Structural basis of THC analog activity at the Cannabinoid 1 receptor.

Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G.

Gallstone ileus: report of two cases and a mini literature review.

Gallstone ileus is a relatively rare complication of cholelithiasis, and an uncommon cause of small bowel obstruction most commonly seen in elderly and debilitated people with associated comorbidities. Symptoms of gallstone ileus are insidious and may be vague while the delay in diagnosis results in a high mortality rate. Herein we report two cases of gallstone ileus in elderly patients with complex medical history who presented at the emergency department with abdominal pain and distension, vomiting and fluid/electrolyte disorders due to cholecysto-enteric fistula and bowel obstruction.

A Rare Case of Retroperitoneal Tumefactive Fibroinflammatory Lesion Related to IgG4-Sclerosing Disease.

We present a unique case of a retroperitoneal tumefactive fibroinflammatory lesion related to IgG4-sclerosing disease; it is a rare manifestation of the IgG4-related disease, which usually causes diffuse fibrosis when located in the retroperitoneum, rather than mass-like lesions. A 49-year-old man presented to the emergency department complaining of abdominal pain and vomiting. Subsequent testing with abdominal ultrasound, CT, and MRI revealed a large retroperitoneal mass of unknown origin, heterogenous, with a concentric circles pattern best visualized in MRI.

Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2.

2-Arachidonoyl glycerol (2-AG) is the principal endogenously produced ligand for the cannabinoid CB1 and CB2 receptors (CBRs). The lack of potent and efficacious 2-AG ligands with resistance against metabolizing enzymes represents a significant void in the armamentarium of research tools available for studying eCB system molecular constituents and their function. Herein we report the first endocannabinoid glyceride templates with remarkably high potency and efficacy at CBRs.

First Study of the ^{139}Ba(n,γ)^{140}Ba Reaction to Constrain the Conditions for the Astrophysical i Process.

New astronomical observations point to a nucleosynthesis picture that goes beyond what was accepted until recently. The intermediate "i" process was proposed as a plausible scenario to explain some of the unusual abundance patterns observed in metal-poor stars. The most important nuclear physics properties entering i-process calculations are the neutron-capture cross sections and they are almost exclusively not known experimentally.

Study Protocol of a Prospective, Monocentric, Single-Arm Study Investigating the Correlation of Endograft Properties with Aortic Stiffness in Abdominal Aortic Aneurysm Patients Subjected to Endovascular Aortic Repair.

The number of endovascular aortic repairs (EVARs) has surpassed the number of open surgical repairs of abdominal aortic aneurysms (AAAs) worldwide. The available commercial endoprostheses are composed of materials that are stiffer than the native aortic wall. As a consequence, the implantation of stent-graft endoprostheses during EVAR increases aortic rigidity and thus aortic stiffness, resulting in a decrease in abdominal aorta compliance.

One-Year Outcomes of CGuard Double Mesh Stent in Carotid Artery Disease: A Systematic Review and Meta-Analysis.

: Prospective single and multicenter studies have shown improved outcomes of patients who underwent carotid artery stenting with the novel CGuard dual-layer mesh stent at 1 year. : The aim of this study is to conduct a systematic review and meta-analysis of all published studies to assess 1-year efficacy and outcomes of CGuard in patients with carotid stenting. Methods: A systematic search was performed.

Effects of cannabinoid agonists and antagonists in male rats discriminating the synthetic cannabinoid AM2201.

The synthetic forms of delta-9-tetrahydrocannabinol (Δ-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ-THC.

Endograft Anaconda in Endovascular Aneurysm Repair: A Systematic Review of Literature and Meta-Analysis.

Backgound: The number of endovascular abdominal aortic aneurysm repairs (EVARs) has surpassed the number of open surgical repair of AAAs worldwide with a great variety of endografts being available. The aim of this study is to conduct a systematic review of the literature and meta-analysis of studies reporting patients with infrarenal abdominal aortic aneurysm (AAA) subjected to EVAR with the Anaconda endograft.

Methods: We performed a systematic review of multiple electronic databases for studies including patients with infrarenal AAA who were subjected to elective EVAR with Anaconda endograft exclusively.

Structural basis for activation of CB1 by an endocannabinoid analog.

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex.

Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats.

Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710.

One-year outcomes following primary stenting of infrapopliteal steno-occlusive arterial disease using a non-polymer sirolimus-eluting stent: Results from a prospective single-centre cohort study.

Background: Clinical outcomes using new generation drug-eluting stents designed specifically for infrapopliteal disease are not widely available, especially in comparison to paclitaxel-based therapies. This series reports 1-year outcomes in patients with diabetes and chronic limb threatening ischaemia (CLTI) undergoing angioplasty, with a sirolimus-eluting tibial stent (Cre8, Alvimedica, Turkey), evaluating the feasibility, safety, and efficacy of this new device. Outcomes were compared to matched patients undergoing infrapopliteal angioplasty using a paclitaxel-coated balloon (DCB).

Effects of cannabinoid exposure on short-term memory and medial orbitofrontal cortex function and chemistry in adolescent female rhesus macaques.

Aim: There is increasing concern that cannabinoid exposure during adolescence may disturb brain maturation and produce long-term cognitive deficits. However, studies in human subjects have provided limited evidence for such causality. The present study utilized behavioral and neuroimaging endpoints in female non-human primates to examine the effects of acute and chronic exposure during adolescence to the cannabinoid receptor full agonist, AM2389, on cognitive processing and brain function and chemistry.

Differential Enantiomer-Specific Signaling of Cannabidiol at CB Receptors.

The two main constituents of are Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ-THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB receptor signaling, likely as a negative allosteric modulator.

The effectiveness and safety of direct oral anticoagulants compared to conventional pharmacologic thromboprophylaxis in hip fracture patients: A systematic review and meta-analysis of randomized controlled trials.

Background: Direct oral anticoagulants (DOACs) are recommended as a possible pharmacologic venous thromboembolism (VTE) prophylaxis in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, current guidelines did not introduce recommendations for administration of DOACs as an option for pharmacologic VTE prophylaxis in patients undergoing hip fracture surgery (HFS). The purpose of this study is to compare the effectiveness and safety of DOACs administered for pharmacologic VTE prophylaxis in patients undergoing HFS to conventional pharmacologic VTE prophylaxis, as well as mortality between these thromboprophylaxis medications.

Altered sleep during spontaneous cannabinoid withdrawal in male mice.

Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal.

Evidence for spontaneous cannabinoid withdrawal in mice.

Although the behavioral effects of acute and chronic exposure to cannabinoids have been extensively studied in mice, spontaneous withdrawal following exposure to cannabinoids has not been well characterized in this species. To address this issue, different groups of mice were treated for 5 days with saline, 20-36 mg/kg/day of the CB partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), or 0.06-0.

Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists.

In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal substitutions. Of the compounds described here, a nabilone analog, AM8936, with the C6'-cyano-substituted side chain, was identified as the most successful analog capable of serving as a potential candidate for further development and a valuable tool for further in vivo studies.

Brain Penetrant, but not Peripherally Restricted, Synthetic Cannabinoid 1 Receptor Agonists Promote Morphine-Mediated Respiratory Depression.

Cannabis acceptance and use continues to rise despite the gaps in knowledge regarding the mechanisms of cannabinoids and the endocannabinoid system in many physiological functions, including respiratory influence. With recent evidence of cannabinoid receptor 1 (CB1R) presence in the collection of respiratory neurons in the brainstem, as well as in the peripheral lung tissue, it is vital that the mechanisms involved in central and peripheral CB1R modulation of respiratory function be delineated. In this study we sought to define the roles of central versus peripheral CB1R activation on respiratory depression alone and in combination with morphine using whole body plethysmography.

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.

Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures and ultra-large libraries of virtual compounds. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries, new approaches to compound screening are needed. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds.

Development of Analytical Strategies for the Determination of Olive Fruit Bioactive Compounds Using UPLC-HRMS and HPLC-DAD. Chemical Characterization of Lesvos Variety as a Case Study.

In this study, an overall survey regarding the determination of several bioactive compounds in olive fruit is presented. Two methodologies were developed, one UPLC-Q-TOF-MS method for the determination of olive fruit phenolic compounds and one HPLC-DAD methodology targeting the determination of pigments (chlorophylls and carotenoids), tocopherols (α-, β, -γ, δ-) and squalene. Target and suspect screening workflows were developed for the thorough fingerprinting of the phenolic fraction of olives.

Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression.

An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic. Opioid respiratory depression results from a decrease in reflexive inspiration within the preBötzinger complex in the brainstem. Cannabinoid receptor agonism is reported to enhance opioid analgesia, yet whether cannabinoids enhance or inhibit opioid-induced respiratory depression is unknown.