The discovery of vanadyl and zinc complexes for treating diabetes and metabolic syndromes

The incidence of diabetes mellitus has increased over the decades because of lifestyle changes. The number of people with diabetes mellitus worldwide is expected to increase from 150 million to 220 million by 2010 and to 300 million by 2025. There are two main types of diabetes mellitus. Type 1 diabetes mellitus is due to the autoimmune-mediated destruction of pancreatic β cells, resulting in absolute insulin deficiency; the patients require exogenous insulin injections. Type 2 is characterized by insulin resistance and abnormal insulin secretion and the patients require exercise, diet control and/or oral hypoglycemics. However, each treatment has some adverse effects, including physical burden, formation of self-antibodies for insulin injections, the severe side effects of hypoglycemics and the discontinuation of insulin synthesis in the pancreas. To overcome these adverse effects and replace the use of these agents, the author attempted to develop new antidiabetic agents with novel structures and mechanisms. This review focuses on the authors' recent development of vanadium and zinc complexes for antidiabetic and antimetabolic syndromes.     

New insights into antidiabetic drugs: Possible applications in cancer treatment

Globally at 2014, it was estimated that there was 347 million people with diabetes in which 90 percent of them were diagnosed with type 2 diabetes mellitus (T2DM). Although the association between diabetes mellitus and cancer risk was found about 100 years ago, the issue is not still clear. Many studies especially cohort and case–control studies have suggested a higher risk of cancer in patients with diabetes mainly in those with type 2 diabetes. Insulin concentration is high in these patients, and due to its mitogenic effects, it may be a possible hypotheses for higher risk of cancer in diabetic patients. Therefore, antidiabetic drugs, which are involved in insulin secretion and sensitivity, may have beneficial effects in cancer treatment. Several groups of drugs with different mechanisms of action, mostly prescribed orally, are used for the treatment of type 2 diabetes mellitus including, insulin sensitizers (thiazolidinediones), insulin secretagogues (sulfonylureas), and biguanides. In this review, the possible effects of antidiabetic drugs (biguanides, thiazolidinediones, and sulfonylureas) and some of their mechanisms for overcoming cancer will be discussed.     

A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics

Diabetes mellitus (DM) is a serious global health concern affecting over 500 million people. To put it simply, it is one of the most dangerous metabolic illnesses. Insulin resistance is the root cause of 90% of all instances of diabetes, all of which are classified as Type 2 DM. Untreated, it poses a hazard to civilization since it can lead to terrifying consequences and even death. Oral hypoglycemic medicines presently available act in a variety of ways, targeting various organs and pathways. The use of protein tyrosine phosphatase 1B (PTP1B) inhibitors, on the contrary, is a novel and effective method of controlling type 2 diabetes. PTP1B is a negative insulin signaling pathway regulator; hence, inhibiting PTP1B increases insulin sensitivity, glucose absorption, and energy expenditure. PTP1B inhibitors also restore leptin signaling and are considered a potential obesity target. In this review, we have compiled a summary of the most recent advances in synthetic PTP1B inhibitors from 2015 to 2022 which have scope to be developed as clinical antidiabetic drugs.     

Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.     

Application of LC-ESI-MS-MS for detection of synthetic adulterants in herbal remedies

Adulteration of allegedly "natural herbal medicines" with undeclared synthetic drugs is a common and dangerous phenomenon of alternative medicine. The purpose of the study was to develop a procedure for detection of most common synthetic adulterants in herbal remedies, using high-pressure liquid chromatography-electrospray tandem mass spectrometry (LC-ESI-MS-MS). Eighty drugs belonging to various pharmacological classes were included in the study. For most drugs two transitions were monitored, using protonated or deprotonated molecules as precursor ions. The drugs were isolated from herbal remedies using simple methanol extraction. Chromatographic separation was done in gradient of acetonitrile-10 mM ammonium formate buffer (pH 3.0). Drugs tested were grouped in suites, comprising analgesic drugs, antibiotics, antidiabetic drugs, antiepileptic drugs, aphrodisiacs, hormones and anabolic drugs, psychotropic drugs, and weight reducing compounds. These suites were used according to the declared benefits of examined preparations. Limits of detection ranged from 5 pg to 1 ng per injected sample. Drug-free herbal remedy spiked with eight various pharmaceuticals occurring in adulterated herbal preparations was used for internal proficiency testing. The recoveries of spiked drugs ranged from 63 to 100%. The procedure was applied in everyday casework. Several undeclared drugs were identified in "herbal" remedies, like e.g. sildenafil, tadalafil, testosterone, or glibenclamide. Pharmacological properties of detected drugs always corresponded with the claims of the "natural" remedies. The method presents a valuable extension of standard GC-MS screening used for this purpose.     

Genetic polymorphisms in placental transporters: implications for fetal drug exposure to oral antidiabetic agents

INTRODUCTION: The prevalence of diabetes among women of childbearing age is increasing. This will inevitably increase the number of pregnancies complicated by diabetes. The management of diabetes mellitus often necessitates the use of oral antidiabetic drugs including biguanides, sulfonylureas, metiglinide analogs and thiazolidinediones. However, a significant concern with the use of these agents in pregnancy is the potential for developmental toxicity. Various antidiabetic drugs have been identified as substrates for transporters present in the syncytiotrophoblast. Therefore, the extent of transfer and fetal exposure to oral antidiabetic drugs used in pregnancy may be altered by polymorphisms in genes encoding these transport proteins. AREAS COVERED: This review covers current research examining genetic polymorphisms in transporters expressed in the syncytiotrophoblast and evidence supporting the involvement of these transporters in the transport of oral antidiabetic agents. The aim is to provide insight into how the transfer of antidiabetic drugs across the placental trophoblast may be altered by polymorphisms in drug transporters. EXPERT OPINION: There is a paucity of studies examining the influence of polymorphisms on transporter activity in the placenta and how the transfer of oral antidiabetics may be altered. Further research employing in vivo models is required to allow for the prediction of the potential consequences of polymorphisms on placental transporter expression and function.     

Using Chinese natural products for diabetes mellitus drug discovery and development

This paper provides a review of natural Chinese drug products, including phytochemic compounds, medicinal herbs and multi-component herbal formulae, that have been reported to possess hypoglycemic activity with mechanisms for antidiabetic action. Along with a great number of combination formulae, ～ 187 different Chinese medicinal herbs are clinically applied to treat diabetes mellitus and its complications in China, most of which have achieved reasonably good clinical outcomes. These valuable data and practical experience provide a promising opportunity for the discovery and development of drug candidates with good therapeutic efficacy and low toxicity. The concept of treating complex, multifactorial metabolic diseases, such as diabetes, using multi-component therapeutics, including single-herb formulae and combination herbal formulae, shall be regarded as a concerted pharmacologic intervention of multiple compounds interacting with multiple targets and possessing interdependent activities that are required for a synergistic or optimal effect. The conventional approach for the discovery and development of antidiabetic drug products from natural products involving a high-throughput, bioactivity guided drug screening of single compounds obtained from thousands of herbs has proven to be a costly and non-productive effort. Hence, an alternative way of developing new drug candidates, as suggested in this review, is to reduce and simplify a well-established combination herbal formula, along with the pharmacologic evaluation of a small group of phytochemic compounds, which are therapeutically effective as the original formula and have known chemical structures, compositions and mechanisms of action that are similar to chemical drugs.     

Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications

Nowadays, the treatment of diabetes mellitus is based on the variable use and combination of diet, antidiabetic oral agents (metformin, sulphanylureas, glynides, acarbose and thiazolidinediones) and insulin or its analogs, depending on the type of diabetes and the needs of the patient. The prevention and treatment of chronic micro- and macrovascular complications, on the other hand, is based on the achievement and maintenance of an optimal glycaemic control and requires the combined use of adjunctive therapy such as antihypertensive drugs and cholesterol-lowering medications. Furthermore, several herbal preparations and dietary supplements, such as antioxidants, essential fatty acids, lipid metabolism activators, vitamins and trace elements, are advertised and prescribed to patients as a useful adjuvant to a diabetic diet and conventional medications in order to improve glycaemic control and reduce the impact of chronic complications. In this regard, we have attempted to review the current concepts dealing with the usefulness of these complementary therapies in treating diabetic patients.     

Recent development of single preparations and fixed-dose combination tablets for the treatment of non-insulin-dependent diabetes mellitus

As a complex endocrine and metabolic disorder, type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM) has become a major threat to human health. Because of the heterogeneous and progressive disorders induced by insulin resistance and pancreatic b-cell dysfunction, the treatment of NIDDM is still challenging. Although antidiabetic drugs with different pharmacological mechanisms of action have been used clinically, different degrees of undesirable glucose control and the incidences of a variety of side effects, including hypoglycemia, cardiovascular complications and weight gain require the better treatment options. This article has overviewed the current literature about commercially available antidiabetic drugs with different pharmacological mechanisms of action in the treatment of NIDDM, and summarized the published data regarding the efficacy, tolerability, and safety of currently available single preparations and fixed-dose combinations, aiming to provide important information for the development and application of antidiabetic drugs in the future. The literature search from 1989 to 2015 was conducted by PubMed, ScienceDirect, Springer, American Diabetes Association, and U.S. FDA Drugs databases.     

Adulteration of herbal antidiabetic products with undeclared pharmaceuticals: a case series in Hong Kong

AIMS

The current study aims to examine the problem of adulteration of herbal antidiabetic products with undeclared pharmaceuticals, including both registered and banned drugs.

METHODS

All cases involving use of adulterated herbal antidiabetic products referred to a tertiary centre for clinical toxicology analysis from 2005 to 2010 inclusive were retrospectively reviewed. The patients'' demographic characteristics, clinical presentations, medical history, drug history and the analytical findings of the herbal antidiabetic products were studied.

RESULTS

A total of 27 cases involving use of 29 adulterated herbal antidiabetic products were identified. Seventeen of the patients (63%) had clinical toxicities associated with the illicit products. Hypoglycaemia was the most common adverse effect, followed by lactic acidosis. Analysis of the 29 illicit herbal antidiabetic products revealed eight undeclared registered or banned oral antidiabetic agents, namely glibenclamide (n = 22), phenformin (n = 18), metformin (n = 6), rosiglitazone (n = 6), gliclazide (n = 2), glimepiride (n = 2), nateglinide (n = 1) and repaglinide (n = 1). Non-antidiabetic drugs were also detected in some products. Up to four adulterants were detected within the same product.

CONCLUSIONS

Adulteration of herbal antidiabetic products with undeclared pharmaceuticals is a significant yet under-recognized problem. Patients taking these illicit products could be at risk of potentially fatal adverse effects. It is important to educate the public to avoid taking pCMs of dubious source. Effective regulatory measures should be put in place to address the problem.     

糖尿病的药物治疗

目的近年,随着糖尿病发病率的日益上升,抗糖尿病药物越来越受到重视,本文主要介绍国内外治疗糖尿病的药物以及抗糖尿病药物的研究方向。为临床合理用药提供参考。方法参阅国外大量相关文献,进行归纳和总结。结果按作用机制和化学结构治疗糖尿病的药物主要有胰岛素促泌剂、胰岛素增敏剂、α-葡萄糖苷酶抑制剂、胰岛素及胰岛素类似物、二肽基肽酶-Ⅳ(DPP-Ⅳ)抑制剂、其他口服降糖药。在临床使用中,二甲双胍、格列齐特、阿卡波糖应用广泛,居主导地位。在糖尿病的治疗中,常常联合用药。结论糖尿病的发生、发展与酶功能的紊乱密切相关。与糖尿病关系较为密切的酶,包括α-葡萄糖苷酶、醛糖还原酶、一氧化氮合酶、血管紧张素转换酶、肉碱脂酰转移酶Ⅰ和Ⅱ、蛋白激酶C、二肽基肽酶Ⅳ、蛋白酪氨酸激酶、蛋白酪氨酸磷酸酶,这些酶都可能成为糖尿病治疗的靶点,是研发糖尿病治疗药物的新方向。     

口服降糖药二肽基肽酶Ⅳ（DPP-4）抑制剂的多器官保护作用

二肽基肽酶Ⅳ（DPP-4）抑制剂是近年来新上市的一种新型口服降糖药物。 DPP-4抑制剂通过抑制DPP-4来抑制胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）降解,发挥降低血糖的作用。 DPP-4抑制剂不仅能双向控制血糖,且具有降糖外的胰腺、心血管、肾脏、肝脏等多器官保护作用和抗炎作用。本文对已有的DPP-4抑制剂及其多器官保护作用进行综述,总结其优势及进一步发展的趋势,为临床用药提供参考。     

我院门诊部178例糖尿病患者路径干预后降糖药物使用情况观察

目的探讨在我院第三门诊部对糖尿病患者进行有效路径干预治疗后,分析门诊部2009～2011年降糖药物的使用情况,为降低糖尿病的并发症、急诊率、住院率,和提高糖尿病临床合理用药提供一些参考。方法采用金额排序法和DDD分析法,对我门诊部2009—2011年度降糖药的用药金额、糖尿病药品所占总药品金额的比例、用药频度（DDDs）、日均费用（DDC）等进行统计与分析。结果2009～2011年降糖药的品种、数量及销售金额等逐年增长;我门诊部用药金额前3位为阿卡波糖、30R胰岛素、那格列奈;用药频度前3位为阿卡波糖、30R胰岛素、格列齐特;日均费用前3位为30R胰岛素、R胰岛素、N胰岛素。结论对我门诊182例糖尿病患者建立观察病历,对178例糖尿病患者治疗前后进行对比,在对糖尿病患者有效路径干预后,降低了临床药占比例,节省了医疗资源。糖尿病干预前、后对比,糖尿病患者并发症、急诊率、住院率明显下降,两组之间差异有统计学意义。我门诊部降糖药路径干预后的应用较为合理。医生开具的处方能够从患者的病情需要出发,真正做到用药经济、安全、合理、有效。     

Herbal hepatotoxicity: a critical review

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.     

临床常用降糖药物的不良反应及防治策略

随着糖尿病(diabetes mellitus,DM)患者的日益增多,采用降糖药物治疗的同时会存在诸多的药物不良反应(ADR),对患者影响甚大,尤其是特殊人群,易造成生活质量的下滑和经济上的巨大损失。本文从介绍临床常用的各种类型降糖药物的ADR开始,提出如何使用不同类型的降糖药物对DM进行治疗,以及怎样避免ADR对患者的影响等措施,从而营造出健康、安全、和谐的生活方式。     

2002～2006年南京24所医院降糖药应用分析

目的：了解南京地区24所医院降糖药的临床使用情况和变化趋势，探讨降糖药的合理使用。方法：比较2002—2006年药品购入数据，采用Microsoft Excel进行统计分析。结果：磺酰脲类和双胍类连续5年为临床主要使用的降糖药，占所有降糖药使用DDDs总值的52％-72％左右，糖苷酶抑制药和胰岛素在临床也有较广泛的使用，占所有降糖药使用DDDs总值的25％-35％左右，其他新型降糖药和中成药的使用占DDDs总值的10％以下。二甲双胍、格列齐特、阿卡波糖、格列吡嗪、胰岛素等为临床一线用药。结论：南京地区降糖药的使用结构比较合理。费用负担是糖尿病患者能否规范、连续用药的一个重要的影响因素。     

Type 2 diabetes in pediatrics and adults: thoughts from a clinical pharmacology perspective

Type 2 diabetes results when insulin secretion is unable to keep the plasma glucose levels as per acceptable range. This leads to chronic hyperglycemia and its associated microvascular complications such as renal impairment (diabetic nephropathy), retinal abnormalities (diabetic retinopathy), and autonomic, sensory, and motor neuropathies (diabetic neuropathy) and macrovascular disease. Historically, type 2 diabetes is well known as an adult-onset disease; however, lately, the incidence of the disease is reported to be increasing in children. Despite the wealth of information concerning type 2 diabetes in adults, data unique to the pediatric age group regarding the pathophysiology and therapy for type 2 diabetes are limited. For treatment in pediatric type 2 diabetes, metformin and insulin are the only antidiabetic agents approved currently. There are data of use of other oral antidiabetic drugs including glimepiride, rosiglitazone, and glyburide (in combination with metformin) in pediatric patients; however, formal clinical trials to establish the safety and efficacy have not been conducted. This review will compare the clinical pharmacology aspects of the oral type 2 diabetic drugs in pediatric and adult populations in order to determine any differences between the two patient groups.     

某三甲医院抗糖尿病药应用分析

目的:了解武警广东总队医院2型糖尿病住院患者抗糖尿病药应用情况。方法:对我院2009年7月—2010年2月208例2型糖尿病住院患者的抗糖尿病治疗情况进行回顾性分析。结果:有118例(56.73%)2型糖尿病患者采用联合用药的方法治疗。在调查的208例2型糖尿病患者中,二甲双胍使用频率最高,占62.50%。出现糖尿病慢性并发症有147例,占70.67%。结论:糖尿病患者应注重药物的联合应用原则、药物间的相互作用、糖尿病并发症的严重危害等,加强对糖尿病患者的合理用药。