CN100431542C - Application of yohimbine and berberine mixture in medicament preparation - Google Patents
Application of yohimbine and berberine mixture in medicament preparation Download PDFInfo
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- CN100431542C CN100431542C CNB200610123395XA CN200610123395A CN100431542C CN 100431542 C CN100431542 C CN 100431542C CN B200610123395X A CNB200610123395X A CN B200610123395XA CN 200610123395 A CN200610123395 A CN 200610123395A CN 100431542 C CN100431542 C CN 100431542C
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Abstract
The invention relates to a method for using yohimbine and berberine to prepare the drug that treats endotoxin multi-organ disturbance syndrome. The yohimbine and berberine can treat endotoxin multi-organ function reduction, to improve the survival rate of endotoxemia patient. And serious injury, burn and Gram-negative bacterium can cause sausage endotoxemia, and the inventive drug can be used auxiliary drug. The invention has wide application.
Description
Technical field
The present invention relates to Yohimbine and the application of berberine mix preparation in pharmacy.
Background technology
Although antibiotic application and clinical treatment measure have obtained significant progress in 50 years in the past, the mortality rate of sepsis patient is still up to 40%-60%, and 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, and the main component endotoxin of gram-negative bacterial cell wall or lipopolysaccharide (LPS) play an important role in the systemic inflammatory response syndrome (SIRS) that this infection causes.Therefore, seek new medical treatment endotoxin induction multiple organ dysfunction syndrome, the mortality rate that reduces sepsis patient is significant.
Since the eighties, the Molecular Study of endotoxin shock has obtained many new progresses, the particularly further investigation of LPS signal transduction pathway, the discovery of the molecular cloning of proinflammatory cytokine and cell adhesion molecule, Endothelin and mediated by nitric oxide effect, 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, D2E7, platelet activating factor antagonist, Antithrombin III, nitric oxide synthase inhibitors, endothelin antagonist etc.Multiple center clinical study is found, is not also had a kind of preparation can significantly reduce mortality rate but up to now.On the other hand, intestinal endotoxemia is the important paathogenic factor of serious burn, the concurrent multiple organ dysfunction of wound, still lacks the active drug of control intestinal endotoxemia 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.
Summary of the invention
In order to overcome the deficiency that above existing medical skill exists, the invention provides the application in the medicine of preparation control endotoxin induction multiple organ dysfunction syndrome of a kind of Yohimbine (yohimbine) and berberine (berberine) mix preparation, and the medicine of this control endotoxin induction multiple organ dysfunction syndrome further is provided, the mass ratio of Yohimbine and berberine is 1～4: 40～60 in the medicine.
The effective ingredient of the medicine of this control endotoxin induction multiple organ dysfunction syndrome is Yohimbine and berberine, and the mass ratio of Yohimbine and berberine is 1～4: 40～60 in the medicine.
As preferred plan, the mass ratio of described Yohimbine and berberine is 2: 50.
Described medicine can be made into various oral formulations.
Through a large amount of experimental results show that: the present invention finds that the berberine (berberine) and the use in conjunction of Yohimbine (yohimbine) mix preparation can prevent and treat the endotoxin induction multiple organ dysfunction syndrome, obviously improve the survival rate of endotoxemia mice, its effect obviously is better than berberine and uses separately, the novel formulation of control endotoxin induction multiple organ dysfunction is provided, has can be used for the treatment of endotoxemia.Clinically, except that gram-negative bacterial infections can cause the endotoxemia, severe trauma, burn can both cause intestinal endotoxemia, this novel formulation also can be used as ancillary drug, therefore, berberine and Yohimbine mixture are used to prevent and treat the endotoxin induction multiple organ dysfunction and are with a wide range of applications.
Description of drawings
Fig. 1 is the survival rate contrast figure of different tests group in 6 days among the embodiment 1.
Fig. 2 is the survival rate contrast figure of different tests group in 6 days among the embodiment 2.
Fig. 3 respectively organizes the mouse liver histology pictures among the embodiment 4.A: matched group, the B:LPS group, C: berberine and Yohimbine mixture control group, D: berberine and Yohimbine mixture group, LPS or normal saline were injected back 12 hours, got liver tissue slices, H﹠amp; E dyeing.
Fig. 4 respectively organizes the mouse kidney histology pictures among the embodiment 4.A: matched group, the B:LPS group, C: berberine and Yohimbine mixture control group, D: berberine and Yohimbine mixture group, LPS or normal saline were injected back 12 hours, got the renal tissue section, H﹠amp; E dyeing.
Fig. 5 respectively organizes the mouse lung histology pictures among the embodiment 4.A: matched group, the B:LPS group, C: berberine and Yohimbine mixture control group, D: berberine and Yohimbine mixture group, LPS or normal saline were injected back 12 hours, got lung tissue section, H﹠amp; E dyeing.
Fig. 6 respectively organizes the mouse small intestine histology pictures among the embodiment 4.A: matched group, the B:LPS group, C: berberine and Yohimbine mixture control group, D: berberine and Yohimbine mixture group, LPS or normal saline were injected back 12 hours, got small intestine's section, H﹠amp; E dyeing.
The specific embodiment
The present invention is further described below in conjunction with drawings and Examples.
Embodiment 1:
Observe the influence of berberine and Yohimbine use in conjunction to the endotoxemia mouse death rate.
The male BALB/C mice of health (body weight 20-25g) is divided into 6 groups at random: do following processing respectively:
1. matched group (control), represent with filled squares among Fig. 1: 3 days in advance, intraperitoneal injection of saline (0.05ml/10g), water is irritated stomach (0.2ml/10g) after 30 minutes, every day 1 time, irritates behind the stomach intraperitoneal injection of saline in last 1 day 1 hour;
2. LPS group (LPS) is represented with hollow triangle among Fig. 1: shift to an earlier date 3 days, intraperitoneal injection of saline (0.05ml/10g), water filling stomach (0.2ml/10g) after 30 minutes, every day 1 time, irritated behind the stomach lumbar injection endotoxin (LPS in last 1 day 1 hour, 055:B5, Sigma, 20mg/kg);
3. berberine control group [Ber (50mg/kg)+LPS], represent with black triangle among Fig. 1: 3 days in advance, intraperitoneal injection of saline (0.05ml/10g), irritate stomach (0.2ml/10g with berberine after 30 minutes, 50mg/kg), every day 1 time, irritated in last 1 day behind the stomach 1 hour, the lumbar injection endotoxin (LPS, 20mg/kg);
4. 50mg/kg berberine and 2mg/kg Yohimbine use in conjunction control group [Y (2mg/kg)+Ber (50mg/kg)+LPS], represent with open squares among Fig. 1: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 2mg/kg), after 30 minutes with berberine irritate stomach (0.2ml/10g, 50mg/kg), every day 1 time, irritated in last 1 day behind the stomach 1 hour, and the lumbar injection endotoxin (LPS, 20mg/kg);
5. 2mg/kg Yohimbine control group [Y (2mg/kg)+LPS], represent with empty circles among Fig. 1: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 2mg/kg), water is irritated stomach (0.2ml/10g) after 30 minutes, every day 1 time, irritates in last 1 day behind the stomach 1 hour, the lumbar injection endotoxin (LPS, 20mg/kg);
6. 50mg/kg berberine and 2mg/kg Yohimbine matched group [Y (2mg/kg)+Ber (50mg/kg)], not expression among Fig. 1: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 2mg/kg), after 30 minutes with berberine irritate stomach (0.2ml/10g, 50mg/kg), every day 1 time, irritated behind the stomach intraperitoneal injection of saline in last 1 day 1 hour.
In endotoxin injection back different time, observe and respectively organize mortality of mice.
Experimental result:
As shown in Figure 1: lumbar injection LPS group, 6 days mortality of mice were 86% (hollow triangle is represented); The 50mg/kg berberine is irritated stomach can obviously reduce the endotoxemia mortality of mice 3 days (every day 1 time), and berberine control group mortality of mice was 60% (black triangle is represented); 2mg/kg Yohimbine control group LPS attacked back 6 days, and mortality of mice was 65% (hollow small circle is represented); It only was 25% (open squares is represented) that 50mg/kg berberine and 2mg/kg Yohimbine use in conjunction control group LPS attack back 6 days mortality of mice; Do not cause dead mouse with 50mg/kg berberine and 2mg/kg Yohimbine merely.Show that 50mg/kg berberine and 2mg/kg Yohimbine use in conjunction can obviously improve the survival rate of endotoxemia mice, its effect obviously is better than berberine or Yohimbine acts on separately.(Fig. 2 together for n=20-21.*P among Fig. 1＜0.05vs LPS group, #P＜0.05vs berberine control group or 2mg/kg Yohimbine control group)
Embodiment 2:
The Yohimbine of various dose and 50mg/kg berberine use in conjunction are to the influence of endotoxemia mouse death rate.
The male BALB/C mice of health (body weight 20-25g) is divided into 5 groups at random: do following processing respectively:
1. matched group (control), represent with open squares among Fig. 2: 3 days in advance, intraperitoneal injection of saline (0.05ml/10g), water is irritated stomach (0.2ml/10g) after 30 minutes, every day 1 time, irritates behind the stomach intraperitoneal injection of saline in last 1 day 1 hour;
2. LPS group (LPS) is represented with hollow triangle among Fig. 2: shift to an earlier date 3 days, intraperitoneal injection of saline (0.05ml/10g), water filling stomach (0.2ml/10g) after 30 minutes, every day 1 time, irritated behind the stomach lumbar injection endotoxin (LPS in last 1 day 1 hour, 055:B5, Sigma, 20mg/kg);
3. 1mg/kg Yohimbine and 50mg/kg berberine use in conjunction control group [Y (1mg/kg)+Ber (50mg/kg)+LPS], represent with hollow small circle among Fig. 2: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 1mg/kg), after 30 minutes with berberine irritate stomach (0.2ml/10g, 50mg/kg), every day 1 time, irritated in last 1 day behind the stomach 1 hour, and the lumbar injection endotoxin (LPS, 20mg/kg);
4. 2mg/kg Yohimbine and 50mg/kg berberine use in conjunction control group [Y (2mg/kg)+Ber (50mg/kg)+LPS], represent with solid small circle among Fig. 2: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 2mg/kg), after 30 minutes with berberine irritate stomach (0.2ml/10g, 50mg/kg), every day 1 time, irritated in last 1 day behind the stomach 1 hour, and the lumbar injection endotoxin (LPS, 20mg/kg);
5. 4mg/kg Yohimbine and 50mg/kg berberine use in conjunction control group [Y (4mg/kg)+Ber (50mg/kg)+LPS], represent with black triangle among Fig. 2: 3 days in advance, lumbar injection Yohimbine (0.05ml/10g, 4mg/kg), after 30 minutes with berberine irritate stomach (0.2ml/10g, 50mg/kg), every day 1 time, irritated in last 1 day behind the stomach 1 hour, and the lumbar injection endotoxin (LPS, 20mg/kg);
In endotoxin injection back different time, observe and respectively organize mortality of mice.
Result of the test:
As shown in Figure 2: the effect of 50mg/kg berberine and 2mg/kg Yohimbine use in conjunction control endotoxemia obviously is better than 50mg/kg berberine and 1mg/kg Yohimbine or 50mg/kg berberine and 4mg/kg Yohimbine use in conjunction, and 50mg/kg berberine and 2mg/kg Yohimbine use in conjunction are the optimal doses of control mice endotoxemia.
Embodiment 3:
2mg/kg Yohimbine and 50mg/kg berberine mix preparation (berberine and Yohimbine mixture) are irritated the influence of stomach to the endotoxemia mouse death rate.
The male BALB/C mice of health (body weight 20-25g) is divided into 4 groups at random: do following processing respectively:
1. matched group (control): water was irritated stomach (0.2ml/10g) 3 days, every day 1 time, irritated behind the stomach intraperitoneal injection of saline in last 1 day 1 hour;
2. LPS group (LPS): water was irritated stomach (0.2ml/10g) 3 days, irritated in last 1 day behind the stomach 1 hour every day 1 time, the lumbar injection endotoxin (LPS, 055:B5, Sigma, 20mg/kg);
3. 3 days control groups of 2mg/kg Yohimbine and 50mg/kg berberine mix preparation [berberine and Yohimbine mixture (3) group]: 2mg/kg Yohimbine and 50mg/kg berberine mix preparation filling stomach, every day 1 time, totally 3 days, irritated behind the stomach lumbar injection LPS (20mg/kg) on the 3rd day 1 hour;
4. 1 day control group of 2mg/kg Yohimbine and 50mg/kg berberine mix preparation [berberine and Yohimbine mixture (1) group]: water was irritated stomach (0.2ml/10g) 2 days, every day 1 time, irritated stomach 1 time with 2mg/kg Yohimbine and 50mg/kg berberine mix preparation on the 3rd day, irritated behind the stomach lumbar injection LPS (20mg/kg) 1 hour;
In endotoxin injection back different time, observe and respectively organize mortality of mice.
Result of the test:
As shown in table 1, on the basis of above-mentioned experiment, the 2mg/kg Yohimbine mixed being made into berberine and Yohimbine mixture with the 50mg/kg berberine, irritated stomach 3 days or 1 day with this mixture, every day 1 time, observe the oral influence of this mix preparation to the endotoxemia mouse death rate.Found that, the LPS group, endotoxin is attacked back 6 days 100% dead mouse; Berberine and Yohimbine mixture are irritated stomach can obviously reduce the endotoxemia mortality of mice in 3 days, and this group mortality of mice only is 20%; Even endotoxin is attacked and was given berberine and Yohimbine mixture in preceding 1 hour and irritate stomach and once also can obviously reduce the endotoxemia mortality of mice.
(Y, 2mg/kg) (Ber, 50mg/kg) mix preparation is irritated the influence of stomach to endotoxemia Balb/C mouse death rate (%) to table 1. Yohimbine with berberine
*P＜0.01 vs Control group,
#P＜0.01 vs LPS group.
Embodiment 4:
Berberine and Yohimbine mixture are irritated the influence of stomach to endotoxemia mice organ-tissue 26S Proteasome Structure and Function.
The male BALB/C mice of health (body weight 20-25g) is divided into 4 groups at random: do following processing respectively:
1. matched group (control): water was irritated stomach (0.2ml/10g) 3 days, every day 1 time, irritated behind the stomach intraperitoneal injection of saline in last 1 day 1 hour;
2. LPS group (LPS): water was irritated stomach (0.2ml/10g) 3 days, irritated in last 1 day behind the stomach 1 hour every day 1 time, the lumbar injection endotoxin (LPS, 055:B5, Sigma, 20mg/kg);
3. berberine and Yohimbine mixture control group: 2mg/kg Yohimbine and 50mg/kg berberine mix preparation are irritated stomach, every day 1 time, totally 3 days, irritate behind the stomach lumbar injection LPS (20mg/kg) on the 3rd day 1 hour;
4. berberine and Yohimbine mixture group: 2mg/kg Yohimbine and 50mg/kg berberine mix preparation are irritated stomach, every day 1 time, totally 3 days, irritate behind the stomach intraperitoneal injection of saline on the 3rd day 1 hour.
Injected back 12 hours in endotoxin, measure and respectively organize Mouse Liver, renal function, and under optical microscope, observe the variation of lung, intestinal, liver, nephridial tissue structure.
Result of the test:
As shown in table 2, LPS attacked back 12 hours, the activity of mice blood urea nitrogen content and blood alanine aminotransferase is apparently higher than matched group, the activity of berberine and Yohimbine mixture control group mice blood urea nitrogen content and blood alanine aminotransferase is starkly lower than the LPS group, give berberine and Yohimbine mixture separately and irritate the stomach group, the activity and the matched group of mice blood urea nitrogen content and blood alanine aminotransferase relatively do not have significant difference.These presentation of results, berberine and Yohimbine mixture are irritated stomach can significantly alleviate liver, the renal dysfunction that endotoxin causes; The berberine and the Yohimbine mixture filling stomach that give this dosage separately can't cause Mouse Liver, renal dysfunction.
Shown in Fig. 3～6, histological examination is found, 12h behind the lps injection, and degeneration swelling, part cell generation apoptosis appear in hepatocyte; Hemorrhage, the renal cells generation water degeneration of matter between kidney; The mice alveolar septum obviously thickens, and a large amount of inflammatory cell infiltrations is arranged, visible lung blood vessel congestion, pneumorrhagia and emphysema; Intestinal villus congestion and edema, necrosis have inflammatory cell infiltration, the visible a large amount of inflammatory cells of enteric cavity.Berberine and Yohimbine mixture are irritated stomach control group, 12h behind the lps injection, and above-mentioned each organ pathological change obviously alleviates.Simple with berberine and Yohimbine mixture filling stomach, do not cause that obvious pathological change takes place for liver, kidney, lung, intestinal.
Table 2. berberine and Yohimbine mixture are irritated the influence of stomach to endotoxemia Mouse Liver, renal function
| Grouping | The example number | Blood urea nitrogen (mmol/L) | Blood alanine aminotransferase (U/L) |
| Matched group LPS group berberine and Yohimbine mixture control group berberine and Yohimbine mixture group | 10 9 9 10 | 3.91±0.92 18.18±2.61* 14.83±1.28 # 4.29±0.80 | 35.9±3.9 199.6±289.8* 80.22±13.0 # 36.0±5.0 |
* P＜0.01 vs matched group,
#P＜0.01 vs LPS group.
Claims (4)
1, Yohimbine and berberine are blended in the application in the medicine for preparing control endotoxin induction multiple organ dysfunction syndrome, and the mass ratio of Yohimbine and berberine is 1～4: 40～60 in the medicine.
2, a kind of medicine of preventing and treating the endotoxin induction multiple organ dysfunction syndrome, it is characterized in that: effective ingredient is Yohimbine and berberine, the mass ratio of Yohimbine and berberine is 1～4: 40～60 in the medicine.
3, medicine according to claim 2 is characterized in that: the mass ratio of Yohimbine and berberine is 2: 50 in the described medicine.
4, according to claim 2 or 3 described medicines, it is characterized in that: described medicine is an oral formulations.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6291483B1 (en) * | 1996-02-14 | 2001-09-18 | National Institute Of Immunology | Methods for prevention and treatment of septic shock |
| CN1757391A (en) * | 2005-03-31 | 2006-04-12 | 暨南大学 | Application of neutral berberine sulfate for preparing medicine to treat and prepvent endotoxic diseases |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6291483B1 (en) * | 1996-02-14 | 2001-09-18 | National Institute Of Immunology | Methods for prevention and treatment of septic shock |
| CN1757391A (en) * | 2005-03-31 | 2006-04-12 | 暨南大学 | Application of neutral berberine sulfate for preparing medicine to treat and prepvent endotoxic diseases |
Non-Patent Citations (4)
| Title |
|---|
| 内毒素性休克的分子机制与中药防治. 王华东，陆大祥，黄启福.中国中西医结合杂志，第24卷第1期. 2004 |
| 内毒素性休克的分子机制与中药防治. 王华东，陆大祥，黄启福.中国中西医结合杂志，第24卷第1期. 2004 * |
| 复方中药对内毒素引起的小鼠死亡率和多器官损伤的影响. 王华东，陆大祥，王彦平等.暨南大学学报（医学版），第25卷第2期. 2004 |
| 复方中药对内毒素引起的小鼠死亡率和多器官损伤的影响. 王华东，陆大祥，王彦平等.暨南大学学报（医学版），第25卷第2期. 2004 * |
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