抗结肠炎药美沙拉嗪的合成研究进展

美沙拉嗪是治疗溃疡性结肠炎的临床用药。本文归纳了其原料药的合成方法,根据合成路线的不同,将合成方法分为四类,并对这四类方法进行了比较分析,总结出各自的优缺点。     

混酸法改进美沙拉嗪的合成

以硝酸和浓硫酸混合硝化水杨酸，然后还原合成美沙拉嗪，总产率为39.2%。该法可用于工业规模生产提高产品纯度。     

硫普罗宁与炎症性肠病

目的就硫普罗宁与柳氮磺胺吡啶(SASP)对溃疡性结肠病的治疗效果进行评估。方法将在我院就诊的溃疡性结肠炎患者40例随机分成2组。硫普罗宁与柳氮磺胺吡啶(SASP)组;单纯(SASP)组各20例,前者口服硫普罗宁0.2g/d,tid,同时口服SASP1g/d,tid,4周为1个疗程;后者口服SASP1g/d4次,4周为1个疗程。结果比较2组治疗,结果加服硫普罗宁组有效17例,3例症状改善不明显;单纯(SASP)组9例有效,11例症状不明显。结论SASP与硫普罗宁治疗溃疡性结肠炎效果明显。     

柱前衍生化高效液相色谱法测定美沙拉嗪肠溶片中5-ASA的含量

采用RP-HPLC测定美沙拉嗪肠溶片中5-氨基水杨酸（5-ASA）的含量。柱前衍生化使样品中5-ASA乙酰化,采用反相高效液相色谱法,色谱柱为ODS C18,流动相为磷酸盐缓冲液-乙腈（92∶8）,流速为0.9 m L·min-1,检测波长为304 nm。结果表明,5-ASA在3.12~50.0μg·m L-1范围内线性关系良好（r=0.999 6）,平均回收率为100.8%,RSD为1.27%,柱前衍生化高效液相色谱法测定美沙拉嗪肠溶片中5-ASA的含量简便、快速、准确、专属性强,适用于美沙拉嗪肠溶片中5-ASA的含量测定。     

马沙拉嗪的合成工艺改进

苯胺重氮化生成重氮盐,和水杨酸偶合形成偶氮化合物,再还原得到马沙拉嗪.得到总收率为80%的马沙拉嗪,产品达到药用标准.该方法简单,原料易得,后处理简单,适合工业化生产.     

马沙拉嗪的合成工艺改进

水杨酸在固体酸的催化下,被硝酸选择性硝化,合成5-硝基水杨酸,再经催化加氢合成马沙拉嗪,总产率接近80%,纯度达到99.0%以上.并且工艺条件易于控制,污染少,具有良好的工业应用前景.     

奥沙拉嗪合成工艺的改进

将9·1g亚硝酸钠在15℃以下滴加到15·3g5-氨基水杨酸(5-ASA)和30mL盐酸组成的混合液中,重氮化反应2h制得中间体5-ASA重氮盐(氯化偶氮水杨酸);然后与0·2mol水杨酸钠在碱性条件下偶合,得到粗品。用水重结晶,得到棕黄色粉状结晶奥沙拉嗪21·2g,即3,3’-偶氮(6-羟基苯甲酸)二钠盐,以5-ASA计收率为61·2%。     

IL-6对诊断和治疗IBD的意义研究

炎症性肠病(IBD)是一种慢性的,易复发的胃肠道炎性疾病.克罗恩氏病(CD)和溃疡性结肠炎(UC)可能是由于环境和遗传易感宿主中肠道菌群之间的平衡受损,从而导致不适当的免疫激活和促炎性细胞因子的过度生产.IL-6是机体发生炎症反应时的重要调节因子,与IBD以及其他慢性炎症性疾病有关.IL-6诱导的信号转导主要出现在相对...     

黛力新联合美常安治疗肠易激综合征(IBS)疗效观察

目的观察黛力新、美常安联合治疗肠易激综合征(IBS)的疗效及毒副反应。方法144例肠易激综合征(IBS)随机分成3组,3组病例具有可比性,治疗组50例,予黛力新10.5mg,每日2次,美常安2粒,每日3次;单用黛力新组46例,口服黛力新10.5mg,每日2次;单用美常安组48例,口服美常安2粒,每日3次。治疗4周后3组进行疗效比较。结果治疗组总有效率94%,单用黛力新组总有效率80.4%,单用美常安组总有效率75%,治疗组与对照组比较,差异有显著性(P<0.05),单用黛力新组总有效率与单用美常安组相比,差异无显著性。3组患者均未发现明显的不良反应。结论黛力新、美常安联合治疗肠易激综合征(IBS)有较好疗效,毒副作用小,值得临床推广应用。     

帕罗西汀(赛乐特)联合马来酸曲美布汀治疗肠易激综合征60例临床观察

目的观察帕罗西汀(赛乐特)联合马来酸曲美布汀治疗肠易激综合征(IBS)的临床疗效。方法将120例临床确诊为肠易激综合征患者,按随机数字法分为治疗组和对照组各60例,治疗组用帕罗西汀(赛乐特)联合马来酸曲美布汀治疗,对照组单独口服马来酸曲美布汀治疗,总疗程4周,观察疗效。结果 2组临床症状均能明显改善,治疗组总有效率89.98%,对照组69.93%,治疗组总有效率高于对照组,2组疗效差异显著(P<0.05)。结论以帕罗西汀(赛乐特)联合马来酸曲美布汀治疗IBS疗效肯定。     

Next-Generation Probiotics for Inflammatory Bowel Disease

Engineered probiotics represent a cutting-edge therapy in intestinal inflammatory disease (IBD). Genetically modified bacteria have provided a new strategy to release therapeutically operative molecules in the intestine and have grown into promising new therapies for IBD. Current IBD treatments, such as corticosteroids and immunosuppressants, are associated with relevant side effects and a significant proportion of patients are dependent on these therapies, thus exposing them to the risk of relevant long-term side effects. Discovering new and effective therapeutic strategies is a worldwide goal in this research field and engineered probiotics could potentially provide a viable solution. This review aims at describing the proceeding of bacterial engineering and how genetically modified probiotics may represent a promising new biotechnological approach in IBD treatment.     

The Era of Janus Kinase Inhibitors for Inflammatory Bowel Disease Treatment

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn’s disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.     

Bile Acid Signaling in Inflammatory Bowel Disease

Inflammatory bowel disease is a chronic, idiopathic and complex condition, which most often manifests itself in the form of ulcerative colitis or Crohn’s disease. Both forms are associated with dysregulation of the mucosal immune system, compromised intestinal epithelial barrier, and dysbiosis of the gut microbiome. It has been observed for a long time that bile acids are involved in inflammatory disorders, and recent studies show their significant physiological role, reaching far beyond being emulsifiers helping in digestion of lipids. Bile acids are also signaling molecules, which act, among other things, on lipid metabolism and immune responses, through several nuclear and membrane receptors in hepatocytes, enterocytes and cells of the immune system. Gut microbiota homeostasis also seems to be affected, directly and indirectly, by bile acid metabolism and signaling. This review summarizes recent advances in the field of bile acid signaling, studies of inflamed gut microbiome, and the therapeutic potential of bile acids in the context of inflammatory bowel disease.     

Presume Why Probiotics May Not Provide Protection in Inflammatory Bowel Disease through an Azoxymethane and Dextran Sodium Sulfate Murine Model

Recent studies have shown dysbiosis is associated with inflammatory bowel disease (IBD). However, trying to restore microbial diversity via fecal microbiota transplantation (FMT) or probiotic intervention fails to achieve clinical benefit in IBD patients. We performed a probiotic intervention on a simulated IBD murine model to clarify their relationship. IBD was simulated by the protocol of azoxymethane and dextran sodium sulfate (AOM/DSS) to set up a colitis and colitis-associated neoplasm model on BALB/c mice. A single probiotic intervention using Clostridium butyricum Miyairi (CBM) on AOM/DSS mice to clarify the role of probiotic in colitis, colitis-associated neoplasm, gut microbiota, and immune cytokines was performed. We found dysbiosis occurred in AOM/DSS mice. The CBM intervention on AOM/DSS mice failed to improve colitis and colitis-associated neoplasms but changed microbial composition and unexpectedly increased expression of proinflammatory IL-17A in rectal tissue. We hypothesized that the probiotic intervention caused dysbiosis. To clarify the result, we performed inverse FMT using feces from AOM/DSS mice to normal recipients to validate the pathogenic effect of dysbiosis from AOM/DSS mice and found mice on inverse FMT did develop colitis and colon neoplasms. We presumed the probiotic intervention to some extent caused dysbiosis as inverse FMT. The role of probiotics in IBD requires further elucidation.     

Stem Cell-Based Therapies for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.     

Chronic Experimental Model of TNBS-Induced Colitis to Study Inflammatory Bowel Disease

Background: Inflammatory bowel disease (IBD) is a world healthcare problem. In order to evaluate the effect of new pharmacological approaches for IBD, we aim to develop and validate chronic trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Methods: Experimental colitis was induced by the rectal administration of multiple doses of TNBS in female CD-1 mice. The protocol was performed with six experimental groups, depending on the TNBS administration frequency, and two control groups (sham and ethanol groups). Results: The survival rate was 73.3% in the first three weeks and, from week 4 until the end of the experimental protocol, the mice’s survival remained unaltered at 70.9%. Fecal hemoglobin presented a progressive increase until week 4 (5.8 ± 0.3 µmol Hg/g feces, p < 0.0001) compared with the ethanol group, with no statistical differences to week 6. The highest level of tumor necrosis factor-α was observed on week 3; however, after week 4, a slight decrease in tumor necrosis factor-α concentration was verified, and the level was maintained until week 6 (71.3 ± 3.3 pg/mL and 72.7 ± 3.6 pg/mL, respectively). Conclusions: These findings allowed the verification of a stable pattern of clinical and inflammation signs after week 4, suggesting that the chronic model of TNBS-induced colitis develops in 4 weeks.     

Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and Potential Therapeutic Targets

Microbe–host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.     

The Interplay between Immune System and Microbiota in Inflammatory Bowel Disease: A Narrative Review

The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain–gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.     

Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease

Tumor necrosis factor (TNF) α is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.