-
RSC Medicinal Chemistry Jun 2024Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are...
Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are incorporated as part of their design. Limited investigation has been performed into elucidating structure-activity relationships around commonly used α-amino acid-derived head groups, mainly with valine and -leucine-derived compounds previously described. As such, proactive synthesis, characterisation and pharmacological evaluation were performed to explore structure-activity relationships of 15 α-amino acid derivatives, with both the natural isomers and their enantiomers at CB and CB investigated using a fluorescence-based membrane potential assay. This library was based around the detected SCRAs MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA, with the latter showing significant receptor activation at CB (pEC = 8.34 ± 0.05 M; = 108 ± 3%) and CB (pEC = 8.13 ± 0.07 M; = 99 ± 2%). Most valine and leucine derivatives were potent and efficacious SCRAs, while smaller derivatives generally showed reduced activity at CB and CB, and larger derivatives also showed reduced activity. SAR trends observed were rationalised induced fit docking. Overall, while natural enantiomers showed equipotent or greater activity than the unnatural isomers in most cases, this was not universal. As such, a number of these compounds should be monitored as emerging NPS, and various substituents described herein.
PubMed: 38911147
DOI: 10.1039/d3md00758h -
Neurosurgical Review Dec 2023We aimed to investigate the efficacy of our multimodal strategies and propose a treatment algorithm for ruptured vertebral artery dissecting aneurysms (VADAs). This...
We aimed to investigate the efficacy of our multimodal strategies and propose a treatment algorithm for ruptured vertebral artery dissecting aneurysms (VADAs). This study included 41 patients treated at a single institution between 2015 and 2022. The treatment modalities were justified based on the collateral circulation and aneurysm location related to the posterior inferior cerebellar artery (PICA). Treatment outcomes and complications of each treatment group were analyzed. The association between the collateral blood flow and the postoperative vertebrobasilar ischemia (VBI) was also investigated. There were 17 post-PICA, 10 PICA-involved, 7 pre-PICA, and 7 non-PICA types. Reconstruction techniques included flow diversion devices (n = 11) and stent-assisted coiling (n = 3). Deconstruction techniques included coil trapping (n=17) and microsurgical parent artery occlusion with (n = 8) or without PICA revascularization (n = 2). Five (18.5%) of the deconstruction group had postoperative VBI. Overall favorable outcomes in both groups were observed in 70.7% of patients with a mean follow-up time of 21.5 months. Poor World Federation of Neurosurgical Societies grade (IV-V) was identified as a predictor of unfavorable outcomes (p = 0.003). In addition, the VA/BA ratio > 0.22, the presence of collateral blood flow from the posterior communicating artery (PcomA), and a contralateral VA diameter > 2.5 mm were associated with a lower risk of postoperative VBI. In summary, the proposed strategic treatment in this study is pragmatic, yielding satisfactory results where a deconstructive technique should be used with caution, particularly when there is a flow mismatch or the absence of collateral PcomA in the vertebrobasilar circulation.
Topics: Humans; Vertebral Artery; Vertebral Artery Dissection; Vascular Surgical Procedures; Treatment Outcome; Combined Modality Therapy; Aortic Dissection; Intracranial Aneurysm; Embolization, Therapeutic; Retrospective Studies; Aneurysm, Ruptured
PubMed: 38040929
DOI: 10.1007/s10143-023-02226-7 -
International Journal of Cardiology Dec 2023Hypertrophic cardiomyopathy (HCM) and Fabry disease cardiomyopathy (FD) are phenocopies, as they show left ventricular hypertrophy (LVH). The left atrium (LA) is...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) and Fabry disease cardiomyopathy (FD) are phenocopies, as they show left ventricular hypertrophy (LVH). The left atrium (LA) is emerging as a potential marker of disease severity in both cardiomyopathies. The present study compares HCM and FD cardiomyopathy with similar degree of LVH, exploring LA morpho-functional parameters and the correlates of clinical outcome.
METHODS
We performed a comprehensive CMR-based comparison between 30 HCM and 30 FD patients matched on age, sex, BSA, LV mass and major cardiovascular risk factors affecting LA remodeling (arterial hypertension and diabetes). 30 healthy controls were also included. CMR feature tracking (CMR-FT) analysis, T1 mapping and conventional parameters were evaluated. Patients also underwent transthoracic echocardiography for LV diastolic function assessment. Clinical events at follow-up were collected (atrial and ventricular events, bradyarrhythmia, heart failure (HF) hospitalization and death).
RESULTS
HCM patients showed greater LA remodeling compared to FD patients, namely higher LA end-systolic volume index (LAVi max), lower LA-ejection fraction (LA-EF) and worse reservoir (εs) and booster function (εa) (all p < 0.05). Accordingly, these parameters have demonstrated good potential for distinguishing between FD and HCM (AUC 0.68-0.73, all p < 0.05), with LAVi max being an independent predictor for HCM diagnosis (OR 1.07, 95%CI 1.011-1.132, p 0.02). Moreover, in HCM patients a significant association between εs and HF occurrence was observed at 2-year follow-up (OR 0.85, 95%CI 0.72-0.99, p 0.04).
CONCLUSIONS
In HCM, LA remodeling is greater than in FD cardiomyopathy with similar LVH, and reservoir strain is associated with HF at follow-up.
PubMed: 37696360
DOI: 10.1016/j.ijcard.2023.131357 -
ACS Chemical Neuroscience Nov 2023The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks, including fatalities....
The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks, including fatalities. Many SCRAs exhibit much higher efficacy and potency compared with the phytocannabinoid Δ-tetrahydrocannabinol (THC) at the cannabinoid receptor 1 (CB1R), leading to dramatic differences in signaling levels that can be toxic. In this study, we investigated the structure-activity relationships of aminoalkylindole SCRAs at CB1Rs, focusing on 5F-pentylindoles containing an amide linker attached to different head moieties. Using in vitro bioluminescence resonance energy transfer assays, we identified a few SCRAs exhibiting significantly higher efficacy in engaging the G protein and recruiting β-arrestin than the reference CB1R full agonist CP55940. Importantly, the extra methyl group on the head moiety of 5F-MDMB-PICA, as compared to that of 5F-MMB-PICA, led to a large increase in efficacy and potency at the CB1R. This pharmacological observation was supported by the functional effects of these SCRAs on glutamate field potentials recorded in hippocampal slices. Molecular modeling and simulations of the CB1R models bound with both of the SCRAs revealed critical structural determinants contributing to the higher efficacy of 5F-MDMB-PICA and how these subtle differences propagated to the receptor-G protein interface. Thus, we find that apparently minor structural changes in the head moiety of SCRAs can cause major changes in efficacy. Our results highlight the need for close monitoring of the structural modifications of newly emerging SCRAs and their potential for toxic drug responses in humans.
Topics: Humans; Cannabinoid Receptor Agonists; Receptor, Cannabinoid, CB1; Cannabinoids; Dronabinol; Receptor, Cannabinoid, CB2
PubMed: 37847546
DOI: 10.1021/acschemneuro.3c00530 -
Industrial Psychiatry Journal 2024Pica, in the form of ingestion of various non-food items like clay, chalks, etc., is commonly reported in Indian settings, but its other variant, pagophagia (ice...
Pica, in the form of ingestion of various non-food items like clay, chalks, etc., is commonly reported in Indian settings, but its other variant, pagophagia (ice eating), gets attention rarely. This case series is about three female patients who presented in psychiatry outpatient clinics with various mental health issues and ice eating habits. A diagnosis of iron deficiency anemia was common among all three cases, and they were managed with oral iron supplementation along with appropriate psychiatric treatments. Pagophagia is an important clinical presentation to be looked for in the changing Indian society.
PubMed: 38853805
DOI: 10.4103/ipj.ipj_178_23 -
World Neurosurgery May 2024Hemifacial spasm (HFS) results from vascular compression at the root exit of the facial nerve. Although the underlying etiology has yet to be identified, it has been...
OBJECTIVE
Hemifacial spasm (HFS) results from vascular compression at the root exit of the facial nerve. Although the underlying etiology has yet to be identified, it has been suggested that congenital vascular anomalies are involved. We have hypothesized common trunk anomaly of the anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA) which may play a role in HFS. However, no previous studies have directly compared the incidence of this anomaly between HFS patients and normal subjects. The present study was designed to address this gap in the literature.
METHODS
This case-control study compared magnetic resonance angiography data from 65 HFS patients and 65 normal subjects. Dominant AICA/PICA is defined as the absence of PICA/AICA, with the remaining AICA/PICA supplying both vascular territories. The term "common trunk" encompasses both dominant AICA and dominant PICA. The frequency of common trunk and dominant AICA/PICA was compared between the 2 groups.
RESULTS
There were no significant differences in the incidence of a common trunk (68.5% and 64.6%), dominant AICA (30.8% and 32.3%) and dominant PICA (37.7% and 32.3%) between the 2 groups. Additionally, no differences were found in the frequency of atherosclerosis risk factors.
CONCLUSIONS
There was no apparent association between common trunk anomaly and HFS. It is suspected that some vascular anomalies other than a common trunk are involved in HFS.
PubMed: 38734163
DOI: 10.1016/j.wneu.2024.05.004 -
International Journal of Emergency... Dec 2023Endotracheal intubation (ETI) in critically ill patients is a high-risk procedure due to the increased risk of cardiac arrest, and several factors may predict poor...
BACKGROUND
Endotracheal intubation (ETI) in critically ill patients is a high-risk procedure due to the increased risk of cardiac arrest, and several factors may predict poor outcomes in these patients. The aim of this study was to investigate the role of some factors, especially newly introduced vital signs such as the reverse shock index (RSI), in predicting post-intubation cardiac arrest (PICA) in critically ill adult patients.
METHODS
This cross-sectional study was conducted on critically ill patients over 18 years of age who were admitted to the emergency department (ED) and underwent ETI within 1 year. Patients who developed PICA and those without this event were included in the study, and their features were compared. The primary outcome was cardiac arrest.
RESULTS
Of 394 patients, 127 patients were included, of whom 95 (74.8%) developed PICA, and 32 (25.2%) did not experience cardiac arrest after intubation. In multivariate analysis, age, RSI, oxygen saturation, and total bilirubin were significantly associated with PICA. In addition, patients with RSI < 1 had a significantly higher risk of developing PICA (odds ratio = 5.22, 95% CI 1.83-14.86, p = 0.002). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for predicting PICA were 51.11%, 83.33%, 90.2%, 36.23%, and 59.17%, respectively. The ROC curve for RSI showed an area under the curve (AUC) of 0.66.
CONCLUSION
RSI may be useful in predicting PICA with higher diagnostic accuracy compared to the shock index. Furthermore, advanced age, hypoxia, and hyperbilirubinemia may increase the risk of PICA in patients admitted to the ED.
PubMed: 38062359
DOI: 10.1186/s12245-023-00569-y -
Behavior Analysis in Practice Sep 2023Parents of three children with neurodevelopmental disorders and pica were taught to use a safety checklist to create pica-safe areas when transitioning to new locations....
UNLABELLED
Parents of three children with neurodevelopmental disorders and pica were taught to use a safety checklist to create pica-safe areas when transitioning to new locations. During baseline, no parent displayed pica-safe behavior, and their children attempted pica at moderate to high rates. After use of the checklist, parent pica-safe behavior increased, and instances of pica diminished to near zero. Results transferred to new contexts and additional substances associated with pica. Using the safety checklist appears to have aided parents in creating pica-safe environments to minimize pica.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40617-023-00798-w.
PubMed: 37680327
DOI: 10.1007/s40617-023-00798-w -
Cureus Dec 2023Iron deficiency is a critical global health issue. One of the intriguing manifestations linked to iron deficiency is the presence of pica. The physiological relationship...
BACKGROUND
Iron deficiency is a critical global health issue. One of the intriguing manifestations linked to iron deficiency is the presence of pica. The physiological relationship between the senses of smell and taste suggests that pica may be accompanied by an inclination towards the smell of earth (geosmin). The smell of geosmin is distinct and generally recognized as a pleasing scent. The objective of this study is to explore this potential association. The sign of liking the smell of earth will now be referred to as "geosminophilia", for the first time, in this study.
METHODS
Patients aged 18 years and above who visited the Iron Deficiency Outpatient Clinic between September 2021 and August 2022 were chosen for this cross-sectional study. The dataset excluded those with ferritin concentrations over 100 mcg/L and transferrin saturation over 45%. Demographics, presence of pica, history of geosminophilia, and laboratory findings were documented in physical and digital patient data. The descriptive statistics, chi-square test, and independent group comparison tests were performed.
RESULTS
With a mean age of 38.7±11.7 years, the study sample comprised 280 patients, of which 263 were female and 17 were male. Ninety-six patients (34.3%) had geosminophilia, while 29 patients (10.4%) had pica. The only factors that significantly distinguished the groups based on the presence of geosminophilia were gender (p=0.04) and age (p=0.02). Using the chi-square test to compare the presence of pica and geosminophilia, a statistically significant relationship was identified (p<0.001). Additionally, 72.4% of patients who presented with pica had geosminophilia. Pica was absent in 96% of patients who did not have geosminophilia. A total of 93.8% (15/16) of pica cases with geophagia subtype exhibited the presence of geosminophilia. A significant correlation (r=0.27, p<0.001) was also observed between geosminophilia and pica.
CONCLUSION
In iron deficiency patients, geosminophilia and the presence of pica may accompany each other. Therefore, geosminophilia has the potential to be a new symptom of iron deficiency.
PubMed: 38222205
DOI: 10.7759/cureus.50460 -
Journal of Eating Disorders Nov 2023Recent research suggests that individuals with eating disorders (EDs) report elevated anhedonia, or loss of pleasure. Although individuals with avoidant/restrictive food...
BACKGROUND
Recent research suggests that individuals with eating disorders (EDs) report elevated anhedonia, or loss of pleasure. Although individuals with avoidant/restrictive food intake disorder (ARFID) often express that they do not look forward to eating, it is unclear whether they experience lower pleasure than those without EDs. Thus, identifying whether individuals with ARFID experience anhedonia may yield important insights that inform clinical conceptualization and treatment.
METHODS
A sample of 71 participants ages 10-23 with full and subthreshold ARFID and 33 healthy controls (HCs) completed the Pica, ARFID, and Rumination Disorder Interview, a diagnostic interview to assess ARFID profile severity (lack of interest in food, sensory sensitivity, fear of aversive consequences) and the Temporal Experience of Pleasure Scale (TEPS), a self-report measure of consummatory and anticipatory pleasure. Statistical analyses were performed using the full TEPS and also the TEPS with food-related items removed.
RESULTS
The ARFID group reported significantly lower anticipatory and consummatory pleasure compared to HCs, but these differences were no longer significant after controlling for depression, nor after removing food items from the TEPS. Within the ARFID sample, greater ARFID severity was associated with lower anticipatory pleasure across analyses, and greater endorsement of the lack of interest in food profile was related to lower anticipatory pleasure. ARFID severity was also associated with lower consummatory pleasure using the full TEPS, but this relationship was no longer significant with food items removed.
CONCLUSIONS
These results provide initial evidence for lower pleasure before potentially pleasurable events in individuals with more severe ARFID, particularly those with the lack of interest phenotype. Our findings also suggest that depression is likely to contribute low pleasure in this population. Future research should seek to further characterize how dimensions of pleasure relate to the maintenance and treatment of ARFID symptoms.
PubMed: 37950288
DOI: 10.1186/s40337-023-00921-w