G蛋白偶联受体119激动剂MBX-2982的合成

目的改进G蛋白偶联受体119(GPR119)激动剂MBX-2982的合成工艺。方法以4-氰基哌啶-1-甲酸叔丁酯为起始原料,经过硫代、缩合、醚化、脱Boc保护以及取代反应制得MBX-2982。结果与结论经5步反应合成目标化合物MBX-2982,其结构经1H-NMR及MS谱确证。对多步反应条件进行了工艺考察及优化,总收率为42.8%(以4-氰基哌啶-1-甲酸叔丁酯计),高于文献收率(30.8%)。     

氯雷他定 、布地奈德联合皮下特异性免疫对变应性鼻炎的临床疗效研究

目的 观察药物联合皮下特异性免疫对变应性鼻炎的免疫调节作用,并评估其临床疗效.方法 收集治疗的变应性鼻炎患者84例,随机分为氯雷他定、布地奈德鼻喷雾剂常规药物治疗(对照组)和氯雷他定、布地奈德鼻喷雾剂联合特异性免疫治疗(观察组),每组42例.Th17和Treg细胞细胞使用流式细胞仪检测,IgE、IL-17、IL-10因子表达使用ELISA法检测.结果 治疗前2组Th17和Treg细胞差异无统计学意义(P>0.05),治疗后2组Th17细胞比例均出现显著减低(P<0.05),Treg细胞比例均出现显著升高(P<0.05),但观察组对Th17和Treg细胞比例的调节作用优于观察组(P<0.05).治疗前2组IgE、IL-17和IL-10表达差异无统计学意义(P>0.05),治疗后2组IgE和IL-17表达均出现显著减低(P<0.05),IL-10表达均出现显著升高(P<0.05),但观察组对IgE、IL-17和IL-10表达的调节作用优于观察组(P<0.05).IgE表达与IL-17呈显著正相关(r=0.412,P<0.05),与IL-10呈显著负相关(r=-0.354,P<0.05).治疗前2组症状评分和用药评分差异无统计学意义(P>0.05),治疗后2组症状评分均出现显著减低(P<0.05),但观察组的改善作用优于观察组(P<0.05),治疗后对照组用药评分与治疗前差异无统计学意义(P>0.05),而对照组用药评分则出现显著减低(P<0.05).结论 特异性免疫治疗可以调节变应性鼻炎患者Th17/Treg细胞失衡,临床疗效显著,且可以减少对症治疗抗组胺以及局部激素药物的用量.     

Cysteinyl leukotriene receptor CysLT1 as a novel therapeutic target for allergic rhinitis treatment

Background: Cysteinyl leukotrienes (cys-LTs) play an important role in allergic rhinitis because CysLT₁ receptor antagonists relieve the symptoms of allergic rhinitis. Objective: I overview the clinical pharmacology of CysLT₁ receptor antagonists and their potential role in patients with allergic rhinitis. Methods: I review the evidence regarding the release of cys-LTs and localization of CysLT₁ receptor on nasal mucosa, and evaluate the clinical efficacy of CysLT₁ receptor antagonist in allergic rhinitis. Results/conclusion: Immunohistochemical studies show that in allergic rhinitis, the major target of CysLT₁ receptor antagonists are the vascular bed and infiltrated leukocytes such as mast cells, eosinophils and macrophages. CysLT₁ receptor antagonists provide a new opportunity for simultaneous management of allergic diseases of the upper and lower respiratory tract.     

白介素-1受体拮抗剂对豚鼠变应性鼻炎的治疗作用

目的：明确白介素-1受体拮抗剂对变应性鼻炎的治疗作用。方法：采用甲苯-2,4-二异氰酸酯（TDI toluene-2,4-diisocyanate)致敏豚鼠,制作变应性鼻炎模型,观察给予白介素-1受体拮抗剂（IL-1ra）处理前后症状和体征的变化,用组织病理学方法观察鼻粘膜的改变,测量鼻粘膜中组胺、血中IgE的含量。结果：用IL-1ra治疗后,变应性鼻炎症状和体征明显改善,HE染色显示,鼻粘膜水肿及炎性细胞浸润,随IL-1ra浓度的提高而改善,鼻粘膜中组胺、血中IgE的含量下降,随白介素-1拮抗剂浓度升高而下降。特别是高剂量组,各指标好于其它各治疗组,阳性对照组也有鼻粘膜水肿,及炎性细胞浸润。结论：局部使用IL-1ra拮抗剂能治疗变应性鼻炎。     

生活方式干预对过敏性鼻炎患者的影响

目的：探讨生活方式干预对过敏性鼻炎患者的影响。方法将116例过敏性鼻炎患者随机分为实验组和对照组,每组各58例,对照组给予常规对症护理,实验组在对照组的基础上给予生活方式干预,采用生活方式情况评价表、治疗效果评价表对两组患者干预前、干预1年后的生活方式情况、治疗效果进行比较。结果与干预前比较,干预1年后实验组的生活方式情况、治疗效果明显优于对照组,差异有统计学意义（ P＜0.05）。结论生活方式干预有利于过敏性鼻炎患者建立健康的生活方式,提高治疗效果,从而进一步提高患者的生活质量。     

丙酸氟替卡松治疗过敏性鼻炎对哮喘的影响

目的：现察丙酸氟替卡松治疗过敏性鼻炎对哮喘控制的影响。方法：74名6—12岁儿童随机分为治疗组和对照组,治疗组38例给予丙酸氟替卡松治疗。对照组36例给予抗组胺药及0．5％呋麻液。随访一年。比较两组患儿哮喘急性发作次数、急诊次数及使用快速缓解药物次数的差异。结果：与对照组相比,治疗组哮喘急性发作次数、急诊次数、使用快速缓解药物次数均明显较对照组为少。结论：丙酸氟替卡松治疗过敏性鼻炎有助于哮喘的控制。     

组胺受体拮抗剂联合白三烯受体拮抗剂治疗过敏性鼻炎的疗效观察

目的 探讨H1组胺受体拮抗剂(H1RAs)联合白三烯受体拮抗剂(LTRAs)治疗过敏性鼻炎(AR)的临床疗效.方法 AR患者84例,采用随机数字表法分为观察组与对照组,各42例.对照组单用H1RAs——盐酸氮卓斯汀治疗,观察组在对照组基础上加用LTRAs——孟鲁司特钠治疗,对比两组的临床疗效,治疗前后评价鼻炎症状评分,检测血清微量元素、嗜酸性粒细胞阳离子蛋白(ECP)、特异性免疫球蛋白E(sIgE)及炎性因子水平.结果 观察组的总有效率为100.00％,显著高于对照组的88.10％(P<0.05);治疗后观察组的鼻炎症状评分显著低于对照组(P<0.05);治疗后观察组的血清sIgE、ECP、白细胞介素(IL)-4、IL-6、IL-8、Cu均显著低于对照组,IL-10、γ-干扰素(INF-γ)、Zn、Mn显著高于对照组(P<0.05).结论 H1RAs联合LTRAs治疗AR能够提高临床疗效、改善鼻炎症状,其机制可能与调节血清微量元素及sIgE、ECP水平、抗炎性反应有关.     

盐酸氮卓斯汀与丙酸氟替卡松喷鼻剂治疗变应性鼻炎临床对比观察

目的观察并比较盐酸氮卓斯汀与丙酸氟替卡松喷鼻剂在治疗变应性鼻炎中的效果。方法 146例变应性鼻炎患者,随机分为观察组和对照组,观察组应用盐酸氮卓斯汀喷鼻剂,对照组应用丙酸氟替卡松喷鼻剂(辅舒良),比较两组疗效及不良反应。结果两组治疗效果比较差异无统计学意义。但观察组起效快、不良反应明显少于对照组。结论对于常年性变应性鼻炎的治疗,应首选盐酸氮卓斯汀,该药起效快、安全有效,值得临床推广应用。     

Enhanced expression of G protein-coupled receptor kinase 2 selectively increases the sensitivity of A2A adenosine receptors to agonist-induced desensitization

1. G protein-coupled receptor kinases (GRKs) are thought to be important in mediating the agonist-induced phosphorylation and consequent desensitization of G protein-coupled receptor (GPCR) responses. We have previously shown that stable expression of a dominant negative mutant G protein- coupled receptor kinase 2 (GRK2) construct in NG108-15 mouse neuroblastoma x rat glioma cells suppresses the agonist-induced desensitization of A_2A and A_2B adenosine receptor-stimulated adenylyl cyclase activity (Mundell et al., 1997). To further determine the role of GRK2 in agonist-induced desensitization of these adenosine receptors, we stably overexpressed wild type GRK2 in NG108-15 cells.
2. In homogenates prepared from cells overexpressing GRK2, the acute stimulation of adenylyl cyclase by activation of A_2A and A_2B adenosine receptors was markedly reduced, but could be reversed by pretreating the cells with AD (adenosine deaminase), to remove extracellular adenosine from the medium. On the other hand, acute stimulation of adenylyl cyclase by secretin, iloprost, NaF and forskolin was the same in GRK2 overexpressing cells and plasmid-transfected control cells.
3. Cells overexpressing GRK2 were more sensitive to adenosine receptor agonist-induced desensitization than plasmid-transfected control cells. This effect was selective since the agonist sensitivity of desensitization for secretin and IP-prostanoid receptor-stimulated adenylyl cyclase activity was not affected by GRK2 overexpression.
4. These results further implicate GRK2 as the likely mechanism by which A₂ adenosine receptors undergo short-term desensitization in NG108-15 cells, and indicate that even when overexpressed, GRK2 retains its substrate specificity for native receptors in intact cells. Furthermore, the susceptibility of GPCRs to desensitization appears to depend on the level of GRK expression, such that in cells that express high levels of GRK2, low agonist concentrations may be sufficient to trigger GRK-mediated desensitization.

     

Disposition and metabolism of the G protein-coupled receptor 40 agonist TAK-875 (fasiglifam) in rats,dogs, and humans

1. The absorption, distribution, metabolism, and excretion of fasiglifam were investigated in rats, dogs, and humans.

2. The absolute oral bioavailability of fasiglifam was high in all species (>76.0%).

3. After oral administration of [¹⁴C]fasiglifam, the administered radioactivity was quantitatively recovered and the major route of excretion of radioactivity was via feces in all species.

4. Fasiglifam was a major component in the plasma and feces in all species. Its oxidative metabolite (M-I) was observed as a minor metabolite in rat and human plasma (<10% of plasma radioactivity). In human plasma, hydroxylated fasiglifam (T-1676427), the glucuronide of fasiglifam (fasiglifam-G), and the glucuronide of M-I were detected as additional minor metabolites (<2% of plasma radioactivity). None of these metabolites were specific to humans. Fasiglifam-G was the major component in the rat and dog bile.

5. In vitro cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) reaction phenotyping indicated that oxidation (to form M-I and T-1676427) and glucuronidation of fasiglifam are mainly mediated by CYP3A4/5 and UGT1A3, respectively.

6. Fasiglifam and fasiglifam-G are substrates of BCRP and Mrp2/MRP2, respectively.

7. Glucuronidation of fasiglifam-G was found to be the predominant elimination pathway of fasiglifam in all species tested, including humans.

     

Salusin beta is a surrogate ligand of the mas-like G protein-coupled receptor MrgA1

The mas-like G protein-coupled receptors form a subfamily of G protein-coupled receptors that includes variable member numbers across different species and that have been shown to bind a wide variety of ligands from peptides to amino acid derivatives. While screening a library of peptides against different orphan G protein-coupled receptors, we found that human salusin beta activates the mouse mas-like G protein-coupled receptor, mMrgA1 with an EC(50) of about 300 nM. Salusin beta is a bioactive peptide recently discovered through bioinformatics analysis which stimulates arginine-vasopressin release from rat pituitary and causes rapid and profound hypotension and bradycardia. However, when we further analyzed the generality of the mMrgA1 activation, we found that human salusin beta does not activate corresponding human mas-like G protein-coupled receptors. Our results show that human salusin beta is a surrogate ligand of the mouse MrgA1 and raises a cautionary flag for experiments that analyze the pharmacological profiles of mas-like G protein-coupled receptors from different species.     

下鼻甲注射得保松等混合药液封闭治疗变应性鼻炎78例临床观察

目的探讨下鼻甲注射复方倍他米松注射液药物封闭治疗变应性鼻炎的临床效果。方法在下鼻甲注射混合药液,每侧3ml（含10%氯化钠2ml、2%利多卡因0.5ml、复方倍他米松注射液0.5ml）,对78例变应性鼻炎患者进行治疗。注射当天和注射后5个月,用VAS评分法对鼻塞、鼻痒、喷嚏、流涕四个主要症状进行评分,比较注射前后的分值变化,确定其疗效。分值降低5分以上为显效,降低3分以上为有效,分值降低不足3分为无效。结果注射后5个月,显效16例（20.5%）,有效54例（69.2%）,近期总有效率89.7%,无效为8例（10.3%）;41例随访2年,11例（14.1%）未复发,为临床痊愈。结论下鼻甲药物注射（氯化钠、复方倍他米松注射液、利多卡因）是治疗变应性鼻炎的简单有效方法之一。     

The orexin receptor OX(1)R in colon cancer: a promising therapeutic target and a new paradigm in G protein-coupled receptor signalling through ITIMs

An exciting aspect of the heptahelical orexin receptor 1 (OX(1)R) has emerged recently, when it was shown that it drives apoptosis in human colon cancer cell lines. Here we review recent findings related to the role of OX(1)R in colorectal cancers and the unexpected mechanism whereby this G protein-coupled receptor works. The OX(1)R is aberrantly expressed at all steps of primary colorectal tumour progression and after local (lymph node) or distant (liver, lung) metastasis. No OX(1)R is detected in normal colonic epithelial cells. Treatment of human colon cancer cells in culture with orexins promotes robust apoptosis and subsequent reduction of growth including in cells that are resistant to 5-fluorouracil, the most commonly used drug in chemotherapy. When human colon cancer cells are xenografted in nude mice, treatment with orexins dramatically slows tumour growth and even reverses the development of established tumours. Thus, OX(1)R agonists might be novel candidates for colon cancer therapy. Activation of OX(1)R drives apoptosis through G(q) protein but independently of classical Gα(q) activation of phospholipase C. In fact, it is the freed βγ dimer of G(q) that plays a pivotal role by stimulating Src-tyrosine kinase. This results in phosphorylation of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in OX(1)R and subsequent recruitment by OX(1)R of the phosphotyrosine phosphatase SHP-2, which is activated thereby. Downstream events include release of cytochrome c from mitochondria and activation of caspase-3 and caspase-7. The role of ITIMs in OX(1)R-driven apoptosis represents a new paradigm of G protein-coupled receptor signalling.     

The effects of histamine and leukotriene receptor antagonism on nasal mannitol challenge in allergic rhinitis

AIMS: It is unclear as to which mediators are involved in mediating the response to nasal mannitol challenge, a novel osmotic stimulus. METHODS: A double-blind, randomized, placebo-controlled, crossover design was employed. Nine patients with allergic rhinitis were randomized to receive a single-dose of desloratadine 5 mg, montelukast 10 mg or placebo, and underwent nasal mannitol challenges with nasal peak inspiratory flow recordings over 60 min. The change in peak nasal inspiratory flow was calculated as percentage change from baseline as the peak response and area under the time-response curve (AUC). RESULTS: Desloratadine and montelukast conferred a significant degree of protection compared to placebo for peak and AUC response, but there were no significant differences between the two drugs. For the peak response as percentage fall, the mean difference (95% CI) vs placebo was 27.7 (8.0, 47.4)% for desloratadine and 17.6 (1.9, 33.3)% for montelukast. CONCLUSIONS: Our results suggest that histamine and cysteinyl-leukotrienes are involved in mediating the response to nasal mannitol in allergic rhinitis.     

The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis

SUMMARY

Objective: The objective of this study was to evaluate montelukast 10?mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season.

Methods: This was a multicenter study of 831 patients (ages 15?years–85?years) with seasonal allergen sensitivity, active symptoms of seasonal allergic rhinitis, and active asthma. Following a single-blind, placebo run-in period of 3?days–5?days, patients were randomized to oral montelukast 10?mg (n = 415) or placebo (n = 416) daily during the 2-week, double-blind, active-treatment period.

Main outcome measures: The primary endpoint was Daily Rhinitis Symptoms score, average of Daytime Nasal Symptoms and Nighttime Symptoms, as self-rated by patients on a 0–3 scale on daily diaries.

Results: Montelukast reduced the Daily Rhinitis Symptoms score: difference between montelukast and placebo in mean change from baseline was –0.12 [95% CI –0.18, –0.06; p ≤ 0.001]. Similar improvements were seen in Daytime Nasal Symptoms (–0.14 [–0.21, –0.07; p ≤ 0.001]) and Nighttime Symptoms (–0.10 [–0.16,–0.04; p ≤ 0.001]). Improvements (p < 0.05) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician, and Rhinoconjunctivitis Quality of Life. In exploratory analyses, improvement in rhinitis symptoms was numerically (though not statistically) larger in patients with greater levels of asthma at study start. Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician: mean differences were –0.24 [–0.41, –0.06; p = 0.008] and –0.17 [–0.33,–0.01; p = 0.037]. Similarly, as-needed β-agonist use (puffs/day) was reduced with montelukast (?p ≤ 0.005).

Conclusion: Montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma.     

泌尿系统肿瘤中雌激素受体作用的研究进展

雌激素受体（ER）是类固醇激素受体超家族成员,可调节生殖系统的增殖和分化,进而影响各种生理功能,对肝、肾、脑、骨骼及心血管等系统亦有不同程度的作用。本文综述泌尿系统肿瘤中雌激素受体作用的研究进展。     

针刺蝶腭神经节联合氯雷他定治疗变应性鼻炎的效果

目的　探析氯雷他定复合针刺蝶腭神经节治疗变应性鼻炎（AR）的效果。方法　选择2020年5月至2022年1月天津医科大学第二医院收治的AR患者71例进行前瞻性研究,其中男性37例,女性34例,年龄（37.99±19.51）岁。按治疗方法将其分成A组（39例）和B组（32例）,A组给予氯雷他定治疗,B组则在A组的基础上联合针刺蝶腭神经节治疗,观察两组临床疗效及相关细胞因子变化情况,并使用SPSS 20.0统计软件分析数据,采用χ²检验、独立样本t检验。结果　治疗后B组中医总症候积分为（4.86±0.89）分,低于A组的（7.32±1.06）分（t=10.447,P<0.001）;B组治疗总有效率为84.38%（27/32）,高于A组的58.97%（23/39）（χ²=4.991,P=0.027）;B组生活质量总得分为（9.15±2.12）分,低于A组的（14.75±1.93）分（t=11.637,P<0.001）;B组治疗后白细胞介素（IL）-4、IL-10、干扰素（INF）-γ、Th1/Th2水平分别为（10.27±0.51）ng/L、（7.55±0.67）ng/L、（18.22±0.23）ng/L、（13.14±0.46）%,A组分别为（12.11±0.31）ng/L、（9.85±0.53）ng/L、（20.92±0.14）ng/L、（15.78±0.22）%,B组各项细胞因子水平均低于A组（均P<0.05）。结论　在针对AR患者的治疗中,与常规单一西药治疗相比,针刺蝶腭神经节联合氯雷他定临床应用效果良好,有利于调节相关细胞因子水平,提高患者日常生活质量。     

伏天穴位贴对经生理盐水鼻腔冲洗治疗的小儿过敏性鼻炎的临床疗效

目的研究伏天穴位贴对经生理盐水鼻腔冲洗治疗的小儿过敏性鼻炎的临床疗效。方法 120例过敏性鼻炎患者随机分为观察组和对照组,每组60例,两组患者均给予基础药物治疗与生理盐水鼻腔冲洗,观察组在此基础上给予伏天穴位贴,观察两组患者治疗3年后的疗效与伴随症状恢复时间。结果治疗3年后,观察组的临床症状及体征评分均低于对照组,总有效率高于对照组,差异均有统计学意义(P<0.05);观察组皮疹发生率高于对照组(P<0.05)。结论在基础药物治疗基础上给予伏天穴位贴与生理盐水鼻腔冲洗能缩短过敏性鼻炎患儿的伴随症状恢复时间,并能提高临床疗效,且不良反应少。     

Acute treatment with the cyclic antidepressant desipramine,but not fluoxetine,increases membrane-associated G protein-coupled receptor kinases 2/3 in rat brain

The homologous regulation of receptors is mediated by G protein-coupled receptor kinases (GRKs) which phosphorylate the agonist-activated receptor. This study was designed to assess the in vivo indirect activation of adrenoceptors or 5-HT receptors by the reuptake blocker desipramine or fluoxetine on the cellular distribution of GRK 2/3 in rat brain. Immunoblot analysis (frontal cortex) with a GRK 2 antibody revealed a unique 80 kDa protein (mixed GRK 2/3) in total homogenate (H) and in membrane (P2) and cytosolic (S2) fractions. The proportion of GRK 2/3 in each fraction, relative to that of H, was: P2/H=0.11 and S2/H=0.45. Acute desipramine (noradrenaline reuptake blocker) increased in a dose- (1-30 mg/kg, i.p.) and time- (1-6 h) dependent manner the content of GRK 2/3 in the membrane (P2/H ratios increased by 37-164%). This effect vanished with a prolonged desipramine (30 mg/kg) exposure (24 h). Desipramine did not alter the content of GRK 2/3 in the cytosol (S2/H ratios). Chronic desipramine (10 mg/kg every 24 h) for 14 days did not change significantly the immunodensity of GRK 2/3 in the membrane or the cytosol. The acute administration (2 h) of fluoxetine (5-HT reuptake blocker; 3-30 mg/kg) did not induce significant changes in the content of GRK 2/3 in the membrane (P2/H ratio) or cytosol (S2/H ratio). The results indicate that the in vivo activation of adrenoceptors by desipramine is associated with a time-dependent modulation of membrane-associated GRK 2/3 (i.e. an acute increase in the kinase content which is followed by a return to the basal expression upon repeated treatment). In contrast, the acute in vivo activation of 5-HT receptors induced by fluoxetine does not result in modulation of GRK 2/3.