Efficacy and safety of glucokinase activators for type 2 diabetes mellitus therapy：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of glucokinase activators in the treatment of type 2 diabetes mellitus. METHODS PubMed， Cochrane Library， Web of Science， Embase and CNKI databases were searched from the inception to March 2022. Randomized controlled trials about glucokinase activators versus placebo （or other oral hypoglycemic agents） in the treatment of type 2 diabetes were included， data were extracted and meta-analysis was analyzed using RevMan 5.4 software. RESULTS A total of 9 studies with 215 0 patients were included. In terms of hypoglycemic effect， compared with control group， glucokinase activators significantly reduced glycosylated hemoglobin （HbA1c） [MD＝－0.40， 95%CI（－0.53， －0.26）， P＜0.000 01]， fasting blood glucose[MD＝－0.53， 95%CI（－0.85， －0.20）， P＝0.001] and 2 h postprandial blood glucose [MD＝－2.28， 95%CI（－2.68， －1.88）， P＜0.000 01] in diabetic patients. In terms of safety， the incidence of hypoglycemia caused by glucokinase activators was higher than control group on the whole [RR＝1.55， 95%CI（1.20，2.01）， P＝ 0.000 8]. According to the subgroup analysis of organs activated by glucokinase activator， the incidence of hypoglycemia in the pancreas-liver dual activator group [RR＝1.44， 95%CI（1.11，1.89）， P＝0.007] and liver-selective activator group [RR＝2.26， 95%CI（1.02，5.03）， P＝0.05] was higher than that in the control group， the difference was statistically significant. CONCLUSIONS Glucokinase activators can effectively reduce HbA1c， fasting blood glucose and 2 h postprandial blood glucose in patients with type 2 diabetes， but the risk of hypoglycemia remains to be addressed.

Simultaneous determination of four kinds of components in Gegen-Huangqin-Huanglian Decoction by UPLC-MS/MS / 国际中医中药杂志

Objective:To develop an UPLC-MS/MS method for the simultaneous determination of baicalin, berberine, glycyrrhizic acid and puerarin in Gegen-Huangqin-Huanglian Decoction. Methods:Isocratic elution was carried out with mobile phase consisting of acetonitrile - 4 mmol/L ammonium formate. The separation was performed on ACE Excel 3 C18 (2.1 mm × 100 mm, 3 μm), and the mass spectrometer was operated in the positive and negative ionization electrospray (ESI) mode using multiple monitoring (MRM) for analysis of four components. External standard method was used for fix quantity. The precursor to product ion transitions monitored for baicalin, berberine, glycyrrhizic acid and puerarin were m/z 447.0→271.0, 336.2→320.2, 821.4→350.9 and 415.2→294.9, respectively. Results:Baicalin, berberine, glycyrrhizic acid and puerarin were all analyzed exactly, the linear ranges were 0.002-0.080, 0.002-0.080, 0.001-0.040, 0.002-0.080 ng, respectively. The r were 0.998 3, 0.999 4, 0.997 9 and 0.999 5, respectively. The recoveries of four analytes ranged from 98.75% to 100.86% and the relative standard deviations were all below 0.74%. Conclusions:UPLC-MS/MS method is sensitive, accuate with rapid speed, which could be used for the determination of baicalin, berberine, glycyrrhizic acid and puerarin in Gegen-Huangqin-Huanglian Decoction.

Simultaneous determination of three compounds in penthorum Chinense pursh by HPLC / 国际中医中药杂志

Objective To establish a method for the simultaneous content determination ofquercetin,kaempferol and pinocembrin in Penthorum Chinense Pursh.Methods The HPLC analysis was carried out on Alltima C18 (250 mm × 4.6 mm,5 μm) with a mixture of methanol-0.2％ phosphate (45:55) as the mobile phase.The determination wavelength was set at 270 nm with the flow rate of 1.0 ml/min.The column temperature was set at 30 ℃.Results The quercetin,kaempferol and pinocembrin showed good linearity in the range of 0.316-10.120 μg (r=0.999 9),0.012-0.397 μg (r=0.999 6) and 0.063-2.016 μg (r=0.999 8) respectively.The average recovery rates of quercetin,kaempferol and pinocembrin were 99.34％ (RSD=1.51％),99.76％ (RSD=l.96％) and 98.34％ (RSD=1.56％) respectively.Conclusions The method is accurate and sensitive,which can be used for the content determination of quercetin,kaempferol and pinocembrin in Penthorum Chinense Pursh.

Simultaneous determination of five compounds in Ganmaoning granules by UPLC-MS/MS / 国际中医中药杂志

Objective To establish a method for the simultaneous determination of adenosine, chlorogenic acid, caffeic acid, baicalin and wogonin in Ganmaoning granules. Methods The UPLC-MS/MS method was adopted. The separation was performed on ZOBAX SB C18 (2.1 mm×150 mm, 5μm) column with mobile phase consisted of methanol-2 mmol/L ammonium acetate aqueous solution (isocratic elution) at the flow rate of 0.2 ml/min. The column temperature was set at 35℃, and the injection volume was 2μl. The electrospray ionization source (ESI) was used. Multiple reaction monitoring (MRM) mode was adopted, using positive and negative ions scanning. The ion source temperature was 300℃, the drying gas temperature was 400℃, the drying gas flow was 20 L/min, the atomizing gas pressure was 55 psi, and the capillary voltage was 4000 V.Results The linear ranges of adenosine, chlorogenic acid, caffeic acid, baicalin and wogonin in Ganmaoling granules were 0.20-12.80 ng (r=0.9996), 1.00-64.00 ng (r=0.9998), 0.40-25.60 ng (r=0.9996), 4.00-256.00 ng (r=0.9992), 0.20-12.8 ng (r=0.9991), which showed the linear relationship was good. The limits of detection were 0.02, 0.10, 0.04, 0.40, 0.02 ng, respectively. The limits of quantitation were 0.04, 0.20, 0.08, 0.80, 0.04 ng, separately. TheRSDs of precision, reproducibility and stability (24 h) tests were no more than 3.5％. The recovery rates were 99.3％-100.75％ (RSD=2.09％-3.17％).Conclusions The method established in this experiment is simple, rapid, sensitive and accurate. It can be used to simultaneously determine the contents of five components inGanmaoling granules, and can be used for quality control ofGanmaoninggranules.

Effect of Ziyin-Jianghuo formula on the neuroendocrine system of menopausal caused by Yin deficiency generating intrinsic heat type of rats / 国际中医中药杂志

Objective To observe the effect of Ziyin-Jianghuo formula in treatment of Yin deficiency generating intrinsic heat type of the levels of monoamine neurotransmitters and estrogens in rats, and investigate its intervention in the neuroendocrine system. Methods There were 7 groups, which were sham operation group, model control group, estrogen tablet group, Gengnian capsule group, Ziyin-Jianghuo formula low, medium and high dose groups. Castration was performed by castration (extraction of ovaries) plus hot traditional Chinese medicine. The rats in the treatment group were given the above drugs 24 hours after the last administration of the hot Chinese medicine, once a day for 30 consecutive days. The sham operation group and the model control group were given an equal volume of purified water by simultaneous intragastric administration. The serum estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL) levels,uterine coefficient and monoamine neurotransmitters dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) content in the hypothalamus were detected after 12 hours of the last treatment. Results Compared with the model group, the levels of serum FSH (4.39 ± 0.22 IU/L, 2.89 ± 0.91 IU/L, 2.84 ± 0.98 IU/L vs. 5.51 ± 0.24 IU/L), LH (14.48 ± 0.24 IU/L, 11.46 ± 0.33 IU/L, 5.28 ± 1.31 IU/L vs. 15.02 ± 0.37 IU/L) in the low, middle and high doses of Ziyin-Jianghuo formula significantly decreased (P<0.05), the levels of serum E2 (39.84 ± 6.08 pmol/L, 48.65 ± 6.77 pmol/L, 64.96 ± 7.97 pmol/L vs. 33.16 ± 4.62 pmol/L) significantly increased (P<0.05). The content of DA, 5-HT, 5-HIAA in the hypothalamus and the 5-HT/NE (0.48 ± 0.02, 0.43 ± 0.03, 0.27 ± 0.02 vs. 0.67 ± 0.02), 5-HIAA/5-HT (1.74 ± 0.09, 1.71 ± 0.10, 1.80 ± 0.17 vs. 2.00 ± 0.10) in the low, middle and high doses of Ziyin-Jianghuo formula significantly decreased ( P<0.05), the content of NE (663.34 ± 9.81 ng/kg, 695.94 ± 10.54 ng/kg, 790.76 ± 16.35 ng/kg vs. 602.95 ± 13.24 ng/kg) in the hypothalamus in the low, middle and high doses of Ziyin-Jianghuo formula significantly increased (P<0.05). The levels of serum PRL (10.16 ± 1.26 μg/L, 7.22 ± 1.26 μg/L vs. 14.80 ± 1.64 μg/L) in the middle and high doses of Ziyin-Jianghuo formula significantly decreased (P<0.05). Conclusions The Ziyin-Jianghuo formula has a significant positive regulation effect on the neuroendocrine system of menopausal Yin deficiency generating intrinsic heat type of rats, and this process is dose-dependent and can improve a series of symptoms caused by autonomic dysfunction.

Determination of the protein-binding rates of gardenioside, paeoniflorin and naringin in Weiyanling granules in different species of plasma / 国际中医中药杂志

Objective To study the protein binding rates ofgardenioside,paeoniflorin and naringin in Weiyanling granules in bovine serum albumin,rat plasma and human plasma.Methods The equilibrium dialysis method was carried to determine the binding-rates of three components in Weiyanling granules in bovine serum albumin,rat plasma and human plasma.The HPLC method was used to determine the mass concentration of three components in weiyanling granules in inner and outer dialysis and to calculate the plasma protein-binding rates.Results The linear relationship,precision,extraction recovery and stability of gardenoside,paeoniflorin and naringin all conformed to the methodological requirements.Within the low,middle and high concentration (5.084,10.04 and 20.08 g/L) of Weiyanling granules,the protein-binding rates of gardenioside and bovine serum albumin were 23.77％ ± 13.39％,10.75％ ± 1.34％,5.82％ ± 6.53％,respectively;the protein-binding rates of paeoniflorin were 51.81％ ± 6.53％,30.12％ ± 6.61％,21.39％ ± 9.45％,respectively;the protein-binding rates of naringin were 70.21％ ± 3.31％,67.61％ ± 1.31％,56.00％ ± 3.46％,respectively;the protein-binding rates of gardenioside and rat plasma were 71.56％ ± 3.00 ％,43.56％ ± 12.22％,40.63％ ± 4.73％,respectively;the protein-binding rates ofpaeoniflorin and rat plasma were 55.72％ ± 1.60％,47.59％ ± 6.33％,40.07％ ± 0.72％,respectively;the protein-binding rates of naringin and rat plasma were 85.85％ ± 3.53％,85.38％ ± 0.99％,79.99％ ± 2.57％,respectively;the protein-binding rates of gardenioside and human plasma were 13.56％ ± 2.40％,3.02％ ± 2.41％,5.82％ ± 2.08％,respectively;the protein-binding rates of paeoniflorin and human plasma were 9.49％ ± 5.23％,5.01％ ± 1.10％,3.98％ ± 1.54％,respectively;the protein-binding rates of naringin and human plasma were 25.04％ ± 2.61％,26.09％ ± 13.82％,20.20％ ± 2.24％,respectively.Conclusions Within 5.084,10.04 and 20.08 g/L,the protein binding-rate of gardenioside,paeoniflorin and naringin were shown asfollow,rat plasma ＞bovine serum albumin ＞ human plasma.There were significant differences in species.

Simultaneous Determination of 8 Components in Total Flavanones of Sedum sarmentosum Bunge by UPLC-MS/MS / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of hyperoside,quercitrin,luteoloside, kaempferol,quercetin,rutin,luteolin and isorhamnetin in total flavanones of Sedum sarmentosum Bunge. METHODS:UPLC-MS/MS method was adopted. The determination was performed on ZOBAX SB C18column with mobile phase consisted of methanol-5 mmol/L ammonium formate aqueous solution(45:55,V/V)at the flow rate of 0.4 mL/min. The column temperature was 30 ℃, and sample size was 2 μL. The electrospray ionization source(ESI)was used;ion source temperature was 400 ℃;desolvation temperature was 300 ℃;desolvation gas flow was 600 L/h;capillary voltage was 3 000 V;nebuliser pressure was 45 psi;the work mode was multiple reaction monitoring mode;detection mode was negative ion mode. The established method was used to determine the contents of 8 components in 3 batches of total flavanones of Sedum sarmentosum Bunge. RESULTS:The linear ranges of hyperoside,quercitrin,luteoloside,kaempferol,quercetin,rutin,luteolin and isorhamnetin were 10.0-640.0,0.5-32.0, 4.5-288.0,8.0-512.0,50.0-3 200.0,2.0-128.0,12.5-800.0 and 25.2-1 612.8 ng/mL(r≥0.991 4),respectively. The limits of detection were 5.0,0.25,2.25,4.0,25.0,1.0,6.25 and 12.6 ng/mL,respectively.The limits of quantitation were 10.0,0.5,4.5, 8.0,50.0,2.0,12.5 and 25.2 ng/mL,separately. RSDs of precision,stability(24 h)and reproducibility tests were no more than 4.3%(n=6). The recoveries were 95.9%-100.6%,and RSDs were 1.5%-3.8%(n=6). The contents of hyperoside,quercitrin, luteoloside,kaempferol,quercetin,rutin,luteolin and isorhamnetin in 3 batches of total flavanones of Sedum sarmentosum Bunge were 507.88-560.37,42.95-50.36,63.52-71.80,1 695.10-1 753.27,10 569.28-10 612.99,25.76-30.13,2 795.22-2 877.43 and 4 869.55-4 971.30 μg/g,respectively. CONCLUSIONS:The established method can be used for simultaneous determination of 8 components in total flavanones of Sedum sarmentosum Bunge.

Study on the Pharmacokinetics and Brain Targeting of Toutongning Nasal Spray in Rats in vivo / 中国药房

OBJECTIVE:To study the pharmacokinetics and brain targeting of Toutongning nasal spray in rats in vivo. METH-ODS:84 SD rats were divided into nasal administration group and vein administration group,42 in each group,with dose of 1.2 mL/kg. 5 mL sample blood was taken in abdominal aorta after 5,10,15,30,60,90,120 min of administration,and brain tissue was taken (6 rats in each time point). HPLC-MS was adopted to determine the concentration of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma and brain tissue of rats in each group,and DAS 2.0 software was used to calculate the pharma-cokinetic parameters and brain targeting indexes. RESULTS:The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in nasal administration group were(0.2024±0.0158),(0.3738±0.0857)μg/mL;tmax were(10.0000±0.0000) min;and AUC0-∞ were (16.5429 ± 2.1103),(27.4527 ± 5.5721)μg·h/mL,respectively. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were (0.1802 ± 0.0384),(0.3204 ± 0.0277)μg/g;tmax were (10.0000 ± 0.0000)min;and AUC0-∞ were(17.1053±2.4329),(24.5416±3.7534)μg·h/g,respectively. The cmax of prim-o-glucosylcimi-fugin and 5-O-methylvisammioside in plasma of rats in vein administration group were (0.3002 ± 0.0161),(0.5267 ± 0.0441)μg/mL;tmax were(10.0000±0.0000)min;and AUC0-∞ were(28.0105±4.1128),(60.2941±11.2902)μg·h/mL,respective-ly. The cmax of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.1498±0.0315),(0.1998± 0.0401)μg/g;tmax were(15.0000±0.0000)min;and AUC0-∞were(22.6434±2.8831),(36.7218±14.8856)μg·h/g,respec-tively. The brain targeting indexes of prim-o-glucosylcimifugin and 5-O-methylvisammioside were 2.3870 and 2.1761,respective-ly. CONCLUSIONS:After nasal administration of Toutongning nasal spray,parts of drugs can directly transport to the brian by na-sal absorption. It is scientific and reasonable to make nasal spray.

Simultaneous Determination of Five Components in Qiangshenpaidu Capsules by UPLC-MS/MS / 医药导报

Objective To develop an UPLC-MS/MS method for simultaneously determination of five components (adenosine,cytidine,guanosine,mannitol and adenine) in Qiangshenpaidu capsules. Methods The UPLC separation was performed on an Agilent ZOBAX SB-C18(2.1 mm×150 mm,5 μm) column.Isocratic elution was carried out with mobile phase consisting of methanol-0.1%formic acid (5∶95) at a flow rate of 0.2 mL.min-1.The mass spectrometer was operated in the positive ionization electrospray ( ESI) mode using multiple monitoring ( MRM) for analysis of five components. Results Adenosine,cytidine,guanosine,mannitol and adenine were all analyzed with good precision and accuracy. The linear ranges were 35-1 120 ng.mL-1( r=0.998 1) ,10-320 ng.mL-1( r=0.996 4) , 30-980 ng.mL-1( r=0.999 3) , 40-1 280 ng.mL-1( r=0.993 4), 25-800 ng.mL-1(r=0.996 5),respectively.The recoveries of six analytes ranged from 97.4% to 103.6% and the relative standard deviations were all below 4.7%. Conclusion A sensitive,accurate and suitable UPLC-MS/MS method has been developed,and the method could be applied for the determination of adenosine,cytidine,guanosine,mannitol,and adenine in Qiangshenpaidu Capsules.

Effect of sarpogrelate hydrochloride on cytochrome P450 2D1/2 in rats / 中国药理学通报

Aim To investigate the influence of sarpog-relate hydrochloride (SH)on the pharmacokinetic pro-file of dextromethorphan (DM),the typical substrate of CYP2D1 /2,in rats when they were administered co-instantaneously.Methods A total of 1 2 SD rats were randomly divided into two groups:the control group (DM,1 0 mg·kg-1 )and the sarpogrelate group (SH, 1 0 mg·kg-1 ;DM,1 0 mg·kg-1 ),which received in-tragastric administration.Plasma samples were collected immediately before and at different time points after drug administration.A LC-MS /MS method was used to determine the concentrations of DM in rat plasma. Pharmacokinetic parameters were analyzed using Drug and Statistics (DAS 2.0).Results There were signif-icant differences in the pharmacokinetic parameters of DM,including T1 2 (2.49 h ±0.93 h vs 1 .47 h ±0.20 h,P <0.05 ),Cmax (325.7 μg·L -1 ±1 33.2 μg· L -1 vs 1 04.5μg·L -1 ±52.4 μg·L -1 ,P <0.05), AUC0 -t(785.5 μg·L -1 ·h ±451 .9 μg·L -1 ·h vs 244.8 μg·L -1 ·h ±1 68.3μg·L -1 ·h,P <0.05) and AUC0 -∞(804.7 μg·L -1 ·h ±445.6 μg·L -1 ·h vs 251 .4 μg·L -1 ·h ±1 73.4 μg·L -1 ·h,P<0.05 )between the two groups.Conclusion SH could significantly inhibit the elimination of DM,the substrate of CYP2D1 /2 in rats.

HGF depress the production of α-SMA and extracellular matrix induced by TGF-β1 in fibroblasts of the flexor tendon sheath / 中华显微外科杂志

Objective To examine the effectiveness of HGF in blocking TGF-β1 induced α-SMA and extracellular matrix production in fibroblasts of the flexor tendon sheath. Methods Seven adult male New Zealand white rabbits (3.75-4.00 kg) were used for this study. Both of their front feet were sterilised and the middle digit flexor digitorum profundus tendon equivalents were identified and isolated. These specimens were used to establish primary cell cultures. Sheath fibroblasts were obtained from rabbit flexor tendons. After the cells reached confluence, cells were detached with trypsin/ethylenediamine tetra-acetic acid. All experiments were performed using the cells at the third passage. At 70% confluence the medium was supplemented with 5 ng/ml of TGF-β1 along with increasing doses of HGF (10-40 ng/ml). After 72 hours incubation, the productions of α-SMA were assayed by Western-Blot. The productions of collagen Ⅰ and fibronectin in supernatants culture were examined using ELISA. Results Evaluation of protein expression revealed that TGF-β1 markedly induced α-SMA expression in cultured rabbit flexor tendon sheath fibroblasts. TGF-β1 treated fibroblasts expressed 1.8-fold more protein compared to non-treated fibroblasts (P ＜ 0.05). However, simultaneous incubation of HGF significantly abrogated TGF-β1 induced α-SMA expression in a dose-dependent manner (P＜ 0.05). Treatment with TGF-β1 significantly stimulated collagen Ⅰ and fibronectin production in flexor tendon sheath fibroblasts (P ＜ 0.01). Remarkably, the addition of HGF reduced productions of all components induced by TGF-β1 in a dose-dependent manner (P ＜ 0.05). Conclusion HGF antagonizes TGF-β1 induced α-SMA, collagen Ⅰ, and fibronectin production in flexor tendon sheath fibroblasts. The findings provide a cellular and molecular basis for HGF's acting as a therapeutic agent for adhesions in flexor tendons.

Annular pancreas in children: a report of 5 cases and literature review / 中国普通外科杂志

Objective To explore clinical characteristics of the digestive tract obstruction due to annular pancreas. Methods We reviewed retrospectively clinical features, operative findings and the autopsy of 5 children with annular pancreas. Results Neonate patients usually present complete upper gastro intestinal obstruction because most of them were complicated with duodenal atresia. Infants present chronic incomplete intestinal obstruction duo to annular pancreas. 35.8% of duodenal constriction was caused by annular pancreas. Conclusions All the symptomatic patients with annular pancreas should undergo exploration to restore the consecution of the digestive tract and to detect if there is a concurrent malformation such as intestinal atresia.