Oxime K074 – in vitro and in silico reactivation of acetylcholinesterase inhibited by nerve agents and pesticides

Abstract

Oxime K074 was formerly considered to be a lead structure for design of novel oximes for reactivation of tabun-inhibited acetylcholinesterase (AChE). In this study, we are summarizing its reactivation activity in case of other nerve agents (sarin, cyclosarin, VX and Russian VX) and pesticides (chlorpyrifos, methylchlorpyrifos and DDVP). For this purpose, standard in vitro method using rat brain homogenate was used. As resulted, oxime K074 was able to reactivate brain ChE (cholinesterases) inhibited by all used nerve agents and pesticides excluding cyclosarin-inhibited ChE. Only slight modification in structure of sarin (isopropyl moiety) and cyclosarin (cyclohexyl moiety) caused extraordinary differences in the reactivation of acetylcholinesterase inhibited by these nerve agents. Obtained molecular docking results suggest that the oxime K074 interacts very well with the inhibitors addressed in this work, and the data obtained by the QM/MM approach showed a good correlation with our experimental results of reactivation rate (%) by the oxime K074.     

The New Acetylcholinesterase Inhibitors PC‐37 and PC‐48 (7‐Methoxytacrine‐Donepezil‐Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes,Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non‐selective AChE/BChE 7‐MEOTA‐donepezil‐like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC‐37 and eight metabolites of PC‐48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1–M7 of PC‐37 and M1–M6 of PC‐48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUC_total was 28179 ± 4691 min.ng/mL for PC‐37 and 23374 ± 4045 min.ng/mL for PC‐48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.     

Aminopeptidase activity in strains of oral streptococci

Ten strains of oral streptococci were analyzed for aminopeptidase activity by isoelectric focusing and crossed immunoelectrophoresis together with enzyme staining procedures. Substrate specificities were determined using 15 aminoacyl-β-naphthylamides. All 10 strains tested showed enzyme activity with the arginine and leucine substrates. None of the strains exhibited activity with the glycine, cystine, or proline substrates. Some strains had multiple enzyme bands with some of the substrates. All strains had aminopeptidase bands located in the pi range 4.1–4.3, except Streptococcus mutans IB and Streptococcus milleri NCTC 10708. The isoelectric profiles of these strains, having enzyme bands in the range 4.45–4.9, differed markedly from the others. These were also the only strains where no arginine aminopeptidase cross-reactivity occurred with the Streptococcus mitis ATCC 903 antiserum.     

SingHealth Radiology Archives pictorial essay Part 2: gastroenterology,musculoskeletal, and obstetrics and gynaecology cases

The Singapore Health Services cluster (SingHealth) radiology film archives are a valuable repository of local radiological cases dating back to the 1950s. Some of the cases in the archives are of historical medical interest, i.e. cerebral angiography in the workup of patients with hemiplegia. Other cases are of historical social interest, being conditions seen during earlier stages of Singapore’s development, i.e. bound feet. The archives form a unique portal into the development of local radiology as well as the national development of Singapore. A selection from the archives is published in commemoration of the International Day of Radiology in 2020, as well as the 200th anniversary of the Singapore General Hospital in 2021. This pictorial essay comprises gastroenterology, musculoskeletal and obstetrics and gynaecology cases from the archives.     

MRI-targeted biopsy for detecting prostate cancer: have the guidelines changed our practices and our prostate cancer detection rate?

International Urology and Nephrology - In our center, until 2018, MRI-targeted biopsy was underused. Since January 2018, we systematically performed MRI-targeted biopsy for suspicious...     

Evaluating the preoperative breast cancer characteristics affecting the accuracy of axillary ultrasound staging

We evaluate the preoperative breast cancer (BC) characteristics that affect the diagnostic accuracy of axillary ultrasound (US) and determine the reliability of US in the different subgroups of BC patients. Axillary US assessments in women with invasive BC diagnosed between 2009 and 2016 in a single institution were retrospectively reviewed. The diagnostic accuracy of axillary US was obtained using surgical nodal histology as the gold standard. Preoperative breast tumor sonographic and histological factors affecting axillary US diagnostic accuracy were examined. Of the 605 newly diagnosed invasive BC cases reviewed, 251 (41.5%) had nodal metastases. Axillary US sensitivity was 75.7%, specificity 92.9%, positive predictive value 88.4%, negative predictive value 84.4%, and false‐negative rate 24.3%. Lower US sensitivity was seen with invasive lobular cancer (ILC) (P = .043), grade I/II, (P = .021), unifocal (P = .039), and smaller tumors (P < .001). US specificity was lower in grade III (P < .001), estrogen receptor (ER)‐negative (P < .001), progesterone receptor (PR)‐negative (P = .004), HER2‐positive (P = .015), triple‐negative (P = .001), and larger breast tumors (P < .001). US has moderate sensitivity and good specificity in detecting metastatic axillary lymph nodes. Based on preoperative cancer characteristics, US was less sensitive for nodal metastases from ILC, unifocal, lower grade, and smaller breast tumors. It was also less specific in grade III, ER‐negative, PR‐negative, HER2‐positive, triple‐negative, and larger breast tumors. Caution is suggested in interpreting the US axillary findings of patients with these preoperative tumor features.     

East/West Visiting Scholars in Pediatric Anesthesia Program (ViSiPAP): Developing tomorrow’s pediatric anesthesia leaders

Promoting and retaining junior faculty are major challenges for many medical schools. High clinical workloads often limit time for scholarly projects and academic development, especially in anesthesiology. To address this, we created the East/West Visiting Scholars in Pediatric Anesthesia Program (ViSiPAP). The program's goal is to help “jumpstart” academic careers by providing opportunities for national exposure and recognition through invited lectures and collaborative opportunities. East/West ViSiPAP benefits the participating scholars, the home and hosting anesthesia departments, and pediatric anesthesia fellowship training programs. By fostering a sense of well‐being and inclusion in the pediatric anesthesia community, East/West ViSiPAP has the potential to increase job satisfaction, help faculty attain promotion, and reduce attrition. Faculty and trainees are exposed to new expertise and role models. Moreover, ViSiPAP provides opportunities for women and underrepresented in medicine faculty. This program can help develop today's junior faculty into tomorrow's leaders in pediatric anesthesia. We advocate for expanding the concept of ViSiPAP to other institutions in academic medicine.     

A WINNING COMBINATION: WOMEN,LITERACY, AND PARTICIPATION IN HEALTH CARE

Health information materials written at the appropriate reading level help individuals manage their own health care. In this study, we assessed the reading ability of clients and readability of the patient information materials at a rural women's health clinic. We administered a reading comprehension test to 50 subjects and tested the patient education materials using a readability formula. More than one in six women could not read all of the patient information, which could limit their understanding, and achievement of good health care. Commercially available materials can be checked readily for reading level using software installed in most computers. This software also allows clinicians who prepare their own materials for their patients to generate versions that are appropriate for different reading levels.