复方谷氨酰胺联合柳氮磺吡啶治疗溃疡性结肠炎的疗效观察

目的 研究复方谷氨酰胺联合柳氮磺吡啶治疗溃疡性结肠炎的临床疗效。方法 选择2017年1月-2019年1月榆林市星元医院的120例溃疡性结肠炎患者作为研究对象,采用抽签法随机分为对照组和观察组,每组各60例。对照组患者口服柳氮磺吡啶肠溶片,6片/次,3次/d。观察组患者在对照组的基础上口服复方谷氨酰胺肠溶胶囊,3粒/次,3次/d。两组均治疗4周。观察两组患者的临床疗效,比较两组治疗前后的相关症状、评分情况,以及炎性因子水平。结果 治疗后,观察组的总有效率为91.67%,明显高于对照组的71.67%（P<0.05）。治疗后,观察组的黏液脓血便消失时间为（10.13±1.27）d,明显短于对照组的（19.73±2.45）d（P<0.05）。两组治疗后的疾病活动指数和腹痛程度评分均明显降低（P<0.05）,且观察组明显更低（P<0.05）。两组治疗后的血清白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）、IL-8、超敏C反应蛋白（hs-CRP）水平均明显降低（P<0.05）,且观察组明显更低（P<0.05）。结论 复方谷氨酰胺联合柳氮磺吡啶对溃疡性结肠炎的疗效较佳,能明显减轻腹痛程度,改善炎症因子水平,降低疾病活动指数。     

Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery

In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-l-glutamyl)-amino-2-salicylic acid (1), (N-l-aspartyl)-amino-2-salicylic-acid (2), 5-aminosalicyl-l-proline-l-leucine (3), and 5-(N-l-glutamyl)-aminosalicyl-l-proline-l-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N=30) and to animals that had undergone prior colostomy (N=30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, andN-acetyl-5-ASA were measured by high-performance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (>65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (<35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-l-Glutamyl)-aminosalicyl-l-proline-l-leucine yielded the highest fecal recovery of 5-ASA and itsN-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.We acknowledge the Depha Team for financial support and Dr. Kenneth D.R. Setchell for discussions.     

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

System x_c⁻ (Sx_c⁻), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sx_c⁻. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sx_c⁻ antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sx_c⁻ inhibitory activity following in vitro Sx_c⁻ inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.     

Maternal use of 5-aminosalicylates in early pregnancy and congenital malformation risk in the offspring

Abstract

Objective. Most previous studies have failed to demonstrate any effect of maternal use of 5-aminosalicylates (5-ASA) on malformation risk, but the number of infants studied have, in most cases, been low. The objective of the study was to get data from a large study with prospectively ascertained exposure information. Material and methods. The study was based on data in the Swedish Medical Birth Register (1996–2011) where identification of maternal drug use is made from midwife interviews in early pregnancy. The presence of congenital malformations was ascertained from three national registers. Adjusted odds ratios were calculated by the Mantel-Haenszel methodology. Results. Among 1,552,109 women, 3651 with 3721 infants had reported the use of 5-ASAs in early pregnancy. The risk of a major malformation was increased (1.37, 95% confidence interval = 1.17–1.62) and still more for a cardiovascular defect (1.74, 1.37–2.22). This effect seemed to be influenced by concomitant use of systemic glucocorticosteroids or immunosuppressants but some confounding by indication may also exist. There was no marked difference between the four 5-ASA drugs studied. Conclusions. Infants born of women who use 5-ASA drugs in early pregnancy have an increased risk of a congenital malformation, notably a cardiovascular defect. This could be a drug effect or an effect of an active inflammatory bowel disease.     

The effects of an orally administered probiotic on sulfasalazine metabolism in individuals with rheumatoid arthritis: a preliminary study

Aim: To carry out a pilot study to investigate the effect of short‐term oral probiotic administration on the metabolism of sulfasalazine (SSZ) in patients with rheumatoid arthritis (RA) stabilized on SSZ. Methods: Twelve subjects with RA taking stable doses of SSZ for a minimum of 3 months prior to the study, received a probiotic preparation contained three strains of bacteria (1.8 × 10⁹ CFU/day) twice daily for 1 week. Single point blood and 12‐h urine samples were taken before and after probiotic treatment and 3 weeks following discontinuation of probiotics, for determination of SSZ and its metabolites. The presence of the probiotic bacteria in the feces of patients was investigated by denaturing gradient gel electrophoresis (DGGE). Results: Adverse events recorded were three instances of gastrointestinal disturbance and one flare of RA. Plasma and urinary levels of SSZ and its metabolites showed no statistically significant changes after probiotic administration and the incidence of gastrointestinal disturbance did not appear to be ascribed to higher sulfapyridine plasma levels. Probiotic‐specific DGGE bands were detected in the feces of some patients after the treatment period. Conclusions: Short‐term treatment of RA patients with a multi‐strain probiotic did not significantly influence SSZ metabolism as has been demonstrated in animal models.     

来氟米特与柳氮磺吡啶治疗强直性脊柱炎的临床对比研究

目的：对来氟米特（leflunomide，LEF）和柳氮磺吡啶（sulfasalazine，SASP）治疗强直性脊柱炎（ankylosing spondylitis，AS）的疗效进行为期2年的临床对比观察，以评价两种药物治疗AS的有效性及安全性。方法：将112例住院治疗的AS患者随机分为两组，每组各56例，分别采用LEF（LEF组）或SASP（SASP组）治疗，两组患者的年龄、性别、病程及病情相匹配，均选择一种非甾体类抗炎药（NSAIDs）作为基础疗法。随访2年，记录症状体征、Bath AS活动指数（BASDAI）、Bath AS功能指数（BASFI）、红细胞沉降率和C-反应蛋白浓度等实验室检查及不良反应。结果：两组患者随访第1、2年与入院时比较，腰骶痛明显减轻，腰背晨僵时间显著缩短，BASDAI和BASFI明显降低，炎性指标红细胞沉降率和C-反应蛋白浓度显著下降（均P〈0．05）；随访第1、2年两组间比较，腰骶痛、腰背晨僵时间、BASDAI、BASFI、红细胞沉降率和C-反应蛋白浓度，LEF组较SASP组改善明显，差异均有统计学意义（P〈0．05）。药物不良反应以胃肠道反应、白细胞数减少和皮疹为主，LEF组胃肠道反应明显低于SASP组（5．2％vs11．8％）（P〈0．05），白细胞数减少和皮疹两组间差异无统计学意义。结论：LEF治疗AS疗效优于SASP。LEF不良反应少，服用方便，患者易耐受，其更长期的疗效及安全性有待进一步观察。     

柳氮磺胺嘧啶对大鼠移植心脏心肌白细胞介素-1β和细胞间黏附分子-1表达的影响

目的: 探讨柳氮磺胺嘧啶 (SSA)对移植心脏的保护作用。方法:建立大鼠异位心脏移植模型,分为 3组:Wistar到Wistar大鼠为对照组, SD到Wistar大鼠为同种移植组, 同种移植SSA治疗组。于移植术后第 3d、5d、7d检测移植心肌组织IL- 1β、ICAM -1,并观察排斥反应发生情况。结果:对照组心肌组织术后第 3d, 5d, 7dIL 1β分别为(124. 89±3. 29)ng/g, (126. 96±2. 73)ng/g, (124. 25±2. 87 )ng/g;ICAM 1分别为 ( 144. 40±22. 11 ),(145. 51±1. 73), (147. 61±2. 05);表达均微弱。同种移植组各时间点IL 1β分别为(154. 48±2. 42)ng/g, (336. 42±3. 24), (336. 72±2. 75)ng/g;ICAM 1分别为(177. 38±2. 16), (196. 16±2. 39), (196. 43±2. 22),与对照组相比均增高(P<0. 05 );SSA治疗组IL 1β分别为 (135. 13±2. 28)ng/g, (145. 50±2. 08 )ng/g, ( 153. 28±1. 73 )ng/g;ICAM 1分别为(153. 95±1. 66), (154. 97±1. 98), (145. 04±2. 36);表达均较同种移植组降低 (P<0. 01 )。对照组心肌组织结构基本正常,同种移植组表现出不同程度的淋巴细胞浸润、心肌间质水肿和组织坏死; SSA治疗组心肌损伤程度降低。结论:大鼠心脏移植急性排斥反应中IL- 1β、ICAM -1的升高,对移植心脏起到保护作用。     

Fourier Transform-Raman Spectroscopy for the Qualitative and Quantitative Characterization of Sulfasalazine-Containing Polymeric Microspheres

FT-Raman spectroscopy (FTRS) has been used to characterize microspheres produced from the pharmaceutical polymer Eudragit RS containing a range of concentrations of the drug sulfasalazine. While pure sulfasalazine produced an intense and complex Raman spectrum, the spectrum of drug-free Eudragit RS microspheres was considerably weaker in intensity and contained only a few prominent Raman scattering peaks. In spectra of the drug–polymer micro-spheres, peaks arising from the individual components could be identified. This enabled a quantitative analysis to be undertaken by calculating the ratio between the area of a sulfasalazine peak and the area of a Eudragit RS peak for each microsphere spectrum. A correlation was shown between the peak area ratio and the microsphere sulfasalazine content. FTRS was then applied to a series of microsphere samples which had been dissoluted into pH 7 buffer for 1, 3, 6, 9, 12, or 24 hr. For each spectrum, the drug-polymer peak area ratio was determined and this in turn enabled calculation of the residual drug content of the microsphere sample. FTRS-calculated data showed good agreement with microsphere drug content values determined spectrophotometrically.