5-hydroxytryptamine subtype 6 receptor modulators: a patent survey

Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT₆ receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.

Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.

What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.

Take home message: Several of 5-HT₆-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease.     

Antidepressant Drugs in the Elderly — Rôle of the Cytochrome P450 2D6

Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacological treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses.

Comedications induce drug interactions that depend on the patient's metabolic capacity, linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphisms on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized.

The author approaches successively the notions of the cytochrome P450 (2D6), its role in drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping, and phenotyping are also explained. The author's experience on the relationship between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly.     

子宫颈鳞癌术后组织中CEACAM6和MMP-7的表达及意义

目的观察子宫颈鳞癌中癌胚抗原相关细胞黏附分子6(CEACAM6)和基质金属蛋白酶-7(MMP-7)的表达,探讨二者在子宫颈鳞癌发生、发展及转移中的作用。方法收集83例子宫颈鳞癌标本作为观察组及50例慢性宫颈炎的上皮组织作为对照组,应用免疫组化技术检测两组中CEACAM6和MMP-7蛋白的表达,比较其在不同临床特征中的表达差别。结果观察组中CEACAM6和MMP-7表达的阳性率明显高于对照组,观察组中CEACAM6和MMP-7在不同分化、不同宫颈管内浸润深度、不同淋巴结转移和不同Ki67阳性率中表达的差别有统计学意义。经相关性分析显示观察组中CEACAM6和MMP-7的表达呈正相关性。结论子宫颈鳞状细胞癌中CEACAM6和MMP-7异常表达,两者可能具有协同作用。CEACAM6对细胞外基质的降解作用可能是其促进肿瘤进展的重要因素。     

235361例新生儿疾病筛查情况分析

目的调查黄冈市2016年1月1日—2019年6月30日新生儿遗传代谢性疾病的筛查结果。方法采用实时数据分析调查的方法,对黄冈市2016年1月1日—2019年6月30日出生并在黄冈市妇幼保健院进行遗传代谢病5项[先天性甲状腺功能减低症(CH)、苯丙酮尿症(PKU)、葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症、先天性肾上腺皮质增生症(CAH)和地中海贫血]检测的235361例活产新生儿的结果及确诊数据进行分析和统计。结果2016年1月1日—2019年6月30日期间共筛查235361例新生儿,确诊CH患儿61例,发病率约为1:3858;确诊PKU患儿14例,发病率约为1:16812;确诊G6PD缺乏症(蚕豆病)患儿179例,发病率约为1:1315;确诊CAH患儿9例,发病率约为1:26151;确诊地中海贫血患儿446例,发病率约为1:528。结论黄冈市CH、PKU、G6PD缺乏症、CAH及地中海贫血发病率均低于全国平均发病率。加强健康教育和普及,通过分析质量控制指标加强质量管理,规范筛查流程,减少漏筛,提高召回确诊病例,不断提高服务质量。     

Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease

AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease.METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease(MELD) and Pediatric End Stage Liver Disease(PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition(Z-score -1.00) and malnutrition(Z-score -2.00). Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median(25th-75 th centile) age of the study population was 60(17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease(72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values were increased in patients at nutritional risk(34.9%) compared with those who were well-nourished [7.12(0.58-34.23) pg/m L vs 1.63(0.53-3.43) pg/m L; P = 0.02], correlating inversely with triceps skinfold-for-age z-score(rs =-0.61; P 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score(P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.     

Performance of EAST in diagnosing inhalant allergens in children with allergic rhinitis

The performance of enzyme linked immunosorbent assays (EAST) for identifying six indoor allergens was evaluated using skin prick test (SPT) as reference tests in 154 children with allergic rhinitis. Sensitivity of EAST ranged from 9% (cat) to 54% (HDM) with specificity of 74%(cockroach) to 100% (cat) with an agreement ranged from 58 to 86%. Cut off values ?> ?0.35 kU/L showed best sensitivity and specificity. Our findings agree with extant literature which suggests that the ability of EAST to determine the precipitating allergen is moderate. Assays for definitively identifying the inhalant allergen are currently not available.     

Broad neutralization against SARS-CoV-2 variants induced by ancestral and B.1.351 AS03-Adjuvanted recombinant Plant-Derived Virus-Like particle vaccines

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted hundreds of millions of people in a worldwide pandemic. Several safe and effective COVID-19 vaccines are now available. However, the rapid emergence of variants and risk of viral escape from vaccine-induced immunity emphasize the need to develop broadly protective vaccines. A recombinant plant-derived virus-like particle vaccine for the ancestral COVID-19 (CoVLP) recently authorized by Canadian Health Authorities and a modified CoVLP.B1351 targeting the B.1.351 variant (both formulated with the adjuvant AS03) were assessed in homologous and heterologous prime-boost regimen in mice. Both strategies induced strong and broadly cross-reactive neutralizing antibody (NAb) responses against several Variants of Concern (VOCs), including B.1.351/Beta, B.1.1.7/Alpha, P.1/Gamma, B.1.617.2/Delta and B.1.1.529/Omicron strains. The neutralizing antibody (NAb) response was robust with both primary vaccination strategies and tended to be higher for almost all VOCs following the heterologous prime-boost regimen.     

二期翻修治疗人工髋、膝关节置换术后感染的研究进展

目的综述二期翻修治疗人工髋、膝关节置换术后感染的研究进展。方法广泛查阅近年国内外相关文献，总结二期翻修治疗人工髋、膝关节感染中间隔器的选择、全身性抗生素使用疗程及预后危险因素评估方面的新进展。结果二期翻修是治疗人工髋、膝关节置换术后感染的常用方式。第 1 阶段术中使用的间隔器类型多样，各有优缺点。其中，非关节型间隔器主要用于关节周围软组织条件欠佳、存在严重骨缺损患者，但间隔器植入后关节活动度不佳；关节型间隔器可使受累关节术后恢复运动，改善后期关节活动度。应用抗生素是治疗过程中不可缺少部分，短期应用抗生素治疗也可获得与长疗程相似疗效。明确影响二期翻修预后的危险因素有助于术前管理以及降低感染复发率。结论目前二期翻修治疗人工髋、膝关节置换术后感染过程中间隔器的选择以及抗生素应用疗程等问题仍存在争议，影响二期翻修预后的影响因素有待探究，需要进一步高质量研究加以明确。