Novel therapy for atherosclerosis and inflammatory vascular disease

How to manage residual atherosclerosis risk after the statin therapy is a major concern in cardiovascular medicine. In addition to life-style modifications, new drugs against atherosclerotic and inflammatory vascular diseases are expected. In current clinical trials, phospholipase A2 inhibitors(darapladib, varespladib), RVX-208, D-4F, CETP inhibitors (anacetrapib, dalcetrapib), succinobucol are investigated. Some has been failed, but others are still promising. On molecular target basis of PAF-AH, CETP, PON, ABC transporters of A1 and G1, SR-BI, HO-1, potential benefits and side effects are discussed.     

Investigating cell therapy for inflammatory bowel disease

ABSTRACT

Introduction: Advances in immuno-modulatory therapies, including anti-TNF-α therapies, have greatly increased the chance to achieve long-term remission of inflammatory bowel disease (IBD) patients. However, as the importance of mucosal healing has been demonstrated in a number of clinical studies, new cell-based therapies that can regenerate and fully restore the intestinal mucosal functions are currently under development.

Area covered: In this review, we feature the recent challenges of cell-based therapies that are applied to the treatment of IBD. In particular, we will focus on hematopoietic stem cells (HSC), mesenchymal stem cells (MSCs) and intestinal stem cells (ISCs) as the candidate source for cell-based therapy targeted to treat IBD. The current status, as well as the expected advantages and disadvantages of those transplantations will be summarized and discussed.

Expert opinion: Transplantation of HSC, MSC and ISC may have different levels of potential in their ability to exert an immunomodulatory or pro-regenerative effect. Combined cell therapies, such as co-transplantation of MSC and ISC, may provide improved therapeutic outcome compared to transplantation of a single cell population. Those cell-based therapies may not only improve the disease activity or tissue regeneration, but may also have the potential to decrease the risk of developing colitis-associated cancers.     

炎症性肠病患者的营养支持治疗

溃疡性结肠炎和克罗恩病等炎症性肠病患者常伴有营养不良及生长发育障碍。营养支持治疗在炎症性肠病治疗中占有重要地位。应常规对炎症性肠病患者进行营养风险筛查,并采用适当方法进行营养评定,以便及时进行营养支持。肠内营养支持作为儿童克罗恩病患者诱导缓解和维持治疗的首选,在成人患者中作为药物的替代治疗。有多种营养制剂,不同患者对不同的营养制剂反应不同,需选择合适的制剂,进行个体化治疗,才能发挥营养制剂的最大效用。     

Alicaforsen therapy in inflammatory bowel disease

Current understanding of inflammatory bowel disease (IBD) has resulted in the development of new treatments that antagonise the pathological pathways associated with T lymphocytes and inflammatory cytokines. Intercellular adhesion molecules (ICAMs) contribute to leukocyte adhesion and migration, local lymphocyte stimulation, and are responsible for T lymphocyte trafficking in the intestine. ICAMs are constitutively expressed by enterocytes and are upregulated in the presence of inflammation. Mobile T lymphocytes in the circulatory system are key to the deleterious inflammatory response resulting in IBD. Alicaforsen, a human ICAM-1 antisense oligonucleotide, blocks ICAM-1 production by disabling target RNA molecules and blocking the translation of protein. This alters the local inflammatory reaction in the intestinal wall. Alicaforsen has been evaluated in both Crohn's disease and ulcerative colitis. The role of the immune system in IBD is reviewed and the responses to treatment with alicaforsen are discussed.     

Newer pharmacologic agents for the therapy of inflammatory bowel disease

Topical 5-ASA Agents. Observations that 5-ASA may be the clinically active component of sulfasalazine have stimulated extensive pharmaceutical efforts to develop a new class of agents for the treatment of the inflammatory bowel diseases. Both oral and rectal forms of 5-ASA have been designed, tested, and released for use in Europe and Canada. Only one rectal 5-ASA formulation is now commercially available in the United States. Studies with topical 5-ASA have demonstrated that this formulation is safe and effective for distal colitis, even in patients with disease refractory to standard therapy. Adverse effects of topical 5-ASA are minimal. However, optimal treatment doses have not been defined, relapse is common after withdrawal of therapy, and issues regarding maintenance regimens are not yet resolved. Other disadvantages include the expense and inconvenience of enema therapy. However, rectally administered 5-ASA is an appropriate initial therapy for the treatment of distal ulcerative colitis, or as a therapeutic option for refractory distal colitis. Data are insufficient to make recommendations regarding the use of topical 5-ASA in Crohn's disease. Whether this class of agents will be of benefit for Crohn's proctitis or for perineal disease must await further clinical trials. Oral 5-ASA Agents. There appears to be a well-substantiated benefit equivalent to that of sulfasalazine achieved by the new oral formulations of 5-ASA when used for the treatment of acute mild to moderate ulcerative colitis, and as maintenance treatment of ulcerative colitis in remission. Adverse reactions to these agents are uncommon, usually mild, and infrequently require withdrawal of therapy. The major problem reported with these agents is watery diarrhea, most commonly associated with olsalazine, but the practical importance of this adverse effect is disputed. Rare occurrences of reversible pericarditis and acute pancreatitis have been encountered during clinical application of these agents. As more experience is obtained, these agents may become the initial therapy of choice for the treatment of mild to moderate ulcerative colitis and for maintenance in inactive disease. Currently available data have defined a role for these agents as an important alternative for the treatment of patients intolerant or allergic to sulfasalazine. As with sulfasalazine, these agents should not be used as the sole treatment for severely active ulcerative colitis. Many unanswered questions remain regarding therapy with these agents for ulcerative colitis. Still undefined are optimal drug dosages, appropriate dosing intervals, and the necessary duration of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interleukin-10-based therapy for inflammatory bowel disease

In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD. This review will discuss the characteristics of IL-10, its immunoregulatory properties in mice and humans, and the use of IL-10 as a treatment for CD. The review will summarise the clinical studies that have taken place and discuss the lessons learned from these trials. Finally, the advantages and disadvantages of promising new strategies of IL-10 treatment, including gene therapy and the use of genetically modified bacteria, will be discussed. Both novel therapies have been shown to be successful in animal models of disease, and clinical testing is currently underway. The future goal of IL-10 treatment should be focused on mucosal delivery and remission maintenance instead of remission induction. In conclusion, it can be said that despite the disappointing results of IL-10 therapy so far, there is still enough rationale for the use of IL-10 as an anti-inflammatory biological treatment in chronic IBD.     

Current status of drug therapy for inflammatory bowel disease

Both topical steroids and sulfasalazine are useful for patients with ulcerative proctitis and distal colitis. For patients with more extensive ulcerative colitis with moderate symptoms, prednisone and/or sulfasalazine will result in improvement in about 80% of patients. Parenteral corticosteroids or ACTH should be used in the setting of severe colitis and antibiotics added if the patient appears toxic. Sulfasalazine is of proven efficacy as maintenance therapy in ulcerative colitis. Prednisone and sulfasalazine are useful in Crohn's disease, although the latter is of limited use in patients with ileitis alone. Immunosuppressive agents such as azathioprine and 6-mercaptopurine may be especially helpful in Crohn's patients refractory to other drugs or dependent on high doses of steroids. Azathioprine is of proven usefulness as maintenance treatment of Crohn's disease. Metronidazole is as effective as sulfasalazine in Crohn's disease involving the colon and has an important role in severe perineal disease. New forms of steroid enemas and topical and oral forms of 5-aminosalicylate based on sulfasalazine should be available soon for patients with both ulcerative colitis and Crohn's disease.     

Biological therapy for dermatological manifestations of inflammatory bowel disease

Ulcerative colitis and Crohn’s disease are the two forms of inflammatory bowel disease (IBD). The advent of biological drugs has significantly changed the management of these conditions. Skin manifestations are not uncommon in IBD. Among the reactive lesions (immune-mediated extraintestinal manifestations), erythema nodosum (EN) and pyoderma gangrenosum (PG) are the two major cutaneous ills associated with IBD, while psoriasis is the dermatological comorbidity disease observed more often. In particular, in the last few years, anti-tumor necrosis factor (TNF)-α agents have been successfully used to treat psoriasis, especially these kinds of lesions that may occur during the treatment with biological therapies. The entity of the paradoxical manifestations has been relatively under reported as most lesions are limited and a causal relationship with the treatment is often poorly understood. The reason for this apparent side-effect of the therapy still remains unclear. Although side effects may occur, their clinical benefits are undoubted. This article reviews the therapeutic effects of the two most widely used anti-TNF-α molecules, infliximab (a fusion protein dimer of the human TNF-α receptor) and adalimumab (a fully human monoclonal antibody to TNF-α), for the treatment of the major cutaneous manifestations associated with IBD (EN, PG and psoriasis).     

磁共振成像在大鼠炎性肠病模型的诊断及疗效监测中的应用

目的 研究大鼠炎性肠病模型的MRI表现以及应用MRI监测柳氮磺胺吡啶（SASP）疗效的可行性.方法 20只炎性肠病大鼠模型随机分为治疗组及对照组,分别给予SASP或对照剂灌肠.在诱导结肠炎前、后不同时间点对两组大鼠进行腹部MRI扫描,测量相近层面结肠壁厚度.最后一次MRI检查后处死大鼠并对结肠炎病理分级.比较两组大鼠不同时间点的结肠壁厚度比例及两组大鼠结肠炎病理分级.结果 非治疗组大鼠各时间点肠壁均明显厚于诱导前,而诱导后各时间点的肠壁厚度间无统计学差异.治疗组随治疗时间的延长各时间点的肠壁厚度显著减低.治疗组炎症分级高于非治疗组,但尚未达到统计学差异.结论 MRI可以作为一种有效的方法对SASP治疗大鼠炎性肠病的疗效进行监测.     

免疫抑制剂在炎症性肠病治疗中的应用进展

炎症性肠病包括溃疡性结肠炎和克罗恩病,是病因尚不十分明确的肠道慢性反复的非特异性炎症。免疫抑制剂是重要的药物治疗方法,维持无激素长期缓解,主要用于克罗恩病和激素依赖或抵抗的溃疡性结肠炎的维持治疗。常用的免疫抑制剂包括硫嘌呤类、甲氨蝶呤、环孢素等药物。     

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1- like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.     

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease

Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.     

Luminescent nanoparticles and their use for in vitro and in vivo diagnostics

Fluorescence spectroscopy has been shown to be a useful tool for a broad variety of biological and medical applications. Many of the analytical methods, as used for tumor marker and gene mutation detection, recognition of pathogens or monitoring of cell-related processes, are based on the labeling of the investigating object with luminescent nanoparticles. Owing to their size, which is comparable to that of biomolecules, and to their extraordinary optical properties, luminescent nanoparticles could well improve the sensitivity and flexibility of current detection techniques. This article provides a general overview of the synthesis, properties and application of luminescent semiconductor, metal and inorganic nanoparticles for in vitro and in vivo diagnostics, also reflecting the aspect of biocompatibility.     

New therapy in inflammatory bowel disease (infliximab)

In inflammatory bowel disease, such as Crohn's disease, certain immunological abnormalities are considered as its cause, but the fundamental mechanism remains unclear. However, recent researches revealed that inflammatory cytokines and adhesion molecules, such as TNFalpha, IL-6, IL-12 and alpha4 integrin, play an important role in the pathogenesis of Crohn's disease. This led to the development of anti-cytokine therapy and anti-adhesion molecules therapy using monoclonal antibodies to theses cytokines and adhesion molecules. Among them, infliximab, a chimeric monoclonal antibody to TNFalpha, is most clinically applied and marked therapeutic effect is seen in Crohn's disease. Moreover various anti-cytokine therapy was introduced in clinical fields.     

炎症性肠病病情活动监测指标的临床价值

目的探讨髓过氧化物酶(MPO)和超氧化物歧化酶(SOD)作为炎症性肠病(IBD)病情活动临床监测指标的价值。方法分别观察了IBD活动组患者15例[其中活动期溃疡性结肠炎(UC)10例,活动期克罗恩病(CD)5例],IBD非活动组患者15例(其中缓解期UC10例,缓解期CD5例)和12例对照组患者的结肠黏膜病理变化,按Oshitani评分标准和d'Haens评分标准进行UC和CD组织学评分,测定结肠黏膜MPO和SOD活性。结果IBD活动组、IBD非活动组病理组织评分均比对照组高(8±5 vs 3±1)、(5±2 vs 3±1)(P<0.01),IBD活动组病理组织评分亦较IBD非活动组高(8±5 vs 5±2)(P<0.01);IBD活动组、IBD非活动组肠黏膜MPO活性均较对照组高[(3.55±0.38)U/g vs(1.52±0.24)U/g、(2.28±0.30)U/g vs(1.52±0.24)U/g](P<0.01),IBD活动组MPO活性较IBD非活动组高[(3.55±0.38)U/g vs(2.28±0.30)U/g](P<0.01);IBD活动组、IBD非活动组肠黏膜SOD活性均较对照组低[(104.58±18.91)U/mg vs(212.44±14.22)U/mg、(170.91±13.57)U/mg vs(212.44±14.22)U/mg](P<0.01),IBD活动组SOD活性较IBD非活动组低[(104.58±18.91)U/mg vs(170.91±13.57)U/mg](P<0.01)。结论MPO活性与IBD病情活动程度呈正相关,SOD活性与IBD病情活动程度呈负相关,两者可作为IBD病情活动的临床监测指标。