fatty liver and the intestinal endotoxemia that cause, reduces laboratory animal blood plasma intestinal source property level of endotoxin.

5, the intravenous injection glycine is to the influence of traumatic shock rat intestinal endotoxemia.1/3 comminuted fracture under causing in the femur of left side with the bone forceps folder, and, make arteriotony drop to 40mmHg in the common carotid artery blood-letting, keep 1h, in 20 minutes, feed back the blood that all lose then and make its recovery.Measure plasma A LT, endotoxin, TNF α respectively at 0h, 6h, 12h, 24h blood sampling. begin to increase in the 0h plasma endotoxin behind the shock recovery, 6h peaks, and 12h-24h descends gradually.Each time group plasma A LT, endotoxin and TNF alpha levels through injection glycine (150mg/kg) animal all are starkly lower than matched group.

The above results shows, can strengthen the barrier action of intestinal through the intravenous injection glycine, thereby suppresses intestinal mucosa to endotoxic absorption, causes blood plasma intestinal source property level of endotoxin to descend.Hepatocyte injury is obviously alleviated, and this is significant to rescue shock.

6, glycine is to the effect of patients with chronic viral hepatitis intestinal endotoxemia.Object of study is carried out the contagious department inpatient of No.1 Hospital, Shanxi Medical Univ.Be divided into matched group (24 example), use treatments such as diammonium glycyrrhizinate, door winter potassium amino acid magnesium, glycine treatment group (24 example) adds with glycine on the used medicine of matched group basis treats.4 of oral glycine capsules (including the 0.5g glycine), every day 3 times, totally 20 days.The plasma endotoxin level is measured in blood sampling before and after the treatment.Glycine treatment group patient plasma endotoxin level (table 3) liver function that all obviously descends is obviously improved (table 4)

Table 3 glycine to the influence of chronic hepatitis patient plasma endotoxin level (x ± s, EU/ml)

Group	The example number	Plasma endotoxin level (EU/ml) before the treatment	Treatment back blood plasma level of endotoxin (EU/ml)	Level of endotoxin poor (EU/ml) in the blood before and after the treatment	t	P
							The glycine group	24	0.158±0.090	0.109±0.034	0.049±0.086	2.79	＜0.02
Matched group	24	0.158±0.053	0.151±0.052	0.007±0.038	0.902	＞0.20
							Treatment group and matched group difference are relatively					2.181	＜0.05

The treatment of table 4 glycine is to the influence of patient's liver function

		ALT(u/L)	AST(u/L)	TB(umol/L)	PA(mg/L)
						The treatment group	Before the treatment	268.08±242.53	217.21±217.17	107.36±139.49	145.42±75.70
After the treatment	68.04±43.85	80.33±74.13	61.71±97.15	219.71±88.74
					Difference		200.04±227.96	137.67±218.53	46.65±88.78	74.29±77.26
The t value	4.29	3.09	2.52	4.71
					The P value		＜0.001	＜0.001	＜0.02	＜0.001
Matched group	Before the treatment	246.54±229.01	162.42±173.01	85.03±127.05							159.38±75.52
					After the treatment	63.71±40.38	130.37±147.20	80.99±135.03	186.67±88.46
	Difference	182.83±293.69	31.88±109.06	4.03±33.98						27.29±56.19
					The t value	3.05	1.43	0.58	2.38
	The P value	P＜0.01	P＞0.10	＞0.05						＜0.05
					Treatment group and matched group difference are relatively		P＜0.05	P＜0.05	P＝0.05		＜0.05

Can find out from table 3, compare the plasma endotoxin level after glycine is treated and before the treatment and obviously descend (P＜0.02), and matched group almost not seen difference (P＞0.20).Difference is relatively learned by statistics and is handled P＜0.05 before and after difference before and after the treatment of treatment group and the treatment of control group.This shows that glycine has the effect of obvious reduction patient plasma endotoxin level.

Table 4 shows that prealbumin (PA) then obviously raise before, total bilirubin level active through glycine treatment blood plasma transaminase (ALT, AST) was starkly lower than treatment.Blood plasma transaminase activity reflection hepatic necrosis degree is so should claim the hepatic injury index.AST raise for a long time the expression pathological changes transfer to chronic, so glycine reduction AST activity is of great value.Liver function mainly contains secretion, synthetic and function of detoxification.The blood plasma bilirubin level reduces the improvement of reflection secretory function; Blood plasma prealbumin (PA) level increases the recovery of reflection hepatocyte synthesis capability, and this is vital for chronic hepatitis.

7, glycine is to the effect of decompensated cirrhosis patient intestinal endotoxemia.Object of study is to carry out in the Digestive System Department inpatient of No.1 Hospital, Shanxi Medical Univ 20 examples (mostly being with upper gastrointestinal hemorrhage hepatic encephalopathy patient).Adopt matching method, be divided into two groups at random, each 10 example.One group is conventional therapy, promptly treats matched group; One group is glycine treatment group, adds on the conventional therapy basis and uses glycine.Average 7 days of treatment time (4-10 day).The result shows that the blood plasma level of endotoxin obviously descends after the glycine treatment, level of endotoxin significant difference before and after the statistical procedures treatment.Matched group does not see that level of endotoxin has notable difference before and after treatment.With the decline of blood plasma intestinal source property level of endotoxin corresponding improvement is arranged also according to clinical observation patient symptom.

From above result, can draw and the invention has the advantages that:

(1) the present invention has excavated new medical application to the known compound glycine, has opened up a new application.

(2) glycine safety non-toxic of the present invention, pharmacological action are strong, are indicating well prospect in medicine.

(3) raw material of substance of the present invention source abundant, inexpensive, do not see toxic and side effects, preparation technology is simple, and can make peroral dosage form (electuary, tablet), injection type etc., and is easy to use.Injection can be done intramuscular injection, can do intravenous drip.

(4) medicine of the present invention can effectively reduce blood plasma intestinal source property level of endotoxin, and these pharmacological actions make great majority be able to effective healing with the various patients of intestinal endotoxemia.

(5) worth proposition is, the current medicine that does not still have desirable reduction blood plasma intestinal source property level of endotoxin both at home and abroad is so indicating that good DEVELOPMENT PROSPECT is arranged.

Four, the specific embodiment:

Embodiment 1.

The application of glycine in reducing blood plasma intestinal source property endotoxin medicine

Clinical research is carried out in the contagious department inpatient of No.1 Hospital, Shanxi Medical Univ.Be divided into matched group, 24 examples are used diammonium glycyrrhizinate, the amino acid based sour potassium magnesium treatment of door winter; Glycine treatment group, 24 examples add on the used medicine of matched group basis with the glycine treatment, and 4 of oral glycine capsules (including the 0.5g glycine), were obeyed 20 days altogether at every day 3 times.Comparison plasma endotoxin level obviously descend (P＜0.02) before glycine treatment back and treatment; And almost not wind variation (P＞0.20) of matched group.

Claims (1)

1. the application of glycine in the property endotoxin medicine of preparation reduction blood plasma intestinal source