Tóm tắt Luận án Evaluate the hypoglycemic effect and several hypoglycemic mechanisms of Andiabet tablets in experiment

The mice were randomized into many groups of 10 animals in each.

In all group, mice were given an equal volume (0.2ml/10g) of Andiabet

with increasing doses up to a highest dose of 44.25g/kg mice. The mice

were observed for 4 consecutive hours, the number of mice was died in

the first 72 hours were counted and the whole body condition in 7 days

after treatment were reported. LD50 dose was determined according to

Litchfield - Wilcoxon method

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n) and 0.64 g/kg/day (3 times the expected dose in humans) for 90 consecutive days . Assess general condition and weight change. Evaluate hematopoietic function, liver, kidney function, liver and kidney histopathology of rabbits 2.2.2. Evaluate the hypoglycemic effect and several hypoglycemic mechanisms of Andiabet tablets in experiment. 2.2.2.1. Hypoglycemic effect of Andiabet in normal mice. The mice were randomized into 4 groups of 10 animals in each. - Group 1 (Control): received with distilled water - Group 2 (positive control): received with gliclazid 80 mg/kg. - Group 3 (Andiabet 0,68g/kg): received with Andiabet 0,68 g/kg/day 6 - Group 4 (Andiabet 2g/kg): received with Andiabet 2g/kg/day Mice were given distilled water or reagents continuously for 2 weeks in the mornings. Blood samples were collected at times: start the treatmnet (to); 1 week (t1) and 2 weeks after oral the reagent (t2). 2.2.2.2. Hypoglycemic effect of Andiabet in T2D mice. - Phase 1: High- fat diet combined with low dose STZ-induced diabetic mice model. Mice is divided into 2 groups: Group 1 (n = 10 animals) eating a normal fat diet (NFD). Group 2 (n = 100 animals): eating a high fat diet (HFD). After 8 weeks, diabetes was induced by a single i.p injection of STZ (100mg/kg) for all mice in group 2, and mice in group 1 were injected by solvent of STZ. Blood samples were taken at 3 points: start the study, before injection of STZ and 72 hours after injection of STZ. 72 hours after injection of STZ or solvent, animals which glucose level develop more than 10 mmol/L were selected. - Phase 2: Assess the hypoglycemic effect of Andiabet in type 2 diabetic mice.The animals were randomly assigned to one of six groups of 10 mice each. The first group were regarded as control group, eating a normal fat diet. The type 2 diabetic (T2D) mice divided into 5 groups from second to sixth groups were studied for the hypoglycemic effect of Andiabet. - Group 1 (control): NFD mice received with saline - Group 2 (nontreatment): T2D mice received with distilled water - Group 3 (positive control):T2D mice + gliclazid 80 mg/kg. - Group 4 (Andiabet 0,68 g/kg):T2D mice + Andiabet 0,68g/kg/d. - Group 5 (Andiabet 1 g/kg): T2D mice + Andiabet 1 g/kg/d. - Group 6 (Andiabet 2 g/kg): T2D mice + Andiabet 2 g/kg/d. After being orally administered with the reagent for 2 consecutive weeks, Evaluate: weight of mice after 2, 4, 6 and 8 weeks had a high fat diet. The average blood glucose levels measured at times: t0, t1, t2. Lipid profiles: TC, TG, HDL-C, LDL-C. Observe the histopathology, 7 weight of liver and pancreas. 2.2.2.3. Evaluate inhibitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerance test in normal and diabetic mice. s Evaluate inhibitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerance test in normal mice. The normal animals were classified into 5 groups (10 mice/groups): - Group 1 (Control): received with distilled water - Group 2 (positive control): received with Acarbose 14 mg/kg/d. - Group 3 (positive control): received with Metformin 250mg/kg/d - Group 4 (Andiabet 1g/kg): received with Andiabet 1 g/kg/d. - Group 5 (Andiabet 2g/kg): received with Andiabet 2 g/kg/day Mice were given distilled water or reagents continuously for 2 weeks in the mornings. The 15th day, glucose (2g/kg-oral) was administered to the mice in each group (glucose tolerance test) or sucrose at 4 g/kg was administered to the mice in each group (sucrose tolerance test) or potato starch at 6 g/kg was administered to the mice in each group (starch tolerance test). Blood samples were taken at 30, 60, 120 min after the glucose/sucrose/starch load for the assay of glucose/sucrose/starch. Evaluation: peak blood glucose (PBG) - The maximum blood glucose level of the whole group after loading glucose/sucrose/starch. The area under of curve (AUC) is calculated following formula: AUC = ( !"#!$"% ) x (t30 – t0) + ( !$"#!&"% ) x (t60 - t30) + ( !&"#!'%"% ) x (t120 - t60) In which, C0, C30, C60, C120 are measured blood glucose levels at the times: before use drugs (t0), 30 minutes (t30), 60 minutes (t60) and 120 minutes (t120). s Evaluate inhibitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerance test in T2D diabetic mice. 8 Performed on type 2 diabetes mice, similar to that in normal mice. 2.2.2.4. Antagonism with insulin resistance of Andiabet in type 2 diabetic mice model. The diabetic mice were divided into 4 groups (7 mice/group), given reagents or distilled water for 2 consecutive weeks. - Goup 1 (control): Normal mice received with distilled water - Group 2 (nontreatment):T2D mice received with distilled water - Group 3 (Andiabet 1g/kg): T2D mice + Andiabet 1g/kg/day - Group 4 (Andiabet 2g/kg): T2D mice + Andiabet 2g/kg/day On the 15th day, the technique "Hyperinsulinemic - euglycemic clamp test" was used to assess insulin resistance. A blood sample was collected from the mouse tail, at the time (t0). Insulin was infused continuously and maintained a constant speed at a rate of 4 mU/kg/min, throughout the experiment. Glucose (20%) was infused stimultaneously: the blood glucose concentration measured at the time (t0) was able to determined the rate infusion. Then, the blood samples were measured every 10 minutes, glucose infusion rate (GIR) was adjusted continuously (blood glucose levels were always ~ 7.5 - 8.3 mmol/L). Blood glucose concentration, glucose infusion rate at the “steady state” (from 80 - 120 minutes) were compared vs control group. 2.3. STATISTICS All data were expressed as mean ± SE. Student's t-test and one-way ANOVA was used for statistical analysis. Significantly different when the p < 0.05. Chapter 3: RESULT 3.1. ACUTE TOXICITY AND CHRONIC TOXICITY OF ANDIABET 3.1.1. Acute toxicity test: The mice in all groups were observed within the first 72 hours after taking the Andiabet, we noticed that in the all of doses groups: Mice displayed operation, eating and 9 drinking normally; feces and urine normally; pink lining, silky hairs and mice had good reflexes with the stimulations. In higheast dose group were 44,25 g/kg mice, none of the dead mice were observed within the first 72 hours. Such that, Andiabet has no acute toxicity at a dose of 44.25 g/kg and LD50 dose has not been determined. 3.1.2. Chronic toxicity test Andiabet at 2 dose levels: 0.21g/kg/day and 0.64g/kg/day orally for 90 consecutive days without any changes in hematological and blood biochemical indices and histopathology of liver and rabbit kidney. 3.2. HYPOGLYCEMIC ACTIVITY AND SEVERAL HYPOGLYCEMIC MECHANISMS OF ANDIABET IN EXPERIMENTAL. 3.2.1. Hypoglycemic effect of Andiabet in normal mice. Table 3.1.Blood glucose levels of normal mice after 2 weeks taking Andiabet Groups (n = 10) Blood glucose levels (mmol/l) (X ± SD) To T1 T2 Group 1: control 3,53 ± 0,72 4,99 ± 1,14 4,97 ± 0,92 Group 2: Gliclazid 80mg/kg 3,55 ± 0,51 4,12 ± 0,58* 3,95 ± 0,72** % reduced vs control ↓ 17,44 % ↓ 20,52 % Group 3: Andiabet 0,68g/kg 3,34 ± 0,21 5,03 ± 0,25 4,26 ± 0,44* % reduced vs control - ↓ 14,3 % Group 4: Andiabet 2 g/kg 3,40 ± 0,60 4,92 ± 0,79 4,12 ± 0,61* % reduced vs control ↓ 1,4 % ↓ 17,1 % p vs control: *: p < 0,05; **: p < 0,01. Comment: At the time T0, blood glucose levels in all mice groups was similar (p > 0.05). The positive control group was used gliclazide 80 mg/kg had a significant hypoglycemic effect 17.44% and 20.52%, respectively after 1 week (T1) and 2 week (T2), compared to the control 10 group (p<0,01). Andiabet at the dose 0.68 g/kg mice and 2g/kg mice after 2 week (T2) displayed significantly reducing blood glucose levels (by 14.3 % and 17.1 %, respectively) compared to the control (p < 0.05). 3.2.2. Hypoglycemic effect of Andiabet in T2D mice. 3.2.2.1. Changes in mouse’s weight after a high-fat diet Table 3.2. Changes in mouse’s weight at diferent times Times Weight (g) (X ± SD) p vs group 1 Groups NFD (n = 10) Groups HFD (n = 100) Start 25,45 ± 0,98 26,09 ± 1,30 > 0,05 After 4 weeks 29,60 ± 1,15*** 37,17 ± 1,89*** < 0,001 % increased ↑ 16,3 ↑ 42,5 After 6 weeks 33,60 ± 1,43*** 42,89 ± 1,93*** < 0,001 % increased ↑ 32,0 ↑ 64,4 After 8 weeks 35,90 ± 1,45*** 48,47 ± 2,27*** < 0,001 % increased ↑ 41,1 ↑ 85,8 ***: p < 0,001: vs before study time. Comment: The weight of mice in the HFD group increased respectively by 42.5 %; 64.4 % and 85.8 % after 4, 6 and 8 weeks, compared to the control group (p <0.001). 3.2.2.2. Changes blood glucose levels in diabetic mice Table 3.3. Changes blood glucose levels after HFD 8 weeks Times Glucose levels (mmol/l) (X ± SD) Groups NFD (n=10) Groups HFD (n=100) p vs group 1 Start 5,37 ± 0,56 5,56 ± 1,02 > 0,05 After 8 weeks 5,77 ± 0,67 6,32 ± 0,93 > 0,05 % change ↑ 7,4 ↑ 13,7 72h after injection of STZ 5,98 ± 0,92 17,09 ± 6,33*** < 0,001 % change ↑ 11,4 ↑ 207,4 11 ***: p < 0,001: p vs before study; (∆∆∆): p < 0,001: p vs after 8 weeks Comment: 72h after injection of STZ, blood glucose levels in HFD group increased strongly (207,4%) compared with control group (increased 11,4%) (p < 0,001) and before injection of STZ (p < 0,001). 3.2.2.3. Hypoglycemic effect of Andiabet in T2D mice. Table 3.4. Effect of Andiabet on blood glucose levels of T2D diabetic mice Group (n=10) Blood glucose levels (mmol/l) (X ± SD) To T1 T2 G1: control 5,54 ± 0,86 5,51 ± 0,81 5,46 ± 0,46 G2: nontreatment 17,88 ± 6,23 18,38 ± 4,46 18,38 ± 4,39 G3: Gliclazid 80mg/kg 17,36 ± 5,26 14,18 ± 5,23* 13,83 ±3,45** % reduced vs nontreatmnet ↓ 22,9 % ↓ 24,8 % G4: Andiabet 0,68g/kg 17,89 ± 6,3 13,99 ± 3,61* 16,71 ± 4,46 % reduced vs nontreatment ↓ 23,9 % ↓ 9,1% G5: Andiabet 1g/kg 19,23 ± 6,3 17,53 ± 3,61 11,83 ± 3,91** % reduced vs nontreatment ↓ 4,6 % ↓ 35,6 % G6: Andiabet 2g/kg 18,04 ± 5,27 11,69 ± 3,78** 14,84 ± 5,01* % reduced vs nontreatment ↓ 36,4 % ↓ 19,3 % p vs nontreatment: *: p < 0,05; **: p < 0,01; ***: p < 0,001. Comment: At 1week oral administration, Andiabet at doses (0.68g/kg and 2g/kg) markedly reduced blood glucose levels (by 23,9% and 36,4%, respectively) compared to the nontreatment (p <0.05 and p <0.01). Andiabet at doses (1g/kg) had a significant hypoglycemic effect up to 35.6% after 2 weeks oral administration (p <0.01). 3.2.2.4. Hypolipidemic effect of Andiabet in high food diet with STZ- induced type 2 diabetic mice. Table 3.5. Effect of Andiabet on lipid profiles of T2D mice 12 Groups (n=10) Lipid indexes mmol/l (X ± SD) TC TG HDL-C LDL-C G1: control 2,75 ± 0,55 0,50 ± 0,17 1,40 ± 0,11 1,12 ± 0,40 G2: Nontreatment 3,85 ± 0,56∆∆∆ 0,89 ± 0,28 ∆∆∆ 1,79 ± 0,22 ∆∆∆ 1,64 ± 0,47 ∆∆∆ G3: Gliclazid 80mg/kg 3,86 ± 0,52 0,81 ± 0,18 1,89 ± 0,31 1,60 ± 0,63 G4: Andiabet 0,68g/kg 3,70 ± 0,61 0,81 ± 0,22 2,29 ± 0,21*** 1,05 ± 0,66*** G5: Andiabet 1g/kg 3,63 ± 0,38 0,9 ± 0,13 2,07 ± 0,16** 1,15 ± 0,32** Group 6: Andiabet 2g/kg 3,23 ± 0,50** 0,62 ± 0,16** 2,15 ± 0,21*** 0,81 ± 0,43*** p vs control: ∆∆∆: p <0,001; p vs nontreatment: *: p < 0,05; **: p < 0,01; ***: p < 0,001. TC: Total Cholesterol, TG: triglyceride Comment: All of Andiabet groups displayed significantly reducing LDL-C levels and increasing HDL-C levels, compared to the nontreament (p <0.01 and p <0.001), after orally reagent for 2 consecutive weeks. In addtion to, Andiabet at 2g/kg/day dose orally for 2 weeks reduced significantly total cholesterol and triglycerid, compared to the nontreatment group (p <0.01). 3.2.2.5. Effect of Andiabet on liver’s weight and pancreas’s weight of type 2 diabetic mice Comment: Andiabet at all of doses had no changed liver’s weigh in T2D mice (p > 0,05). The weight of pancreas in all group was similar to that of control, the difference was not statistically significant (p> 0.05). 3.2.2.6. Histopathological changes. v Observe the liver in general: Group 1 was dark pink, uniform in color. The tissue density was firm and uniform. Liver of mice were 13 injected STZ had a silver color, were less uniform, the tissue density were somewhat loosecompared to the control group. v Observe the microscopic liver: In nontreatment group, 100% of samples had severe fat degeneration. Andiabet at all of doses improved this situation: 2/3 of samples had mild fat degeneration and 1/3 of the sample had medium fat degeneration. v Observe the pancreas in general: Pancreas in all group were pale pink, the tissue’s density were tough and firm and didn’t have congestion or injury. v Observe the microscopic pancreas: In nontreatment group, 100% of samples were severe degenerated. Andiabet at all of doses improved this situation: the degeneration of pancreastic islet cells reduced, pancreastic islets decreased slightly in size, and the density of islets was smaller than normal. 3.2.3. Effect inhbitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerance test in normal and diabetic mice. 3.2.3.1. Effect inhibitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerance test in normal mice. v Oral glucose tolerance test Table 3.6. Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally glucose administration in normal mice Groups (n =10) PBG (mmol/L) % ¯ PBG AUC (mmol/L) % ¯ AUC Normal mice Gr1: control 9,28 ± 2,15 13,58 ± 3,05 Gr 2: acarbose 14mg/kg 7,86 ± 0,99 15,3 11,33 ± 1,58 16,57 Gr metformin 250mg/kg 7,37 ± 1,13* 20,58 11,95 ± 1,23 12 14 Gr 4 Andiabet 1g/kg 9,95 ± 1,87 - 13,88 ± 2,55 - Gr 5 Andiabet 2g/kg 8,22 ± 1,90 11,4 11,65 ± 1,99 14,2 p vs control: * p<0,05; ** p<0,01: *** p<0,001 Comment: Metformin at 250 mg/kg dose lowered PBG by 20.58% and decreased significantly AUC compared to control (p <0.05). But acarbose at 14 mg/kg dose and both groups Andiabet at 1g/kg and 2g/kg dose did not changed PBG and AUC, compared to the control (p> 0.05). v Oral sucrose tolerance test Table 3.7. Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally sucrose administration in normal mice Groups (n =10) PBG (mmol/L) % ¯ PBG AUC (mmol/L) % ¯ AUC Normal Mice Gr 1: control 10,93 ± 1,29 16,82 ± 1,98 Gr 2: acarbose 14mg/kg 9,33 ± 1,52* 16,47 15,07 ± 1,15* 10,40 Gr 3 metformin 250mg/kg 8,39 ± 2,43* 23,24 14,37 ± 1,69* 14,57 Gr 4: Andiabet 1g/kg 10,90 ± 1,44 0,27 16,55 ± 2,09 1,60 Gr 5: Andiabet 2g/kg 10,15 ± 1,29 2,9 15,05 ± 1,49* 10,52 p vs group control: * p < 0,05; ** p < 0,01: *** p < 0,001 Comment: acarbose at 14 mg/kg dose and metformin at 250 mg/kg dose both decreased significantly PBG and AUC, compared to control (p <0.05). Andiabet at the doses 1g/kg and 2g/kg did not lowered PBG and only Andiabet at the dose 2g/kg lowered AUC significantly, compared to control (p <0.05). v Oral starch tolerance test Table 3.8 Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally starch administration in normal mice Groups PBG % ¯ AUC % ¯ 15 (n =10) (mmol/L) PBG (mmol/L) AUC Normal mice Gr control 8,93 ± 1,52 13,99 ± 1,47 Gr acarbose 14mg/kg 7,51 ± 0,98* 15,9 13,32 ± 0,83 4,79 Gr metformin 250mg/kg 7,24 ± 0.37* 18,92 12,71 ± 1,39 9,15 Gr Andiabet 1g/kg 7,85 ± 1,12 12,09 12,82 ± 1,61 8,36 Gr Andiabet 2g/kg 7,29 ± 1,27* 18,36 12,88 ± 1,62 7,93 p vs group control: * p < 0,05; ** p < 0,01: *** p < 0,001 Comment: All 3 groups of acarbose, metformin and Andiabet 2g/kg inhibited PBG compared to the control group (p <0.05). All 4 batches of Acarbose, Metformin, Andiabet 1g and 2g / kg did not significantly reduce AUC compared to the control group. 3.2.3.2. Effect inhibitivity on hyperglycemic postprandial blood glucose of Andiabet in glucose/sucrose/starch tolerant test in diabetic mice. v Oral glucose tolerance test Table 3.9. Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally glucose administration in T2D mice Groups (n =10) PBG (mmol/L) % ¯ PBG AUC (mmol/L) % ¯ AUC STZ-induced diabetic mice NT diabetic group 32,33 ± 1.01 58,71 ± 7,61 Gr acar 14 mg/kg 29,41 ± 5,50 9,03 50,06 ± 10,84 14,73 Gr met 250 mg/kg 18,43 ± 5,21** 42,99 21,69 ± 6,31*** 63,05 Gr Andiabet 1 g/kg 26,10 ± 4,15* 19,27 39,96 ± 9,87* 31,94 Gr Andiabet 2 g/kg 24.93 ± 4,05* 22,89 39,71 ± 7,56** 32,36 p vs nontreatment (NT) group: * p<0,05; ** p<0,01: *** p<0,001 Comment: Andiabet at 2 doses 1g/kg and 2g/kg had a significant reduction in PBG compared to the nontreatment group, the reduction 16 of PBG was 19.27% and 22.89%, respectively (p <0.05). At the same time, 2 groups of Andiabet also lowered AUC by 31.94% and 32.36% (p < 0.01 respectively), which is lowerd better than that of the positive control. The reduction of metformin group’s PBG was 43% (p <0.01) and AUC was 63% (p <0.001). And acarbose at 14 mg/kg dose did not reduced PBG and AUC (p > 0.05). v Oral sucrose tolerance test Table 3.10. Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally sucrose administration in T2D mice Groups (n =10) PBG (mmol/L) % ¯ PBG AUC (mmol/L) % ¯ AUC STZ-induced diabetic mice NT diabetic group 32,89 ± 1,10 66,22 ± 7,89 Gr acar 14mg/kg 23,14 ± 6,57* 29,64 34,88 ± 10,45*** 47,32 Gr met 250mg/kg 20.15 ± 9.54* 38,74 32,96 ± 15,73*** 50,22 Gr Andiabet 1g/kg 25,87 ± 7,71 21,34 40,11 ± 14,74** 39,43 Gr Andiabet 2g/kg 25,33 ± 4,97* 22,98 42,12 ± 8,92** 36,39 p vs nontreatment (NT) group: * p < 0,05; ** p < 0,01: *** p < 0,001 Comment: 3 groups were acarbose 14 mg/kg, metformin 250 mg/kg and Andiabet 2g/kg displayed significantly inhibiting PBG compared to the nontreatment group (p < 0,05). The Andiabet group at the dose 1g/kg had no inhibited the PBG. However, all of groups displayed significantly reducing AUC by 47,32% (Acarbose 14mg/kg group); 50,22% (Metformin 250mg/kg group) and 39,43 % (Andiabet 1g/kg); 36,39 % (Andiabet 2g/kg), respectively. v Oral starch tolerance test Table 3.11. Effect of Andiabet on PBG and blood glucose AUC after 2 hours orally starch administration in T2D diabetic mice Groups PBG % ¯ AUC % ¯ 17 5 7 9 80 90 100 110 120 B lo od g lu co se le ve ls (m m ol /L ) Times (min) Chứng trắng Chứng bệnh Andiabet 1g/kg Andiabet 2g/kg (n =10) (mmol/L) PBG (mmol/L) AUC STZ-induced diabetic mice NT diabetic group 29,24 ± 4,14 47,92 ± 6,16 Gr 2: Acar 14mg/kg 19,59 ± 8,49 33,03 29,86 ± 1,28* 37,69 Gr 3: Met 250mg/kg 18,16 ± 3,73** 37,89 22,90 ± 4,69** 52,21 Gr 4: Andiabet 1g/kg 19,26 ± 11,12 34,13 36,33 ± 2,27 24,18 Gr 5: Andiabet 2g/kg 15,18 ± 4,19*** 48,08 24,94 ± 6,81** 47,95 p vs nontreatment (NT) group: * p < 0,05; ** p < 0,01: *** p < 0,001 Comment: 2 groups are metformin and andiabet at 2g/kg dose significantly inhibited PBG, compared to the nontreatment group (p <0.01 and p <0.001). AUC of 3 groups (acarbose, metformin and Andiabet 2g/kg) were significantly reduced, comparing to the nontreatment group. The percentage reduction of AUC of 3 groups were 37.69% (p <0.05), 52.21% (p <0.01) and 47.95% (p <0.01), respectively. 3.2.4. Antagonism with insulin resistance of Andiabet in type 2 diabetic mice. Figure 3.1. Blood glucose levels in Hyperinsulinemic - euglycemic clamp test in T2D diabetic mice. 18 Figure 3.2. Glucose infusion rate in Hyperinsulinemic - euglycemic clamp test in T2D diabetic mice Comment: In the figure 3.3.The blood glucose level of all 4 groups was maintained steady state in the range of 7.5 - 8.3 mmol/L during the “clamping time” from 80-120 minutes. In the figure 3.2. Glucose infusion rate gradually decreased from the control group, to Andiabet 2g/kg, Andiabet 1g/kg and was lowest in the nontreatment group. Chapter 4. DISCUSSION Lagerstroemia speciosa (L.) Pers; Gynostemma pentaphyllum (Thunb.) Makino; Anemarrhenae Aspheloides (Bunge) are traditional Vietnamese herbal medicines that is widely used to treat type 2 diabetes. With the desire to create an effective diabetes treatment product, derived from herbs, Traphaco company had extracted and prepared Andiabet, a hard capsules. Andiabet is a compound of 3 Vietnamese herbal medicines composition above. To be able to use Andiabet to support treatment of type 2 diabetes, it is necessary to study the safety as well as pharmacological effects and study some mechanisms of action of Andiabet tablets. 4.1. ACUTE AND LONGTERM TOXICITY OF ANDIABET 4.1.1. Acute toxicity of Andiabet 0 0.4 0.8 1.2 1.6 2 80 90 100 110 120 G lu co se ìn us io n ra te ( m l/h ) Time (min) Andiabet 2g/kg Chứng trắng Chứng bệnh Andiabet 1g/kg 19 At the highest dose of 44,25 g/kg, Andiabet has no acute toxicity for mice. Andiabet showed that it to be relatively safe because the ratio between maximum tolerance dose (44.25 g/kg) to therapeutic dose (the lowest dose which has hypoglycemic effect (0.68 g/kg) is 66: 1. Therefore, high recommended a trial dose of Andiabet on the human from 0.45 g/kg - 4.4 g/kg/day (in the range of 1/100 - 1/10 maximum tolerance dose). Andiabet hard capsule includes 200 mg of dried leaves (Lagerstroemia speciosa (L.) Pers) 70% with 200 mg of dried stems, roots, leaves Gynostemma pentaphyllum (Thunb.) Makino and 133 mg dried root Anemarrhenae Aspheloides (Bunge). The content of the active ingredient which contained in a hard Andiabet capsule is 533 mg. So the maximum dose in humans is 8 capsules/day, extrapolating 1 g/kg/day in mice (extrapolation coefficient in mice are 12 and adults’s weight is about 50 kg). Therefore, our next study used 3 doses of Andiabet: 0.68g/kg (equivalent to clinical dose); 1 g/kg (1.5 times the clinical dose) and 2 g/kg (3 times the clinical dose). 4.1.2. Longterm toxicity of Andiabet Vinabetes is a soft form and has components the same at Andiabet, that has been studied for longterm toxicity in rabbits for 4 weeks with 2 doses of 1.8 g/kg/day and 3.6 g/kg/day. The results showed that Vinabetes caused the damage on hepatocellular. Therefore, in the present study, the longterm toxicity test of Andiabet was conducted on rabbits for 90 consecutive days with 2 doses: 0.21 and 0.64 g/kg/day. The result showed that, Andiabet has no noticeable sign of long term toxicity after 90 days oral consecutive administration. 4.2. HYPOGLYCEMIC ACTIVITY AND SEVERAL HYPOGLYCEMIC MECHANISMS OF ANDIABET IN EXPERIMENTAL. 4.2.1. Hypoglycemic effect of Andiabet in normal mice. Results from table 3.7 showed that Andiabet has hypoglycemic effect on normal white mice. Andiabet at 0.68 g/kg/day and 2 g/kg/day doses orally for 2 weeks reduced the blood glucose levels by 14.3% and 17.1% compared to the control group (p <0.05). Gliclazide at the dose 20 of 80mg/kg reduced better than Andiabet (20.52% vs 17.1%) in normal mice, because all three herbs contain many active ingredients with different hypoglycemic mechanisms, not only stimulate the pancreas to increase insulin secretion such as gliclazide, but it can also have many other mechanisms such as promotion the insulin sensitivity, inhibition of glycogen metabolism in the liver and other tissues in the body, and or inhibition of hepatic gluconeogenesis. .. and the effects were not shown in normal mice. 4.2.2. Hypoglycemic effect of Andiabet in type 2 diabetic mice. 4.2.2.1. Type 2 diabetes model. Recently, scientists have developed a new type 2 diabetes model by combining a high-fat diet (fat ~ 40-60% of calories) for a long time (1- 2 months) to cause insulin resistance. Then, pancreastitis were induced by low-dose STZ injection. In this way, we have type 2 diabetes mice. Mice had obesity characteristic: after 4, 6 and 8 weeks, the weight of mice in the HFD groups were by 42.5%; 64.4% and 85.8%, respectively. The difference compared to the NFD group was statistically significant (p <0.001), (table 3.8). Mice also had insulin resistance, increasing blood glucose level characteristics: After 72 hours of STZ injection 100 mg/kg, blood glucose concentration in the HFD group was 17.09 mmol/l, an increase of 207.4% compared to the previous study and compared to the control group (p <0.001), (Table

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