Inhibitory potential of nitrogen,oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

Heterocycles are the key structures in organic chemistry owing to their immense applications in the biological, chemical, and pharmaceutical fields. Heterocyclic compounds perform various noteworthy functions in nature, medication, innovation etc. Most frequently, pure nitrogen heterocycles or various positional combinations of nitrogen, oxygen, and sulfur atoms in five or six-membered rings can be found. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes is a popular strategy for the management of numerous mental diseases. In this context, cholinesterase inhibitors are utilized to relieve the symptoms of neurological illnesses like dementia and Alzheimer''s disease (AD). The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD. Moreover, a detailed structure–activity relationship (SAR) has been established for the future discovery of novel drugs for the treatment of AD. Most of the heterocyclic motifs have been used in the design of new potent cholinesterase inhibitors. In this regard, this review is an endeavor to summarize the biological and chemical studies over the past decade (2010–2022) describing the pursuit of new N, O and S containing heterocycles which can offer a rich supply of promising AChE and BChE inhibitory activities.

The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD.     

成人不同垂直及矢状骨面型髁突特征的研究

目的 通过测量分析具有不同垂直和矢状骨面型的成人髁突特征的差异,研究成人骨面型与髁突特征的相关性。方法 选取颞下颌关节正常的成人患者180例,根据∠ANB、∠MP-FH和∠MP-SN将患者分为不同的垂直及矢状骨面型,共9组,每组20例。使用Invivo6软件测量所有样本的髁突长轴径、髁突短轴径、髁突最大横截面积、髁突颈部宽度、髁突上部高度、髁突高度、下颌升支高度,关节前、后、上、内侧间隙,关节结节后斜面角度和关节窝深度、宽度。使用SPSS 23.0软件进行统计学分析,比较各组测量指标的差异。结果 低角患者髁突粗大,关节间隙大,关节窝深而窄,关节结节后斜面角度大,升支长;高角患者则相反。骨性Ⅲ类患者髁突粗大,关节间隙小,关节窝浅而宽,关节结节后斜面角度小;而骨性Ⅱ类患者则相反。结论 骨性Ⅱ类高角、骨性Ⅲ类低角患者髁突特征明显,与下颌发育有关;髁突特征与垂直骨面型、矢状骨面型之间存在关联;垂直骨面型与髁突特征的关联程度比矢状骨面型更强。在临床治疗过程中要加强对髁突及其周围结构的关注。     

Knowledge and attitudes of physicians toward forensic psychiatry in Saudi Arabia

Objectives:To assess the knowledge and attitudes of physicians of different specialties, including psychiatrists, regarding forensic psychiatry to determine whether further modification or training is needed in the psychiatry residency program.Methods:This cross-sectional study was carried out using a 3-page, 3-section questionnaire containing 21 questions disseminated randomly online via Google forms using social media platforms. The 482 participants were residents, specialists, and consultants of various specialties. The study was conducted between September 2020 and August 2021 in various tertiary hospitals across Saudi Arabia.Results:A total of 482 physicians were recruited. The most common age group was 25-35 years, comprising mostly Saudis (62.4%). Based on the results, “poor” and “good” knowledge of forensic psychiatry was identified in 89% and 11% of the physicians, while “negative” and “positive” attitudes were identified in 16.4% and 83.6% of the physicians.Conclusion:Although the perspective of physicians regarding forensic psychiatry was found to be positive, their knowledge of the topic seems to be lacking.     

B-cell lymphoma-associated hemophagocytic lymphohistiocytosis: A case report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.     

Prenatal Bisphenol a Exposure and Postnatal Trans Fat Diet Alter Small Intestinal Morphology and Its Global DNA Methylation in Male Sprague-Dawley Rats,Leading to Obesity Development

In this study, we aimed to determine whether a postnatal trans fat diet (TFD) could aggravate prenatal bisphenol A (BPA) exposure effects on offspring’s small intestine and adulthood obesity, due to the relatively sparse findings on how the interaction between these two variables interrupt the small intestinal cells. Twelve pregnant rats were administered with either unspiked drinking water (control; CTL) or BPA-spiked drinking water throughout pregnancy. Twelve weaned pups from each pregnancy group were then given either a normal diet (ND) or TFD from postnatal week (PNW) 3 until PNW14, divided into control offspring on normal diet (CTL-ND), BPA-exposed offspring on normal diet (BPA-ND), control offspring on trans fat diet (CTL-TFD), and BPA offspring on trans fat diet (BPA-TFD) groups. Body weight (BW), waist circumference, and food and water intake were measured weekly in offspring. At PNW14, small intestines were collected for global DNA methylation and histological analyses. Marked differences in BW were observed starting at PNW9 in BPA-TFD (389.5 ± 10.0 g; p < 0.05) relative to CTL-ND (339.0 ± 7.2 g), which persisted until PNW13 (505.0 ± 15.6 g). In contrast, water and food intake between offspring were significantly different (p < 0.01–0.05) at earlier ages only (PNW4–6 and PNW7–9, respectively). Furthermore, substantial differences in the general parameters of the intestinal structures were exclusive to ileum crypt length alone, whereby both BPA-ND (150.5 ± 5.1 μm; p < 0.001), and BPA-TFD (130.3 ± 9.9 μm; p < 0.05) were significantly longer than CTL-ND (96.8 ± 8.9 μm). Moreover, BPA-ND (2.898 ± 0.147%; p < 0.05) demonstrated global small intestinal hypermethylation when compared to CTL-ND and CTL-TFD (1.973 ± 0.232% and 1.913 ± 0.256%, respectively). Prenatal BPA exposure may significantly affect offspring’s physiological parameters and intestinal function. Additionally, our data suggest that there might be compensatory responses to postnatal TFD in the combined BPA prenatal group (BPA-TFD).     

Acute,sub-acute and general pharmacological evaluation of 5-(3,4-methylenedioxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide (SK-20): A novel drug bioavailability enhancer

An efflux pump inhibitor, SK-20 (5-(3,4-methylenedioxyphenyle)-4 ethyl-2E,4E-pentadienoic acid piperidide), was assessed for its toxicity at three different pharmacological profiles: acute, sub-acute and general pharmacology with pharmacokinetics. In acute study, the SK-20 was found safe up to a dose of 2000 mg/kg (b.wt.); and at sub-acute, dosages of 50 and 100 mg/kg (b.wt.) were found to be safe. However, dosages of 200 mg or above per kg (b.wt.) showed some morphological alterations in cellular architecture of both liver and kidneys in both sexes, viz., mild vascular congestion along with sporadic hemorrhages and infiltration into renal and hepatic parenchyma by mononucleate cell. General pharmacological studies did not result into any alterations in analgesic, convulsions, rectal temperatures and in the rhythm or the rate of the intestinal motility or the secretion of the bile. While the respiratory and the cardiac rate remained normal, the only parameter to show was the blood pressure, which at all the doses tested, showed a tendency toward reduction. Characteristically, the SK-20 at all doses influenced pentobarbital-induced hypnosis positively and negatively to spontaneous motor activity in a dose dependent manner. Pharmacokinetics of SK-20 revealed it to have retention time at 10.2 min and half life 2.47 h.     

A Phase II Study of Biodegradable Stents Plus Palliative Radiotherapy in Oesophageal Cancer

AimsSelf-expanding metal stents provide rapid improvement of dysphagia in oesophageal cancer but are associated with complications. The aim of the present study was to test the effectiveness of an alternative treatment of combining biodegradable stents with radiotherapy.Materials and methodsA Simon two-stage single-arm prospective phase II trial design was used to determine the efficacy of biodegradable stents plus radiotherapy in patients with dysphagia caused by oesophagus cancer who were unsuitable for radical treatment. Fourteen patients were recruited and data from 12 were included in the final analyses.ResultsFive of 12 patients met the primary end point: one stent-related patient death; four further interventions for dysphagia within 16 weeks of stenting (41.7%, 95% confidence interval 15.2–72.3%). The median time to a 10-point deterioration of quality of life was 2.7 weeks. Nine patients died within 52 weeks of registration. The median time to death from any cause was 15.0 weeks (95% confidence interval 9.6–not reached).ConclusionThe high re-intervention observed, which met the pre-defined early stopping criteria, meant that the suggested alternative treatment was not sufficiently effective to be considered for a larger scale trial design. Further work is needed to define the place of biodegradable stents in the management of malignant oesophageal strictures.