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Journal of Managed Care & Specialty... Mar 2022Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute...
Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Beinfeld, Nhan, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Wasfy, Walton, and Sarker received funding from ICER for the work described in this summary. Walton also reports consulting fees from Second City Outcomes Research. Wasfy reports personal fees from Biotronik and Pfizer; grants from National Institutes of Health, National Football League Players Association and American Heart Association; and travel support from American College of Cardiology. Sarker has nothing additional to disclose.
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Cost-Benefit Analysis; Humans; United States; Uracil
PubMed: 35199575
DOI: 10.18553/jmcp.2022.28.3.369 -
NBOMe: new potent hallucinogens--pharmacology, analytical methods, toxicities, fatalities: a review.European Review For Medical and... Sep 2015NBOMe is a class of emerging new psychoactive substances that has recently gained prominence in the drug abuse market. NBOMes are N-2-methoxy-benzyl substituted 2C class... (Review)
Review
OBJECTIVE
NBOMe is a class of emerging new psychoactive substances that has recently gained prominence in the drug abuse market. NBOMes are N-2-methoxy-benzyl substituted 2C class of hallucinogens, currently being marked online as "research chemicals" under various names: N-bomb, Smiles, Solaris, and Cimbi. This article reviews available literature on the pharmacology; the analytical methods currently used for the detection and quantification of NBOMe in biological matrices and blotters, together with intoxication cases and NBOMe-related fatalities.
MATERIALS AND METHODS
Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through June 2015 using the following keywords: "NBOMe", "Nbomb", "Smiles", "intoxication", "toxicity" "fatalities", "death", "pharmacology", "5-HT2A receptor", "analysis" and "analytical methods". The main key word "NBOMe" was individually searched in association to each of the others.
RESULTS
The review of the literature allowed us to identify 43 citations on pharmacology, analytical methods and NBOMe-related toxicities and fatalities.
CONCLUSIONS
The high potency of NBOMes (potent agonists of 5-HT2A receptor) has led to several severe intoxications, overdose and traumatic fatalities; thus, their increase raises significant public health concerns. Moreover, due to the high potency and ease of synthesis, it is likely that their recreational use will become more widespread in the future. The publication of new data, case reports and evaluation of the NBOMes metabolites is necessary in order to improve knowledge and awareness within the forensic community.
Topics: Benzylamines; Drug Overdose; Hallucinogens; Humans; Phenethylamines; Substance-Related Disorders
PubMed: 26400534
DOI: No ID Found -
Journal of Cellular and Molecular... Jan 2022Persistent cardiac Ca /calmodulin-dependent Kinase II (CaMKII) activation was considered to promote heart failure (HF) development, some studies believed that CaMKII was...
Persistent cardiac Ca /calmodulin-dependent Kinase II (CaMKII) activation was considered to promote heart failure (HF) development, some studies believed that CaMKII was a target for therapy of HF. However, CaMKII was an important mediator for the ischaemia-induced coronary angiogenesis, and new evidence confirmed that angiogenesis inhibited cardiac remodelling and improved heart function, and some conditions which impaired angiogenesis aggravated ventricular remodelling. This study aimed to investigate the roles and the underlying mechanisms of CaMKII inhibitor in cardiac remodelling. First, we induced cardiac remodelling rat model by ISO, pre-treated by CaMKII inhibitor KN-93, evaluated heart function by echocardiography measurements, and performed HE staining, Masson staining, Tunel staining, Western blot and RT-PCR to test cardiac remodelling and myocardial microvessel density; we also observed ultrastructure of cardiac tissue with transmission electron microscope. Second, we cultured HUVECs, pre-treated by ISO and KN-93, detected cell proliferation, migration, tubule formation and apoptosis, and carried out Western blot to determine the expression of NOX2, NOX4, VEGF, VEGFR2, p-VEGFR2 and STAT3; mtROS level was also measured. In vivo, we found KN-93 severely reduced myocardial microvessel density, caused apoptosis of vascular endothelial cells, enhanced cardiac hypertrophy, myocardial apoptosis, collagen deposition, aggravated the deterioration of myocardial ultrastructure and heart function. In vitro, KN-93 inhibited HUVECs proliferation, migration and tubule formation, and promoted apoptosis of HUVECs. The expression of NOX2, NOX4, p-VEGFR2 and STAT3 were down-regulated by KN-93; mtROS level was severely reduced by KN-93. We concluded that KN-93 impaired angiogenesis and aggravated cardiac remodelling and heart failure via inhibiting NOX2/mtROS/p-VEGFR2 and STAT3 pathways.
Topics: Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Endothelial Cells; Heart Failure; Myocytes, Cardiac; NADPH Oxidase 2; Neovascularization, Physiologic; Rats; STAT3 Transcription Factor; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Ventricular Remodeling
PubMed: 34845819
DOI: 10.1111/jcmm.17081 -
Andrology May 2015Premature ejaculation (PE) is the most prevalent male sexual dysfunction. This is associated with negative personal and interpersonal psychological outcomes. The... (Review)
Review
Premature ejaculation (PE) is the most prevalent male sexual dysfunction. This is associated with negative personal and interpersonal psychological outcomes. The pharmacologic treatment of PE includes the use of antidepressants, local anesthetic agents, and phosphodiesterase type 5 inhibitors. While numerous treatments can control PE, only antidepressants and topical anesthetic creams and sprays have recently been shown to be more effective. This review focuses on the physiology and pharmacology of ejaculation, the pathophysiology of PE and the most effective pharmacological treatment of PE. Pharmacotherapy of PE with off-label short-acting selective serotonin reuptake inhibitors (SSRIs) is common, effective, and safe. Dapoxetine, a SSRI with a short half-life, has been recently evaluated for the treatment of PE by several countries and results are promising. In clinical practice, follow-up side effects are an important part of the management strategy for PE. The understanding of etiology, pathophysiology, and treatment modalities of PE would be beneficial to clinician in helping patients with this disappointing sexual problem.
Topics: Androgens; Anesthetics, Local; Antidepressive Agents; Benzylamines; Ejaculation; Endocrine System; Humans; Male; Naphthalenes; Phosphodiesterase 5 Inhibitors; Premature Ejaculation; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 25951512
DOI: 10.1111/andr.12032 -
The Israel Medical Association Journal... Aug 2004Classic anticoagulant drugs, such as heparin and warfarin, are very effective. However, although in use for more than 50 years, they do have some clinical drawbacks.... (Review)
Review
Classic anticoagulant drugs, such as heparin and warfarin, are very effective. However, although in use for more than 50 years, they do have some clinical drawbacks. Heparin, now better termed unfractionated heparin, can only be used intravenously and its laboratory control is complicated. Warfarin is orally administered, but its therapeutic window is very narrow and patients need repeated laboratory tests. Moreover, both drugs are non-specific, as they inhibit the coagulation cascade at several steps. Pharmaceutic research has developed new drugs, some of which are already on the market, such as fondaparinux, a pentasaccharide that can interact with antithrombin, thus inhibiting factor Xa. This pentasaccharide is part of the parent heparin molecule and can be chemically synthesized, with the advantage of avoiding extractive compounds. Fondaparinux has a half-life compatible with once-a-day administration; modification of its structure (idraparinux) has led to more stable binding with antithrombin and to an increase in its half-life to allow once-a-week administration. Alternatives to oral anticoagulants have been developed following the study of some compounds like hirudin, which directly binds thrombin and blocks its catalytic site. One of these molecules, ximelagatran, is in advanced clinical development. Ximelagatran is converted into its active form, melagatran, in the circulation, and thrombin activity can be blocked by oral administration twice daily. There is no need for laboratory control and phase II and phase III studies are encouraging. The next few years should bring great changes to the treatment of patients with thromboembolic disorders.
Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation Disorders; Fondaparinux; Half-Life; Humans; Oligosaccharides; Polysaccharides
PubMed: 15326828
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2011Cancer increases the risk of thromboembolic events even while on anticoagulation. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cancer increases the risk of thromboembolic events even while on anticoagulation.
OBJECTIVES
To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.
SEARCH STRATEGY
A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively-confirmed VTE.
DATA COLLECTION AND ANALYSIS
Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.
MAIN RESULTS
Of 8187 identified citations, nine RCTs were eligible and reported data for 1908 patients with cancer. Meta-analysis of seven RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). Other results did not exclude a beneficial or harmful effect of LMWH compared to VKA for the outcomes of major bleeding (RR 1.05; 95% CI 0.53 to 2.10) or thrombocytopenia (RR 1.02; 95% CI 0.60 to 1.74). The quality of evidence was low for mortality, major bleeding and minor bleeding and moderate for recurrent VTE. One RCT comparing six months extension of anticoagulation with 18 months ximelagatran 24 mg twice daily versus placebo found a reduction in VTE (HR 0.16; 95% CI 0.09 to 0.30) but did not exclude beneficial or harmful effects for the outcomes of mortality and bleeding. One RCT, comparing dabigatran to VKA, did not exclude beneficial or harmful effect of one agent over the other.
AUTHORS' CONCLUSIONS
For the long-term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.
Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K
PubMed: 21678361
DOI: 10.1002/14651858.CD006650.pub3 -
The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease.Pharmacology & Therapeutics Jan 2018The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess... (Review)
Review
The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.
Topics: Animals; Atherosclerosis; Benzoates; Benzylamines; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Inflammation; Liver X Receptors; Models, Biological; Molecular Targeted Therapy; Sulfonamides
PubMed: 28720427
DOI: 10.1016/j.pharmthera.2017.07.010 -
Angewandte Chemie (International Ed. in... Apr 2017Meta-C-H functionalization of benzylamines has been developed using a Pd /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO Me)...
Meta-C-H functionalization of benzylamines has been developed using a Pd /transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.
Topics: Amination; Benzylamines; Catalysis; Halogenation; Ligands; Palladium; Pyridones
PubMed: 28371173
DOI: 10.1002/anie.201701803 -
Scientific Reports Dec 2014Premature ejaculation (PE) is the most common male sexual dysfunction. Dapoxetine hydrochloride, belonging to a class of drugs known as selective serotonin reuptake... (Meta-Analysis)
Meta-Analysis Review
Premature ejaculation (PE) is the most common male sexual dysfunction. Dapoxetine hydrochloride, belonging to a class of drugs known as selective serotonin reuptake inhibitors or, was the first drug originally approved for the on-demand treatment of men with PE. We aimed to compare the intravaginal ejaculatory latency time (IELT), patient-reported global impression of change (PGIC), and adverse effect (AE) incidence associated with the use of dapoxetine (30 mg and 60 mg) versus placebo, and evaluate the differences in administering 60 mg versus 30 mg as on-demand medical oral therapy for the treatment of PE via a literature review and meta-analysis. Relevant randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (Cochrane Library) databases. Ultimately, a total of seven RCTs with 8039 patients were included. Our meta-analysis demonstrated that dapoxetine (in the 30 mg and 60 mg subgroup) resulted in significantly higher IELT, PGIC, and AE incidence relative to the placebo, with higher proportions observed for 60 mg versus 30 mg of dapoxetine administration. The most common AEs were mild and tolerable. We conclude that dapoxetine (particularly the 60 mg dosage) may be considered a safe and effective drug for patients with PE.
Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Benzylamines; Comorbidity; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Humans; Internationality; Male; Middle Aged; Naphthalenes; Patient Satisfaction; Premature Ejaculation; Prevalence; Risk Factors; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Young Adult
PubMed: 25434754
DOI: 10.1038/srep07269 -
Bioorganic & Medicinal Chemistry Sep 2021A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and...
A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and as inhibitors of amyloid peptide (Aβ) aggregation, for treatment of Alzheimer's disease (AD). These dual acting compounds exhibited good AChE inhibitory activities ranging from 0.34 to 6.35 µM. Analogs8g and 8n were found to be the most potent AChE inhibitors in the series with ICvalues of 0.38 µM and 0.34 µM, respectively. All the analogs (8a-8n) exhibited weak BuChE inhibitory activities ranging from 14.60 to 21.65 µM. Analogs8g and 8n exhibited BuChE with ICvalues of 15.38 µM and 14.60 µM, respectively, demonstrating that these analogs were greater than 40-fold more selective for inhibition of AChE over BuChE. Additionally, compounds8g and 8n were also found to be the best inhibitors of self-induced Aβ peptide aggregation with ICvalues of 3.91 µM and 3.22 µM, respectively; 8g and 8n also inhibited AChE-induced Aβ peptide aggregation by 68.7% and 72.6%, respectively. Kinetic analysis and molecular docking studies indicate that analogs 8g and 8n bind to a new allosteric pocket (site B) on AChE. In addition, the observed inhibition of AChE-induced Aβ peptide aggregation by 8n is likely due to allosteric inhibition of the binding of this peptide at the CAS site on AChE. Overall, these results indicate that 8g and 8n are examples of dual-acting lead compounds for the development of highly effective anti-AD drugs.
Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzylamines; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Horses; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Structure-Activity Relationship
PubMed: 34304133
DOI: 10.1016/j.bmc.2021.116311