糖尿病血管并发症的循证防治

<正> 糖尿病是一组由遗传与环境因素相互作用引起的临床综合征。其特征为胰岛素分泌或作用缺陷或两者的共同缺陷所导致的以高血糖为特征的临床综合征。在糖尿病的最主要类型中,1型糖尿病的主要病理生理特征为胰岛素绝对缺乏和高血糖,在严重胰岛素缺乏时还可出现脂质代谢紊乱。随着年龄     

Atorvastatin and diabetic vascular complications

Statins inhibit 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol synthesis, and share the common mechanism of lowering circulating levels of low-density lipoprotein cholesterol. Among various statins, atorvastatin is the most widely used statin for the treatment of hypercholesterolemia. Recent clinical trials show that atorvastatin reduces the risk of cardiovascular events and slows the progression of atherosclerosis in patients with coronary artery diseases. Further, intensive therapy with atorvastatin is also associated with an early clinical benefit in patients with acute coronary syndrome. These observations support the concept that beyond lipid-lowering effects of atorvastatin, that is, pleiotropic effects, could contribute at least in part to cardiovascular event reduction. Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. However, whether atorvastatin therapy decreases the risk for the development and progression of diabetic vascular complications and the way that it might achieve these effects are not fully elucidated. In this paper, we focus on diabetic vascular complications and review the efficacy and safety of atorvastatin in the treatment of these devastating disorders. We further discuss here the possible vasculoprotective properties of atorvastatin in patients with diabetes.     

糖尿病患者心血管并发症的危险因素分析

目的探讨糖尿病患者心血管并发症,尤其是高血压的危险因素。方法总结本院156例糖尿病患者的临床表现,并分析糖尿病与心血管并发症,尤其是高血压的关系。结果糖尿病病史在5年以内的患者出现高血压的概率为18.75%,显著低于5年或以上的患者（P〈0.05）,两组间发生冠心病和心绞痛的比较差异无统计学意义（P〉0.05）。结论糖尿病发生心血管并发症与多种因素有关,临床较为常见的是高血压,而结合有效的辅助检查更能较好的早期发现和预防糖尿病的心血管并发症。     

糖尿病并发症防治药物研究进展

糖尿病并发症是随糖尿病(diabetes mellitus,DM)病程的延长而导致的眼、肾、神经、血管及心脏等多组织的慢性病变,是糖尿病致死致残的主要原因.防治糖尿病并发症的药物主要有醛糖还原酶抑制剂、蛋白非酶糖基化阻滞剂、生长激素/胰岛素样生长因子阻滞剂、血流改善剂、抗氧剂和必需脂肪酸、神经营养剂、蛋白激酶C抑制剂等.另外笔者还介绍了一些防治糖尿病并发症的中药和治疗对策.     

Pigment epithelium-derived factor (PEDF): its potential therapeutic implication in diabetic vascular complications

Diabetic micro- and macroangiopathies are leading causes of acquired blindness, end-stage renal failure and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large landmark clinical studies have shown that intensive control of blood glucose or blood pressure (BP) reduces the risk for vascular complications in diabetes. However, the strict control of blood glucose or BP is often difficult to maintain, and current therapeutic options are far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target vascular complications in diabetes may be actually desired for most patients with diabetes. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex neurotrophic, neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties, any of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes. This article summarizes the pathophysiological role of PEDF for vascular complication in diabetes and its potential therapeutic implication in this devastating disorder.     

Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β₂ inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications.     

恶性肿瘤静脉血管并发症的介入治疗

目的探讨恶性肿瘤静脉血管并发症介入治疗的疗效及安全性问题。方法 2001年10月至2009年9月于我院就治的恶性肿瘤静脉血管并发症患者49例,受累部位:颈静脉3例,上肢静脉8例,上腔静脉24例,下腔静脉5例,门静脉癌栓4例,髂静脉5例。分别采用腔静脉滤器置入及静脉置管溶栓术、静脉球囊成形及支架置入术进行治疗。术后给予抗凝、抗炎治疗5~7 d。随访3~12个月。结果 49例患者中,13例行滤器置入及静脉置管溶栓术,技术成功率100%;平均静脉置管溶栓时间7.38 d;临床症状完全消失11例,明显好转2例。36例患者行静脉球囊成形及支架置入术,技术成功率为94%;临床症状完全消失21例,明显好转13例,无明显变化2例。术中无出现血管穿孔、破裂等介入操作相关并发症。术后未出现肺动脉栓塞的临床表现。随访47例,13例患者因原有肿瘤进展而死亡,3例再次出现临床症状,31例患者血管超声提示治疗部位静脉血流通畅。结论介入技术治疗恶性肿瘤静脉血管并发症创伤小、耐受性好、症状改善明显、技术成功率高,具有良好的临床应用价值。     

Emerging growth factor receptor antagonists for the treatment of advanced melanoma

Introduction: Therapy for metastatic melanoma has undergone a rapid transformation over the past 5–10 years. Advances in immunotherapy with checkpoint inhibitors, including both anti-CTLA-4 and anti-PD-1/PD-L1, have led to durable responses in up to 50% of patients. As our understanding of the processes driving the transformation of melanocytes has improved, progress in targeted therapies has also continued.

Areas covered: Angiogenesis and the tumor’s dependence on an expanded vascular supply has been a target for novel therapies since the 1970’s, as this tissue is derived from endothelial cells that are genetically stable in adults. A phase II trial studying combined therapy with bevacizumab (an inhibitor of angiogenesis) and ipilimumab found promising results. Other agents such as sorafenib have not been as successful, failing to extend progression free or overall survival in clinical trials. In this paper other targeted growth factor inhibitors will also be discussed.

Expert opinion: Ultimately, melanoma may not be vulnerable solely to chemotherapy or targeted therapy, but may be efficaciously treated with immunotherapy due to its high mutational rate resulting in the expression of numerous neo-antigens. Therapies with combinations of agents including growth factor receptor and either other targeted therapies or immunotherapy may be a promising complimentary approach.     

Emerging growth factor receptor antagonists for ovarian cancer treatment

Introduction: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes.

Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors.

Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response.     

Molecular targets of diabetic vascular complications and potential new drugs

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.     

Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma

Introduction: The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials.

Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC.

Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.     

Novel investigational vascular endothelial growth factor (VEGF) receptor antagonists for psoriasis

Introduction: Affecting 1 million people in the UK, psoriasis is a commonly diagnosed inflammatory disease arising from autoimmune processes that are triggered by environmental factors in genetically susceptible individuals. The pathophysiology of psoriasis has been widely studied and there is evidence that angiogenesis is a key component.

Areas covered: In this review the role of vascular endothelial growth factor-A (VEGF), as a key angiogenic mediator in psoriasis pathogenesis is discussed. VEGF is found in higher levels in plaques, normal skin and plasma of patients with psoriasis. The level of VEGF also fluctuates in accordance with disease activity and in response to conventional treatments. There are several VEGF inhibitors currently licenced for use; primarily in the fields of oncology and there are case reports of patients being treated with these therapies for metastatic cancer who have demonstrated significant improvement in their psoriasis. VEGF inhibitory agents have suggested promising utility for the treatment of psoriasis following animal studies.

Expert opinion: VEGF may represent a novel treatment target in psoriasis. However, VEGF inhibitors can cause significant side effects such as hypertension and left ventricular dysfunction. The risks of treatment must be carefully evaluated before VEGF inhibitors are trialled or advocated for psoriasis.     

Role of asymmetric dimethylarginine (ADMA) in diabetic vascular complications

Nitric oxide (NO) is a well-recognized anti-atherogenic factor; it inhibits the inflammatory-proliferative processes in atherosclerosis. Indeed, endothelial dysfunction due to reduced synthesis and/or bioavailability of NO is thought to be an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with diabetes. These findings suggest that the elevated ADMA in diabetes could contribute to acceleration atherosclerosis in this population. Further, since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the inhibition of ADMA via up-regulation of DDAH may be a novel therapeutic target for the prevention of CVD in patients with diabetes. In this paper, we review the pathophysiological role of ADMA and DDAH system for accelerated atherosclerosis in diabetes and the therapeutic utility of ADMA suppression in CVD in diabetes.     

Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications

The worldwide population afflicted with diabetes is growing at an epidemic rate. There are almost five times the number of people suffering from this disease today as compared to 10 years ago and the worldwide diabetic population is expected to exceed 300 million by the year 2028. This trend appears to be driven by the world's adoption of a "western lifestyle" comprising a combination of unhealthy dietary habits and a sedentary daily routine. Today, diabetes is the sixth leading cause of death in the United States and the death rates associated with diabetes have increased by 30% over the last decade. While medications are available to reduce blood glucose, approximately one third of the patients on oral medications will eventually fail to respond and require insulin injections. Consequently, there is a tremendous medical need for improved medications to manage this disease that demonstrate superior efficacy. Emerging knowledge regarding the underlying mechanisms that impair glucose-stimulated insulin secretion and the action of insulin on its target tissues has grown tremendously over the last two decades. During that same period of time, an understanding of the important role that phosphorylation state plays in signal transduction has drawn attention to several kinases as attractive approaches for the treatment of diabetes. Recent advances include the discovery of a"small molecule" allosteric binding site on the insulin receptor, inhibitors of glycogen synthase kinase-3(GSK-3) which improve insulin sensitivity in diabetic animal models and inhibitors of protein kinase C- beta that are presently being evaluated in clinical trials for diabetic retinopathy. This review will detail these recent discoveries and highlight emerging biological targets that hold potential to normalize blood glucose and prevent the progression of diabetes related complications.     

Growth factor treatment of stroke

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP-1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.     

Herbal medicines and nutraceuticals for diabetic vascular complications: mechanisms of action and bioactive phytochemicals

Diabetes is one of the most prevalent chronic diseases throughout the world. The majority of its complications arise from vascular-related inflammation apparently initiated by endothelial cell injury. One cause of this injury has been attributed to hyperglycaemia-induced reactive oxygen species. Consequently, current drug developmental strategy has targeted specific inflammatory and oxidative stress pathways for the prevention of diabetic vascular complications. Herbal medicines have traditionally been used for the treatment of diabetes and its complications. In fact, current pre-clinical and clinical studies have demonstrated that many of them exhibit potent anti-inflammatory and anti-oxidative properties, and have also identified the active phytochemicals responsible for their activities. The present review summarises the latest research on the molecular mechanisms of diabetic vascular complications, and evaluates the level of scientific evidence for common herbal medicines and their bioactive phytochemicals. These agents have been shown to be effective through various mechanisms, particularly the NF-κB signalling pathways. Overall, herbal medicines and nutraceuticals, as well as their bioactive components, which exhibit anti-inflammatory and anti-oxidative properties, provide a promising approach for the prevention and treatment of diabetic complications.     

Serum vascular endothelial growth factor and diabetic nephropathy progression

To determine the serum levels of vascular endothelial growth factor (VEGF) at different stages of diabetic nephropathy. Study subjects were divided into three groups: subjects in group 1 were microalbuminuric diabetic (n = 33), in group 2 subjects were normoalbuminuric diabetic group (n = 32), and group 3 was formed from nondiabetic healthy control subjects (n = 18). VEGF, microalbuminuria, HbA1c, creatinine, triglycerides, total cholesterol, fasting serum glucose, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured. Serum VEGF concentrations were significantly higher in the diabetic groups than in the control group even at the normoalbuminuric stage. Serum VEGF levels were higher in the microalbuminuria group than in the normoalbuminuria group. Serum VEGF levels increased with diabetic nephropathy stage. In the diabetic group, serum VEGF appeared to be positively correlated with fasting plasma glucose, HbA1c, LDL, creatinin and microalbuminuria. Serum VEGF was found to be negatively correlated with serum HDL. We have shown that serum levels of VEGF represents an early marker of generalized vascular dysfunction, and this peptide contributes to endothelial damage in diabetes. Elevated serum VEGF levels in the normoalbuminuric stage could indicate that generalized vascular dysfunction is present even at this stage.     

Sex-gender differences in diabetes vascular complications and treatment

Diabetes mellitus and cardiovascular diseases act as two sides of the same coin: diabetes is an important risk factor for cardiovascular disease while patients with ischemic cardiovascular diseases often have diabetes or pre-diabetes. As firstly shown by Framingham study, diabetic women have an increased cardiovascular risk about 3.5 fold higher than non diabetic women, against an increase of "only" 2.1 fold found in male subjects. In view of the impact of sexual hormones on glucose homeostasis, the molecular pathways involved in insulin resistance suggest a sex-gender specificity mechanism in the development of diabetic complications leading to the unmet need of sex-gender therapeutic approaches. This has also been seen in other diabetic complications such as renal diseases, which seems to progress at a faster rate in females compared with males and women benefit less from treatment than do men. Of note, none of the trials done so far are primarily designed to assess sex-gender differences in the benefit from a specific intervention strategy, de facto excluding fertile women from experimentation. In order to provide a more evidence based medicine for women and to reach equity between men and women, sex-gender epidemiological reports, preclinical and clinical research are mandatory to evaluate the impact of gender on the outcomes and to improve sex-gender awareness and competency in the health care system. Future studies should consider sex-gender differences in the setting of randomized controlled trials with drugs.     

Statins for diabetic cardiovascular complications

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.