CN1757391A - Application of neutral berberine sulfate for preparing medicine to treat and prepvent endotoxic diseases - Google Patents
Application of neutral berberine sulfate for preparing medicine to treat and prepvent endotoxic diseases Download PDFInfo
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- CN1757391A CN1757391A CN 200510033828 CN200510033828A CN1757391A CN 1757391 A CN1757391 A CN 1757391A CN 200510033828 CN200510033828 CN 200510033828 CN 200510033828 A CN200510033828 A CN 200510033828A CN 1757391 A CN1757391 A CN 1757391A
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Abstract
An application of the neutral berberine hydrochloride in preparing the medicines for preventing and treating the endotoxin-type diseases and helping the treatment to heart failure, serious wound, burn and hepatism.
Description
Technical field
The present invention relates to the new purposes of neutral berberine sulfate, especially relate to the purposes that neutral berberine sulfate is used to prepare the medicine of preventing and treating the endotoxin induction disease.
Background technology
Because application, pernicious vehicle accident, burn and the elderly patients' of the generation of bacterial drug resistance, invasive treatment measure increase, pyemic incidence rate is still raising.Although antibiotic application and clinical treatment measure have obtained significant progress in 50 years in the past, the mortality rate of sepsis, patients with septic shock is still up to 40%-60%.(multiple organ dysfunction syndrome MODS) is the sepsis patient main causes of death to the multiple organ dysfunction syndrome of septic shock (intractable hypotension) and generation subsequently.Reducing infectious multiple organ dysfunction syndrome mortality in said patients is a great problem that present medical science faces.Studies show that, the sepsis of 45%-60% is to be caused by gram-negative bacterial infections, endotoxin or lipopolysaccharide (lipopolysaccharide, LPS) (systemic inflammatory response syndrome's systemic inflammatory response syndrome that causes in this infection plays an important role in SIRS).And, the most concurrent intestinal endotoxemia of congestive heart failure, hepatitis and other hepatopathies, endotoxemia plays a significant role in these advancing of disease processes.Therefore, seek new medical treatment endotoxin induction multiple organ dysfunction syndrome, mortality rate, treatment heart failure and the hepatic disease that reduces sepsis patient is significant.
Since the eighties, the Molecular Study that endotoxin shock and MODS take place has obtained many new progresses, the particularly further investigation of LPS signal transduction pathway, the molecular cloning of proinflammatory cytokine and cell adhesion molecule, Endothelin (endothelin, ET) and nitric oxide (nitric oxide, NO) discovery of mediation, caused the generation of the treatment preparation of a series of blocking-up LPS signal paths and the various single media of antagonism, as: anti-LPS antibody, the IL-1 receptor antagonist, anti-tumor necrosis factor (tumornecrosis factor, TNF) antibody, liposome PGE1 (liposomal PGE1), brad ykinin antagonists, platelet activating factor antagonist, Antithrombin III, activated protein c, nitricoxide synthase (nitricoxide synthase, NOS) inhibitor, endothelin antagonist etc.These preparations all demonstrate certain curative effect in animal experiment study, but up to now, multiple center clinical study is found, also do not had a kind of preparation can significantly reduce mortality rate.On the other hand, intestinal endotoxemia is an important risk factor of quickening heart failure and liver disease progression, does not still have preparation can prevent and treat the endotoxin induction cardiac dysfunction at present.Therefore, (multiple organ dysfunction syndrome MODS) is the important topic that medical science faces always how to prevent and treat the endotoxin induction multiple organ dysfunction syndrome.
Generally speaking, some antibiotic can promote endotoxic release when killing gram negative bacteria, and this is the weak point of some antibiotic when the treatment gram-negative bacterial infections often.Berberine is used for many years as the treatment that antibacterials are used for intestinal infection, but can berberine be prevented and treated the endotoxin induction disease and it be unclear that.
Summary of the invention
The object of the present invention is to provide neutral berberine sulfate (neutral sulfate berberine, hemisulfate berberine) to be used to prepare the purposes of the medicine of preventing and treating the endotoxin induction disease.
The present invention is an experimental subject with the male mouse of kunming, observes the influence of neutral berberine sulfate to endotoxemia mice multiple organ dysfunction and mortality rate.The result proves, preceding 5 days of lumbar injection endotoxin is irritated stomach and is given neutral berberine sulfate (every day 1 time, each 25,50 or 100mg/kg) or endotoxin attack back 1h and irritate stomach and give neutral berberine sulfate (50mg/kg) and all can alleviate lung, liver, the kidney organ's function damage that endotoxin causes, reduce endotoxemia mortality of mice (7 days mortality rates of endotoxemia mice are 78%, and 5 days prevention groups of the neutral berberine sulfate of 50mg/kg mouse death rate is 21%, the neutral berberine sulfate treatment of 50mg/kg group mouse death rate is 47%).Utilize isolated rat heart perfusion model, find that neutral berberine sulfate can suppress in the myocardial cell that endotoxin causes the unusual and tumor necrosis factor of calcium homeostasis and generate and increase, alleviate the endotoxin induction cardiac function and damage.Based on above-mentioned result of study, the present invention has confirmed that neutral berberine sulfate has control endotoxin induction multiple organ dysfunction syndrome, control endotoxin induction cardiac dysfunction, reduce the new purposes of the mortality rate of endotoxemia, the treatment preparation that can be used for endotoxemia, and as the adjuvant therapy medicaments of heart failure and hepatic disease.Medicine with neutral berberine sulfate preparation has prevention and therapeutic effect preferably to raising endotoxemia mice survival rate, the damage of control endotoxin induction cardiac function.
The invention provides the pharmaceutical composition that is used to prevent and treat the endotoxin induction disease, comprise the neutral berberine sulfate as active component of dose therapeutically effective, and acceptable carrier on the materia medica.Because it is oral that neutral berberine sulfate is generally used for, therefore described pharmaceutical composition can be mixed with oral formulations.Aforementioned pharmaceutical compositions is used to infect the treatment of the endotoxemia that causes, also can be used for the adjuvant therapy medicaments of severe trauma, burn, hepatic disease.
Beneficial effect of the present invention is: neutral berberine sulfate can be prevented and treated the endotoxin induction multiple organ dysfunction syndrome, particularly prevents and treats the endotoxin induction cardiac dysfunction, improves the long-term survival rate of endotoxemia mice.Neutral berberine sulfate is used to prepare the medicine of control endotoxin induction disease, can be used for the treatment of endotoxemia, and, be with a wide range of applications as the ancillary drug of heart failure, severe trauma, burn, hepatic disease.
Description of drawings
Fig. 1 describes the influence of neutral berberine sulfate to the endotoxemia mouse death rate.
Fig. 2 describes the neutral berberine sulfate of various dose and irritates the stomach influence to the endotoxemia mouse death rate in 5 days.
Fig. 3 describes the Histological change (A, B, C, D:12h, E, F:24h, light microscopic * 250) that respectively organizes mouse lung, wherein, and A figure, E figure: HB+LPS; B figure, F figure: H2O+LPS; C figure: H2O+NS; D figure: HB+NS; A, B, C, D figure: 12 hours; E, F figure: 24 hours.A, E:HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the injury of lung due to the LPS; B, F:H2O+LPS (endotoxemia group), behind the lps injection 12 hours and 24 hours, visible pulmonary interstitial edema, a large amount of inflammatory cell infiltrations and pneumorrhagia; C:H2O+NS (normal control group); D:HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), the no abnormality seen structural change.
Fig. 4 respectively organizes the Histological change (24h, light microscopic * 250) of Mouse Liver.
A:HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the hepatic injury due to the LPS; B:H
2O+LPS (endotoxemia group), behind the lps injection 24 hours, visible hepatocellular degeneration, edema, necrosis and congestion; C:H
2O+NS (normal control group); D:HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), no abnormality seen changes.
Fig. 5 respectively organizes the Histological change (24h, light microscopic * 250) of little Ren Mus
A:HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the injury of kidney due to the LPS; B:H
2O+LPS (endotoxemia group), behind the lps injection 24 hours, visible renal cells edema, degeneration and a matter were hemorrhage; C:H
2O+NS (normal control group); D:HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), no abnormality seen changes.
The specific embodiment
1, experiment material and method
(1) the neutral berberine sulfate of observation different time administration is divided into 7 groups to the influence of endotoxemia mouse death rate at random with healthy male mouse of kunming (body weight 20-25g): do following processing respectively, matched group (H
2O+InjN.S): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, intraperitoneal injection of saline;
Neutral berberine sulfate group [HB (5)+InjN.S]: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, intraperitoneal injection of saline;
LPS organizes (H
2O+LPS): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, O55:B5, Sigma, 28mg/kg);
Gave neutral berberine sulfate control group [HB (5)+LPS] in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave neutral berberine sulfate control group [HB (3)+LPS] in advance in 3 days: shift to an earlier date 3 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave neutral berberine sulfate control group [HB (1)+LPS] in 1 hour in advance: irritate stomach (0.2ml/10g, 50mg/kg irritate stomach 1 time) with neutral berberine sulfate, behind the filling stomach 1 hour, the lumbar injection endotoxin (LPS, 28mg/kg);
Neutral berberine sulfate treatment group [LPS+HB (1)]: (28mg/kg, ip) back 1h irritates stomach and gives neutral berberine sulfate (50mg/kg, 1 time) lumbar injection LPS again.
In endotoxin injection back different time, observe and respectively organize mortality of mice.
(2) observation gave the influence of the neutral berberine sulfate of various dose to the endotoxemia mouse death rate in advance in 5 days
Healthy male mouse of kunming (body weight 20-25g) is divided into 6 groups at random: do following processing respectively,
Matched group (H
2O+NS): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, intraperitoneal injection of saline;
Gave 25mg/kg neutral berberine sulfate control group [HB (25)+LPS] in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 25mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave 50mg/kg neutral berberine sulfate control group [HB (50)+LPS] in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave 100mg/kg neutral berberine sulfate control group [HB (100)+LPS] in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 100mg/kg irritates stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
LPS organizes (LPS): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
In endotoxin injection back different time, observe and respectively organize mortality of mice.
(3) observation gave the influence of the neutral berberine sulfate of 50mg/kg to endotoxemia mice organ-tissue structure in advance in 5 days
Healthy male mouse of kunming (body weight 20-25g) is divided into 4 groups at random: do following processing respectively,
Matched group (H
2O+NS): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, intraperitoneal injection of saline (NS);
LPS organizes (H
2O+LPS): water was irritated stomach (0.2ml/10g irritates stomach every day 1 time) in 5 days in advance, 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave 50mg/kg neutral berberine sulfate control group (HB+LPS) in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, the lumbar injection endotoxin (LPS, 28mg/kg);
Gave 50mg/kg neutral berberine sulfate group (HB+NS) in advance in 5 days: shift to an earlier date 5 days with neutral berberine sulfate and irritate stomach (0.2ml/10g, 50mg/kg irritate stomach every day 1 time), 1h behind the last 1 day filling stomach, intraperitoneal injection of saline (NS);
Injected back 12 hours and 24 hours in endotoxin, observe and respectively organize the structural change of mice organ-tissue
2. experimental result
(1) the neutral berberine sulfate of different time administration to the influence of endotoxemia mouse death rate shown in Fig. 1 and table 1: neutral berberine sulfate can obviously reduce the endotoxemia mortality of mice, it is very obvious that LPS attacks preceding 5 days administering effects, meaningfully, also can reduce the endotoxemia mortality of mice even attack back 1h administration at LPS.
The neutral berberine sulfate (HB) of table 1 different dosing time is to the influence of endotoxemia mouse death rate (%)
| Grouping | The example number | Time behind the lps injection (h) | |||||||||
| ?24 | ?36 | 48 | ?60 | ?72 | ?84 | ?96 | ?108 | ?120 | ?144 | ||
| HB(5)+LPS | ?29 | ?14 * | ?21 * | 21 * | ?21 | ?21 | ?21 | ?21 | ?21 | ?21 | ?21 * |
| HB(3)+LPS | ?29 | ?17 * | ?24 * | 24 * | ?24 | ?24 | ?24 | ?24 | ?24 | ?24 | ?24 * |
| HB(1)+LPS | ?30 | ?30 * | ?47# | 47# | ?47 | ?47 | ?47 | ?47 | ?47 | ?47 | ?47# |
| LPS+HB(1) | ?32 | ?31 * | ?44# | 47# | ?47 | ?47 | ?47 | ?47 | ?47 | ?47 | ?47# |
| H2O+LPS | ?32 | ?66 | ?75 | 78 | ?78 | ?78 | ?78 | ?78 | ?78 | ?78 | ?78 |
| H2O+InjN.S | ?20 | ?0 | ?0 | 0 | ?0 | ?0 | ?0 | ?0 | ?0 | ?0 | ?0 |
| HB(5) +InjN.S | ?20 | ?0 | ?0 | 0 | ?0 | ?0 | ?0 | ?0 | ?0 | ?0 | ?0 |
In the table one,
*P＜0.01, #P＜0.05 vs H2O+LPS group.HB (5)+LPS, HB (3)+LPS, HB (1)+LPS represent to give in 5,3 days or 1 hour in advance neutral berberine sulfate (50mg/kg irritates stomach every day 1 time) respectively, 1h behind the last 1 day filling stomach, lumbar injection LPS (28mg/kg, ip); (28mg/kg, ip) back 1h irritates stomach and gives neutral berberine sulfate (50mg/kg, 1 time) LPS+HB (1) expression lumbar injection LPS again.
Fig. 1 describes the influence of neutral berberine sulfate to the endotoxemia mouse death rate.Among Fig. 1,
*P＜0.01, #P＜0.05 vs H2O (water)+LPS group.
HB (5)+LPS, HB (3)+LPS, HB (1)+LPS represent to give in 5,3,1 days in advance neutral berberine sulfate (50mg/kg irritates stomach every day 1 time) respectively, 1h behind the last 1 day filling stomach, lumbar injection LPS (28mg/kg);
LPS+HB (1) expression lumbar injection LPS (28mg/kg) back 1h irritates stomach again and gives neutral berberine sulfate (50mg/kg, 1 time).
During laboratory observation, all there is not dead mouse with neutral berberine sulfate group and matched group merely.
Fig. 1 shows: neutral berberine sulfate can obviously reduce the endotoxemia mortality of mice, and it is very obvious that LPS attacks preceding 5 days administering effects, meaningfully, also can reduce the endotoxemia mortality of mice even attack back 1h administration at LPS.
(2) gave of the influence of the neutral berberine sulfate of various dose in advance in 5 days to the endotoxemia mouse death rate
Fig. 2 describes the neutral berberine sulfate of various dose and irritates the stomach influence to the endotoxemia mouse death rate in 5 days.HB (25)+LPS, HB (50)+LPS, HB (100)+LPS represent to give respectively in 5 days in advance neutral berberine sulfate (25,50,100mg/kg irritates stomach every day 1 time) respectively, 1h behind the last 1 day filling stomach, lumbar injection LPS (28mg/kg); 5 days in advance waters of LPS group expression are irritated stomach, irritate stomach every day 1 time, 1h behind the last 1 day filling stomach, lumbar injection LPS (28mg/kg).
Fig. 2 shows: the neutral berberine sulfate of 50mg/kg is irritated stomach can reduce the endotoxemia mortality of mice 5 days (every day 1 time) significantly, is optimum effective dose.Matched group does not all have dead mouse during laboratory observation.
(3) gave of the influence of the neutral berberine sulfate of 50mg/kg in advance in 5 days to endotoxemia mice organ-tissue structure
Behind the lps injection 12 hours and 24 hours, visible pulmonary interstitial edema, a large amount of inflammatory cell infiltrations and pneumorrhagia (as shown in Figure 3); Behind the lps injection 24 hours, visible hepatocellular degeneration, edema, necrosis and congestion (Fig. 4); Renal cells edema, degeneration and a matter hemorrhage (Fig. 5).And neutral berberine sulfate can obviously alleviate the organ-tissue structural damage (Fig. 3,4,5) due to the LPS.
Fig. 3 describes Histological change (A, B, C, the D:12h that respectively organizes mouse lung; E, F:24h; Light microscopic * 250), wherein, A figure, E figure: HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the injury of lung due to the LPS; B figure, F figure: H2O+LPS (endotoxemia group), behind the lps injection 12 hours and 24 hours, visible pulmonary interstitial edema, inflammatory cell infiltrations and pneumorrhagia in a large number; C figure: H2O+NS (normal control group); D figure: HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), no abnormality seen structural change.
Fig. 4 respectively organizes the Histological change (24h, light microscopic * 250) of Mouse Liver.
Wherein, A figure: HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the hepatic injury due to the LPS; B figure: H
2O+LPS (endotoxemia group), behind the lps injection 24 hours, visible hepatocellular degeneration, edema, necrosis and congestion; C figure: H
2O+NS (normal control group); D figure: HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), no abnormality seen changes.
Fig. 5 respectively organizes the Histological change (24h, light microscopic * 250) of little Ren Mus.
Wherein, A figure: HB+LPS (neutral sulphuric acid Radix Berberidis Amurensis treatment group), neutral berberine sulfate can obviously alleviate the injury of kidney due to the LPS; B figure: H
2O+LPS (endotoxemia group), behind the lps injection 24 hours, visible renal cells edema, degeneration and a matter were hemorrhage; C figure: H
2O+NS (normal control group); D figure: HB+NS (neutral sulphuric acid Radix Berberidis Amurensis matched group), no abnormality seen changes.
Claims (3)
1, neutral berberine sulfate is used to prepare the purposes of the medicine of preventing and treating the endotoxin induction disease.
2, be used to prevent and treat the pharmaceutical composition of endotoxin induction disease, it is characterized in that: comprise the neutral berberine sulfate as active component of dose therapeutically effective, and acceptable carrier on the materia medica.
3, pharmaceutical composition according to claim 2 is characterized in that: described pharmaceutical composition is mixed with oral formulations.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100431542C (en) * | 2006-11-07 | 2008-11-12 | 暨南大学 | Application of yohimbine and berberine mixture in medicament preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100431542C (en) * | 2006-11-07 | 2008-11-12 | 暨南大学 | Application of yohimbine and berberine mixture in medicament preparation |
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