Basics on the use of acid-sensing ion channels' inhibitors as therapeutics

Since the discovery of acid-sensing ion channels in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. Acid-sensing ion channels play important roles in mediating pain sensation during diseases such as stroke, inflammation, arthritis, cancer, and recently migraine. More interestingly, acid-sensing ion channels may explain the sex differences in pain between males and females. Also, the ability of acid-sensing ion channel blockers to exert neuroprotective effects in a number of neurodegenerative diseases has added a new dimension to their therapeutic value. The current failure rate of ～45% of new drugs(due to toxicity issues) and saving of up to 7 years in the life span of drug approval makes drug repurposing a high priority. If acid-sensing ion channels' blockers undergo what is known as "drug repurposing", there is a great potential to bring them as medications with known safety profiles to new patient populations. However, the route of administration remains a big challenge due to their poor penetration of the blood brain and retinal barriers. In this review, the promise of using acid-sensing ion channel blockers as neuroprotective drugs is discussed.     

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

Brigatinib (BGB) is a newly approved anaplastic lymphoma kinase (ALK) inhibitor. On April 28, 2017, BGB was approved by the U.S. FDA for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. The toxicity profile of BGB includes nausea, fatigue, diarrhea, elevated lipase, dyspnoea, hypertension, hypoxia, pneumonia, elevated amylase, pulmonary embolism, elevated ALT, hyponatraemia and hypophosphatemia. Using LC-MS/MS, we investigated the in vitro phase I metabolism of for BGB in rat liver microsomes (RLMs). In the in vitro metabolism of BGB, iminium reactive intermediates were trapped by potassium cyanide forming a stable complex that can be characterized by LC-MS/MS. Four BGB in vitro phase I metabolites were identified. In vitro phase I metabolic pathways were N-dealkylation, α hydroxylation and α oxidation. Additionally, three iminium reactive metabolites were found and the bioactivation mechanisms were proposed. A piperidine ring was found to be responsible for BGB bioactivation. The presence of these three reactive metabolites may be the main reason for BGB side effects. A literature review showed no previous article reported the in vitro phase I metabolism study of BGB or structural identification of the formed reactive metabolites.

Four phase I BGB metabolites and three cyano adducts for BGB were detected using LC-MS/MS. The piperidine ring was found to be responsible for BGB bioactivation and the bioactivation pathways are proposed.     

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency,clinical relevance and outcome

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients’ outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80?±?7 vs. 80?±?7 years; p?=?0.198) and EuroSCORE II (3.6% [2.1–5.7] vs. 3.6% [2.1–5.9]; p?=?0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p?<?0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p?=?0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n?=?48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p?=?0.339, 1-year: 11% vs. 14%; p?=?0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.     

Age is not a predictor of patent foramen ovale with right-to-left shunt in patients with cerebral ischemic events

BACKGROUND: Patent foramen ovale (PFO) with or without atrial septal aneurysm (ASA) is highly associated with cerebral ischemic events in young patients. The prevalence of PFO and ASA in elderly patients with cerebral ischemic events is not well described. OBJECTIVE: Our study is to evaluate the frequencies of PFO with right-to-left shunt (RLS) and ASA in elderly patients and to determine whether age is a predictor of flow-reversed PFO with RLS in cerebral ischemic events. METHODS: A prospective registry for all consecutive patients with cerebral ischemic events who were evaluated by transesophageal echocardiography (TEE) for the detection of possible cardiac source of embolization was established and maintained in a university hospital. Patients' demographics including age, gender, ethnic origin, cerebrovascular risk factors, and all positive TEE data were collected from July 2000 to August 2001 for statistical analysis. A univariate and multivariate stepwise logistic regression analysis was performed. RESULTS: In older patients the prevalence of PFO with RLS, PFO, and ASA was 25/118 (20%), 28/118 (24%), and 38/118 (32%), respectively, as opposed to younger patients, in whom it was 35/119 (30%), 39/119 (33%), and 38/119 (32%), respectively. Older patients had higher frequencies of hypertension (59; 69%), CAD (25; 21%), and prior history of stroke (23; 20%) as opposed to younger patients. Younger age (<60 years), gender, smoking history, hypertension, hyperlipidemia, CAD, and prior history of stroke were not associated with higher prevalence of PFO with RLS. Patent foramen ovale was associated with ASA (P < 0.001) and LVH (P < 0.019) in patients with TIA and stroke. In multivariate analysis only ASA (P < 0.001) remained significant with PFO, with RLS controlling for age, gender, and LVH. CONCLUSIONS: PFO with RLS and ASA are frequently present in elderly stroke and/or TIA patients and age is not a predictor for PFO. Transesophageal echocardiography should be considered for all stroke and/or TIA patients irrespective of their age.     

The Essence of Accommodating Older Adults into the Social Care Sector in Malaysia

Population ageing puts pressure on the workforce and increase the demands for aged workforce. The demographic shifts have made the issue of healthier workers, especially those of advanced age and physically related job scopes, a fundamental aspect to employing older workers. Hence, this study aimed to explore the best practices to employ older adults into the social care sector. The social care sector was chosen in view of the nature of job and declining demand among younger workers. A qualitative study was conducted involving series of focus group discussions (FGD) with social care workers of long-term care centers in the peninsular Malaysia. Data was collected using a validated and pre-tested semi-structured interview protocol. Each focus group discussions and in-depth interviews were lasted between 45 min to 1 h. A total of 57 workers were consented for the study which was divided into young and old workers based on the mean age of 41.43 [SD ± 9.97] years old. The content of the interviews was transcribed verbatim and thematic analysis was performed to inductively identify the coding and themes within the data related to the challenges employing older workers into the social care sector. Three categories of coding were identified (individual, environmental and management factors), leading to the identification of two important themes which are healthy workplace and work autonomy. The findings indicate the needs for work culture transformations to cultivate healthy working environment and freedom of speech particularly among the older workers.     

Design and formulation of polymeric nanosponge tablets with enhanced solubility for combination therapy

Three drugs namely caffeine, paracetamol, and aceclofenac are commonly used for treating various acute and chronic pain related ailments. These 3 drugs have varied solubility profiles, and formulating them into a single tablet did not have the desired dissolution profile for drug absorption. The objective of the present research was to tailor the drug release profile by altering drug solubility. This was achieved by loading the drug into nanosponges. Here, three-dimensional colloidal nanosponges were prepared using β-cyclodextrin with dimethyl carbonate as a cross-linker using the hot-melt compression method. The prepared nanosponges were characterized by FTIR, ¹H NMR spectroscopy, DSC, XRPD studies and SEM. The FTIR and DSC results obtained indicated polymer-drug compatibility. The ¹H NMR spectroscopy results obtained indicated the drug entrapment within nanosponges with the formation of the inclusion complex. XRPD studies showed that the loaded drug had changed crystalline properties altering drug solubility. SEM photographs revealed the porous and spongy texture on the surface of the nanosponge. Box–Behnken experimental design was adopted for the optimization of nanosponge synthesis. Among the synthesized nanosponges containing paracetamol, aceclofenac and caffeine, batch F3–P31, F3–A31 and F3–C31 were considered optimized. Their particle size was 185, 181 and 199 nm with an entrapment efficiency of 81.53, 84.96, and 89.28% respectively. These optimized nanosponges were directly compressed into tablets and were studied for both pre and post-compression properties including in vitro drug release. The prepared tablet showed desired drug dissolution properties compared to the pure drug. The above outcomes indicated the applicability of nanosponges in modulating the drug release with varied solubility for combination therapy.

Polymeric nanosponges as potential carriers for successful combination therapy of poorly soluble drugs (paracetamol, aceclofenac, caffeine).     

Prevalence of post-traumatic stress disorder during the COVID-19 pandemic in Saudi Arabia

BackgroundThe coronavirus diseases of 2019 (COVID-19) pandemic was classified as one of the worst pandemics in the 21st century. Its rapid transmission, unpredicted mortality rate, and the uncertainty surrounding its transmission method have evoked additional fear and anxiety. Nonetheless, to the best of our knowledge, no prior study has explored PTSD prevalence three months after the start of the quarantine procedures in Saudi Arabia nor has examined PTSD prevalence by three different methods.ObjectiveThis observational cross-sectional study aimed to identify the prevalence, severity, and influencing factors of PTSD in different regions of Saudi Arabia three months after the onset of the quarantine procedures related to the COVID-19 pandemic.MethodsThrough the month of June 2020, 1374 people (49.05% men and 50.95% women) completed a 35-item, 10-minute online. The prevalence of PTSD was measured using PCL-S (specific for COVID-19) that assesses the 17 symptoms of PTSD. Resilience was measured using 2-items Arabic version of the Connor-Davidson Resilience Scale 2 (CD-RISC 2).ResultsWe calculated the prevalence by three methods, namely, PTSD cut-off score, criteria, and combined, and the prevalence was 22.63%, 24.8%, and 19.6%, respectively. Female participants showed higher prevalence than male. As well, participants who were either tested positive or suspected of having been infected with COVID-19 showed higher PTSD prevalence. Higher resilience was associated with lower PTSD prevalence.ConclusionsThis was the first study to report PTSD prevalence by three differential methods three months after the onset of the quarantine procedures related to the COVID-19 pandemic in Saudi Arabia. We observed a significant impact of the COVID-19 pandemic in the Saudi population; therefore, great attention should be performed in implementing new procedures that deal with the highlighted risk factors, especially in vulnerable groups, to overcome the psychological impact of the COVID-19 pandemic.