Protein-polymer grafts,IV A. Modification of amino acids: IIai. Modification of free lysine with reductive arylation

Inability to increase the yield of reaction between 2, 4 dihydroxybenzaldehyde and gelatin beyond 55 and 60% has led to an extensive investigation of reductive alkylation with free lysine. Even with free lysine, the extent of reaction was about 60%. Since this could be attributed to the electron donation by the phenolic hydroxyls, reductive alkylation was performed between 0-, m-, and p-nitrobenzaldehydes and free lysine; 0- and m-nitrobenzaldehyde were ineffective in increasing the yield while with p-nitrobenzaldehyde a yield of 72% was achieved. The unreacted 28% of the lysines are susceptible to epichlorohydrin. These results suggest that the slow, reversible first step in reductive alkylation, the formation of the Schiff s base, is responsible for the low yield.     

Synthesis of N-carboxyalkyl and N-aminoalkyl functionalized dipeptide building units for the assembly of backbone cyclic peptides

Abstract: To improve the assembly of backbone cyclic peptides, N-functionalized dipeptide building units were synthesized. The corresponding N-aminoalkyl or N-carboxyalkyl amino acids were formed by alkylation or reductive alkylation of amino acid benzyl or tert-butyl esters. In the case of N-aminoalkyl amino acid derivatives the aldehydes for reductive alkylation were obtained from N,O-dimethyl hydroxamates of N-protected amino acids by reduction with LiAlH₄. N-carboxymethyl amino acids were synthesized by alkylation using bromoacetic acid ester and the N-carboxyethyl amino acids via reductive alkylation using aldehydes derived from formyl Meldrums acid. Removal of the carboxy protecting group leads to free N-alkyl amino acids of very low solubility in organic solvents, allowing efficient purification by extraction of the crude product. These N-alkyl amino acids were converted to their tetramethylsilane-esters by silylation with N,O-bis-(trimethylsilyl)acetamide and could thus be used for the coupling with Fmoc-protected amino acid chlorides or fluorides. To avoid racemization the tert-butyl esters of N-alkyl amino acids were coupled with the Fmoc-amino acid halides in the presence of the weak base collidine. Both theN-aminoalkyl and N-carboxyalkyl functionalized dipeptide building units could be obtained in good yield and purity. For peptide assembly on the solid support, the allyl type protection of the branching moiety turned out to be most suitable. The Fmoc-protected N-functionalized dipeptide units can be used like any amino acid derivative under the standard conditions for Fmoc-solid phase synthesis.     

Clinical effectiveness and safety evaluation of long-term pioglitazone treatment for erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis

Background: We aimed to assess the effect of long-term pioglitazone treatment on erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis.

Methods: We conducted a prospective, open-label, parallel-group, controlled study of 63 type 2 diabetic hemodialysis patients who were randomly assigned to two groups: pioglitazone group (P-group; 15 – 30 mg/day pioglitazone plus conventional oral hypoglycemic agents) and control group (C-group; conventional oral hypoglycemic agents alone). We determined the efficacy of pioglitazone by monitoring anemia, glycemic control, insulin resistance, and levels of inflammatory cytokines and high-molecular-weight (HMW) adiponectin for 96 weeks.

Results: Pioglitazone effectively reduced erythropoietin dose and maintained the target hemoglobin levels by improving insulin resistance up to the end of the study. In the P-group, hemoglobin A_1c, glycated albumin, and triglycerides significantly decreased compared with the C-group. There was a significant reduction in homeostasis model assessment for insulin resistance and the level of high-sensitivity C-reactive protein, and a significant increase in HMW adiponectin level in the P-group; these changes were significantly different compared with values for the C-group. No serious adverse effects such as hypoglycemia, liver impairment, or heart failure were observed in any of the patients.

Conclusion: Pioglitazone treatment resulted in better glycemic control, improved lipid levels, an increase in insulin sensitivity and adiponectin levels, and a decrease in inflammatory markers, thus improving the risk factors of cardiovascular disease. Erythropoietin responsiveness improved with a reduction in erythropoietin dose and may be associated with the improvement in insulin resistance due to long-term pioglitazone treatment.     

Active ingredients of traditional Chinese medicine in the treatment of diabetes and diabetic complications

Introduction: Diabetes mellitus (DM) is a chronic progressive systemic disease caused by metabolic disorder. In recent years, significant amounts of studies have shown that traditional Chinese medicine (TCM) and its active ingredients have obvious hypoglycemic effect.

Areas covered: This paper summarizes single herbs and their active ingredients from TCM with the role of treating DM, and relevant literatures published in the past decades are reviewed. The active ingredients are divided into polysaccharides, saponins, alkaloids, flavonoids, terpenoids and others, which are described in this article from the aspects of active ingredients, sources, models, efficacy, and mechanisms.

Expert opinion: Mechanisms of TCM in treating DM are concluded: i) to promote insulin secretion and increase serum insulin levels; ii) to increase the sensitivity of insulin and improve its resistance; iii) to inhibit glucose absorption; iv) to affect glucose metabolism of insulin receptor; and v) to scavenge radicals and prevent lipid peroxidation. The separation and extraction of effective monomer from TCM is an important direction of anti-diabetic drug discovery currently. Future research about hypoglycemic mechanism of TCM based on the clinical should combine with modern scientific methods and regulatory approach to strive for more meaningful discovery and innovation.     

Empagliflozin,a sodium glucose co-transporter 2 inhibitor,in the treatment of type 1 diabetes

Introduction: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM.

Areas covered: Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM.

Expert opinion: Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.     

Synthesis of novel gefitinib‐based derivatives and their anticancer activity

Drug latentiation is a process of modifying a drug molecule structurally to improve its binding affinity as well as increasing the drug–receptor interactions and potentiate its therapeutic potential. In the quest for discovering more potent epidermal growth factor receptor (EGFR) inhibitors, gefitinib‐based derivatives were designed by simple structural modification at the secondary amine of gefitinib by N‐alkylation. Three gefitinib derivatives (gefitinib‐NB, ‐NP, and ‐NIP) were synthesized by N‐alkylation and phase transfer catalysis. Structural characterization, physicochemical parameters such as solubility, log P, and p K _a were determined. Molecular docking studies were carried out to investigate the binding interactions at the active site. Further drug‐bovine serum albumin (BSA) protein and drug‐calf thymus (CT) DNA interactions were performed to understand the pharmacokinetics of the synthesized derivatives. All the compounds were screened for preliminary in vitro cytotoxic activity against A549, A431 lung, and MDA‐MB‐231 breast cancer cell lines by MTT assay. The gefitinib‐NP and gefitinib‐NB derivatives exhibited strong cytotoxic activity compared with gefitinib. They also showed higher drug‐BSA and drug‐DNA interactions. Molecular docking studies showed the orientation and binding interactions with the EGFR as well as with BSA and CT DNA. The results establish a strong correlation between the experimental and molecular docking studies. EGFR inhibition studies were also carried out for the derivatives and we identified the NP derivative of gefitinib as a potential lead compound. The gefitinib‐based derivatives reported herein are cytotoxic agents and can be tested for further pharmacokinetic profiles and toxicity studies which might be helpful for designing more potent gefitinib‐based derivatives in the future.     

Synthese potentieller Squalenepoxidase-Hemmer mit konformativer Fixierung der Strukturelemente des Butenafins

Synthesis of Potential Inhibitors of Squalenepoxidase with Conformational Fixation of the Structural Elements of Butenafine The synthesis of the naphthalinemethanamines 6b - h is reported. To obtain products with conformative rigidity, substituents with gradually increased space demand were placed into the α-position. Since the direct reductive amination of the naphthylalkanones 3 with the amines 9 or 10 was only of very limited use the α-substituted naphthalinmethanamines 2 and 4 were synthesized as useful intermediates by various methods and the desired N-substitution pattern of the target compounds was subsequently built up applying - mostly reductive - alkylation methods.     

Effect of various treatments on leptin,adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus

Introduction: Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM).

Areas covered: The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM.

Expert opinion: Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated.     

Tyrphostin-8 Enhances Transferrin Receptor-Mediated Transcytosis in Caco-2 Cells and Increases Hypoglycemic Effect of Orally Administered Insulin-Transferrin Conjugate in Diabetic Rats

Purpose. To investigate the effect of tyrphostin 8 (T-8), a GTPase inhibitor, on transferrin receptor (TfR)-mediated transcytosis of insulin-transferrin (In-Tf) conjugate in cultured enterocyte-like Caco-2 cells and on gastrointestinal (GI) absorption of In-Tf in streptozotocin (STZ)-induced diabetic rats. Methods. Caco-2 cells and diabetic rats were used as in vitro and in vivo models, respectively. TfR-mediated transcytosis was measured using ¹²⁵I-In-Tf. The absorption of insulin in diabetic rats was demonstrated by the hypoglycemic effect. Rat blood glucose level was determined using a ONE TOUCH® blood glucose monitoring system. Results. T-8 increased apical-to-basolateral transport of In-Tf conjugate by enhancing TfR-mediated transcytosis in filter-grown Caco-2 cell monolayer, and this enhancement was higher and faster than the previously reported brefeldin A (BFA)-induced effect. The measurement of transepithelial electrical resistance (TEER) during the transport study showed that T-8 was less destructive on the cell tight junction than BFA. The GI absorption of In-Tf was evaluated by its hypoglycemic effect after oral administration in STZ-induced diabetic rats. The glucose-lowering effect of orally administered In-Tf in STZ-induced diabetic rats was improved by either T-8 or BFA. However, the effect of T-8 was more potent than that of BFA, especially at 7 h after administration. Either non-conjugated insulin or insulin-human serum albumin (In-HSA) conjugate by itself or in combination with T-8 did not show any hypoglycemic effect after oral administration, indicating that T-8-enhanced hypoglycemic activity of In-Tf was due to a selective enhancement of TfR-mediated transcytosis. Conclusions. Our data indicated that T-8 could be used to increase the GI absorption of insulin as a transferrin conjugate. T-8, as an enhancer of TfR-mediated transcytosis, is better than the previously reported BFA. T-8 produces a higher increase on the transport of In-Tf and a lower toxicity on epithelial cells. Our findings provide an alternative approach to promote the GI absorption of insulin, as well as other peptide or protein drugs.     

Syntheses of two isotopically labeled CB1 receptor antagonists

Synthesis of deuterium‐labeled CB₁ receptor antagonist 2‐d₉ was accomplished in three steps by alkylation of 2‐nitrophenylacetonitrile with cyclopentyl‐d₉ bromide, reductive cyclization of the resulting secondary nitrile into the 3‐cyclopentyl indole‐d₉ and its N‐sulfonylation with corresponding p‐amidosulfonyl chloride. Another, structurally related, CB₁ receptor antagonist 1 was radiolabeled with carbon‐14 by oxidative cleavage of 3‐cyclopentyl indole followed by the ring closure of o‐acyl substituted N‐formylaniline with potassium cyanide‐[¹⁴C], in situ reduction‐elimination of the intermediate amino alcohol, and N‐sulfonylation of the resulting 3‐cyclopentyl indole‐2‐[¹⁴C].     

盐酸绿卡色林的工艺研究

目的 研究减肥药盐酸绿卡色林（1）的合成工艺。方法 以N-烯丙基-N-[2-（4-氯苯基）乙基]氨基甲酸叔丁酯（3）为原料,经一步反应同时实现分子内的傅-克烷基化反应和脱Boc保护基反应,再经L-（+）-酒石酸手性拆分和成盐制备得到1。结果 合成工艺总收率为24.7%,化学纯度为99.9%,光学纯度ee值>99.8%。各中间体和目标产物经¹H NMR、¹³C NMR、ESI-MS表征。结论 所研制的合成工艺路线操作简便、经济实用,适合工业化生产。     

啤酒花总查尔酮的提取工艺及对氧化损伤心肌细胞的保护作用研究

目的 探讨啤酒花总查尔酮的最佳提取工艺及其对过氧化氢(H₂O₂)氧化损伤H₉C₂心肌细胞的保护作用。方法 采用正交试验法研究了提取时间、料液比与提取次数对啤酒花总查尔酮得率的影响,并研究了总查尔酮对过氧化氢氧化损伤H₉C₂心肌细胞保护作用。结果 总查尔酮最佳提取工艺条件为,提取时间5 min、料液比1:20、提取次数2次,此条件下黄腐酚得率可达19.9 µg·mL^-1,明显提高过氧化氢损伤H9C2细胞细胞存活率,并降低乳酸脱氢酶（LDH）含量、提高超过氧化歧化酶（SOD）和过氧化氢酶（CAT）活性。结论 在最佳条件下黄腐酚具有较高的提取得率,对过氧化氢损伤H9C2心肌细胞具有较好的保护作用,为啤酒花进一步研究与开发提供依据。     

口服降糖药联合胰岛素对糖尿病患者胰岛β细胞功能、骨代谢的影响

目的 探讨不同口服降糖药联合胰岛素对糖尿病患者胰岛β细胞功能、骨代谢和成本效果的影响,为临床治疗提供参考依据。方法 选取西安市第一医院2015年3月—2018年3月收治100例糖尿病患者,根据入院先后顺序随机分为观察组和对照组,每组50例,两组患者于每晚睡觉前皮下注射胰岛素,起始剂量为0.2 U/（kg·d）,并停用其他降糖药物。观察组患者在此基础上,口服沙格列汀片5 mg/次,1次/d。对照组患者口服格列美脲片1 mg/次,1次/d,两组均连续治疗12周。对比两种不同口服降糖药物对糖尿病患者胰岛β细胞功能、骨代谢和成本的影响。结果 两组患者治疗前胰岛β细胞（Homaβ）、修正胰岛β细胞分泌指数（MBCI）、早期胰岛素分泌指数（EISI）、血糖曲线下面积（AUCglu）、胰岛素曲线下面积（AUCins）和C肽曲线下面积（AUCcp）对比无显著性差异;治疗后,两组的Homaβ、MBCI、EISI、AUCins和AUCcp水平在治疗后显著升高,而AUCglu水平治疗后显著降低,同组治疗前后比较差异均有统计学意义（P<0.05）;且观察组治疗后Homaβ、MBCI、EISI、AUCins和AUCcp水平显著高于对照组,而AUCglu水平显著低于对照组,组间差异均有统计学意义（P<0.05）。两组患者经不同用药方案治疗后的骨密度均明显改善,与同组治疗前相比具有统计学差异（P<0.05）,而与对照组相比,观察组患者的骨密度改善程度更加明显,组间差异有统计学意义（P<0.05）。两组患者治疗后血糖的控制情况空腹血糖（FPG）、餐后2 h血糖（2h PG）和糖化血红蛋白（HbA1C）比治疗前均显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组治疗后FPG、2h PG和HbA1C均显著低于对照组治疗后（P<0.05）。观察组患者降糖药物成本低于对照组,但两种治疗方案药物成本对比无统计学差异。结论 糖尿病患者采取口服沙格列汀降糖药物联合胰岛素治疗方案是可行的,可结合患者具体特点,在早期应用药物,改善患者的胰岛β细胞功能,改善骨代谢,控制血糖水平,延缓糖尿病进展,经济效果较佳,可减轻患者的经济负担。     

Comparative evaluation of biphasic insulin with metformin and triple oral hypoglycemic agents (OHA) in type 2 diabetes patients

IntroductionThe prevalence of secondary failure to oral hypoglycemic agents among type 2 diabetes mellitus (T2DM) patients ranges from 30 to 60%. The alternative approaches to overcome this issue are either switching to triple oral hypoglycemic agents (OHA) or intensifying the regimen by adding insulin.ObjectiveTo compare the glycemic control achieved with biphasic insulin plus metformin and triple OHA in T2DM patients who were not adequately controlled with two OHA regimen.MethodsA qualitative prospective study was conducted at Asir diabetes center, Abha, KSA. Poorly controlled T2DM patients with two OHA for at least 1 year with glycated hemoglobin (HbA1c) >7.0% were included. Subjects were divided into group I (a third OHA was added to the existing two OHA regimen) and group II (switched over to Biphasic insulin and metformin). At baseline and 3-month intervals, level of HbA1C, Fasting Plasma Glucose (FPG), Postprandial Plasma Glucose (PPG), Blood Pressure (BP), lipid profile and hypoglycemic episodes were obtained and evaluated for one year.Results41.1% of patients were in group I and 58.9% were in group II. At the end of the study, there was a significant reduction in HbA1c in group II subjects comparing to group I (8.18 ± 1.32 vs 8.79 ± 1.81, p = 0.0238). FPG and PPG were improved also in group II. The mean body weight increased from baseline in group II is +4.48 kg and decreased from baseline in group I (−0.46 kg). 11.3% from group I and 23.7% from group II reported hypoglycaemic incidences.ConclusionBiphasic insulin and metformin regimen could be an appropriate therapeutic option for achieving good glycemic control compared with triple OHA in patients with two OHA failure.     

Drug interactions and synthesis of cefpirome with hypoglycemic agents

The present work is aimed to study the interactions between cefpirome and hypoglycemic agents (gliquidone, metformin, and pioglitazone) by chromatographic and spectroscopic techniques. In the first case, reversed-phase high-performance liquid chromatographic methods have been developed, validated for the simultaneous determination of cefpirome with hypoglycemic agents, and was applied for interaction studies. These interactions were carried out in simulated gastric juice (pH1), buffers of pH 4, 7.4, and 9 at 37 °C for 3 h. In the second case, cefpirome–hypoglycemic agents complexes were synthesized and elucidated on the basis of FT-IR, ¹H-NMR, and ¹³C-NMR studies.     

Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles

ABSTRACT

Objective: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability.

Methods: Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats.

Results: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times.

Conclusion: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.     

The use of insulin in elderly patients with type 2 diabetes mellitus

Introduction: Older patients with diabetes sometimes present comorbidities that increase the risk of other common geriatric syndromes. In such patients, treatment with insulin is usually started when full doses of oral hypoglycemic agents are no longer adequate to achieve acceptable glycemic control.

Areas covered: This article reviews the available literature on the use of insulin in elderly patients with type 2 diabetes. The aims are to gain information on: the benefits and risks of initiating insulin treatment, the efficacy and safety of different types of insulin and the most appropriate initial dosing and titration regimens. Thirteen published trials have evaluated the effects of different insulin regimens in the management of elderly subjects with type 2 diabetes but, given that older people are generally excluded in clinical studies with insulin, only three published reports on subgroup analyses are limited to elderly patients.

Expert opinion: The available literature shows that the addition of insulin to current oral treatments is generally safe and effective in improving metabolic control, with a low risk for hypoglycemia. Further research is needed to better understand the most appropriate insulin regimens necessary to achieve glycemic goals while appropriately addressing the risk of hypoglycemia.     

Therapeutic targets for neuroblastomas

Introduction: Neuroblastoma (NB) is the most common and deadly solid tumor in children. Despite recent improvements, the long-term outlook for high-risk NB is still < 50%. Further, there is considerable short- and long-term toxicity. More effective, less toxic therapy is needed, and the development of targeted therapies offers great promise.

Areas covered: Relevant literature was reviewed to identify current and future therapeutic targets that are critical to malignant transformation and progression of NB. The potential or actual NB therapeutic targets are classified into four categories: i) genes activated by amplification, mutation, translocation or autocrine overexpression; ii) genes inactivated by deletion, mutation or epigenetic silencing; iii) membrane-associated genes expressed on most NBs but few other tissues; or iv) common target genes relevant to NB as well as other tumors.

Expert opinion: Therapeutic approaches have been developed to some of these targets, but many remain untargeted at the present time. It is unlikely that single targeted agents will be sufficient for long-term cure, at least for high-risk NBs. The challenge will be how to integrate targeted agents with each other and with conventional therapy to enhance their efficacy, while simultaneously reducing systemic toxicity.     

新型国产重组甘精胰岛素对1型糖尿病模型大鼠的降糖作用研究

目的 探讨新型国产重组甘精胰岛素注射液对1型糖尿病模型大鼠的降糖作用。方法 选择健康SD大鼠和链脲佐菌素诱导的1型糖尿病大鼠,甘精胰岛素注射液（来得时）为阳性对照药,健康SD大鼠单次sc 2、4 IU/kg剂量的重组甘精胰岛素注射液,大鼠尾静脉采血,分别测定0 h（给药前）及给药后1、2、4、6、8 h空腹血糖;1型糖尿病模型大鼠连续5 d sc 4、8 IU/kg剂量的重组甘精胰岛素注射液,每天分别测定给药前（0 h）和给药后（4 h）空腹血糖,给药第1、5天测定给药后1、2、4、6、8 h空腹血糖。结果 健康大鼠sc重组甘精胰岛素注射液2、4 IU/kg后,血糖值在2 h下降到最低,与对照组比较差异显著（P<0.01）;模型大鼠连续5 d sc 4、8 IU/kg重组甘精胰岛素注射液,血糖于给药后4~6 h下降至最低点,与模型组比较差异显著（P<0.01）;每天给药4 h后血糖均呈平稳下降趋势,与模型组比较差异显著（P<0.01）,8 IU/kg血糖值与对照组接近。结论 国产重组甘精胰岛素注射液对1型糖尿病模型大鼠有较好的降糖效果,与同剂量阳性药降糖效果相当。