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Audience: This scenario was developed to educate emergency medicine residents about the diagnosis and management of the agitated psychiatric patient., Introduction: The prevalence of agitation among patients in the emergency department is increasing, with an estimated 1.7 million events occurring annually in the United States.1 There are various methodologies for de-escalation, including verbal and chemical de-escalation and physical restraints. Chemical and/or physical restraints are sometimes necessary to ensure patient and staff safety when verbal de-escalation is ineffective, particularly since agitation is the leading cause of hospital staff injuries.2 Chemical restraints have been shown to be less physically traumatizing to patients.3 4 Adverse events associated with physical restraints include persistent psychological distress, blunt chest trauma, aspiration, respiratory depression, and asphyxiation leading to cardiac arrest.5 In regards to chemical restraints, adverse event reporting has been heterogeneous among studies, but the most consistent reported events involve respiratory compromise such as desaturation, airway obstruction, and respiratory depression.3 A study measuring QTc (corrected QT interval) after high-dose intramuscular ziprasidone or haloperidol did not demonstrate any QTc longer than 480 msec.6 Other events linked to chemical restraints include uncommon cardiovascular events and extrapyramidal side effects from medications.3 The main classes of medications utilized for chemical restraint include first-generation antipsychotics (eg, haloperidol and droperidol), second-generation antipsychotics (olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone), benzodiazipenes (eg, lorazepam and midazolam), and N-methyl-D-aspartic acid (NMDA) receptor antagonists (eg, ketamine).7,8 It is important to exclude other medical causes of agitation, consider the differential diagnoses, and then select a medication that is tailored to address underlying etiologies while remaining cognizant of the side effect profiles of these chemical agents. Educational Objectives : At the conclusion of the simulation session, learners will be able to: 1) Obtain a relevant focused history and physical examination on the agitated psychiatric patient. 2) Develop a differential for the agitated psychiatric patient, including primary psychiatric conditions and other organic pathologies. 3) Discuss the management of the agitated psychiatric patient, including the different options available for chemical sedation. 4) Prioritize safety of self and staff when caring for an agitated psychiatric patient., Educational Methods: This session was conducted using simulation with a standardized patient, followed by a debriefing session and lecture on the presentation, differential diagnosis, and management of the agitated psychiatric patient. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board examination case., Research Methods: The residents are provided a survey at the completion of the debriefing session to rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. This survey is specific to the local institution's simulation center., Results: Feedback from the residents was overwhelmingly positive, although many stated that they felt some degree of intimidation or stress from the standardized patient who did not break from their role throughout the scenario.The local institution's simulation center feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form9 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. This session received mostly 7 scores (extremely effective/outstanding)., Discussion: This is a physically safe method for reviewing management of the agitated psychiatric patient. There are multiple potential presentations of the agitated psychiatric patient, as well as varying underlying etiologies. These scenarios may be tailored to the needs of the learner, including identifying agitation, pharmacologic review, and de-escalation techniques., Topics: Medical simulation, agitated psychiatric patient, chemical sedation, verbal de-escalation, emergency medicine, psychiatry., (© 2020 Pabst, et al.)

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4- epi -isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for G M1 -gangliosidosis and Morquio B disease.

From 1,2;3,4-di- O -isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d- galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N -acetyl-d-hexosaminidase activities in vivo., Competing Interests: The authors declare no conflict of interest.

N-Functionalized amino(hydroxymethyl)cyclopentanetriols are potent inhibitors of β-d-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for G M1 -gangliosidosis-associated lysosomal acid β-galactosidase thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

From 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, a series of highly functionalized (hydroxymethyl)cyclopentanes was easily available. In line with reports by Reymond and Jäger on similar structures, these amine containing basic carbasugars are potent inhibitors of β-D-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for G M1 -gangliosidosis-associated lysosomal acid β-galactosidase mutant R201C, thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,β-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed. As an example, the synthesis of C-(5aR)- and C-(5aS)-5a-C-pentyl-4-epi-isofagomines, powerful inhibitors of β-galactosidases, is outlined. In line with reported data, the (C-5aR) epimer was found a highly potent experimental pharmacological chaperone for G M1 -associated human lysosomal β-galactosidase mutant R201C., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

From an easily available partially protected analog of 1-deoxy-L-gulo-nojirimycin, by chain-branching at C-4 and suitable modification, lipophilic analogs of the powerful β-D-galactosidase inhibitor 4-epi-isofagomine have been prepared. New compounds exhibit considerably improved inhibitory activities when compared with the unsubstituted parent compound and may serve as leads toward new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful β-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the β-galactosidase (β-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N(2)-(dansyl)-N(6)-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a dansyl group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)(2)OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-D: -galactitol) and (TFM)(3)OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-D: -galactitol) on the β-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5-10 μM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.

G(M1)-gangliosidosis (GM1) and Morquio B disease (MBD) are rare lysosomal storage disorders caused by mutations in the gene GLB1. Its main gene product, human acid beta-galactosidase (beta-Gal) degrades two functionally important molecules, G(M1)-ganglioside and keratan sulfate in brain and connective tissues, respectively. While GM1 is a severe, phenotypically heterogenous neurodegenerative disorder, MBD is a systemic bone disease without effects on the central nervous system. A MBD-specific mutation, p.W273L, was shown to produce stable beta-Gal precursors, normally transported and processed to mature, intralysosomal beta-Gal. In accordance with the MBD phenotype, elevated residual activity against G(M1)-ganglioside, but strongly reduced affinity towards keratan sulfate was found. Most GM1 alleles, in contrast, were shown to affect precursor stability and intracellular transport. Specific alleles, p.R201C and p.R201H result in misfolded, unstable precursor proteins rapidly degraded by endoplasmic reticulum-associated protein degradation (ERAD). They may therefore be sensitive to stabilization by small molecules which bind at the active site and provide proper conformation. Thus the stabilized protein may escape from ERAD processes, and reach the lysosomes in an active state, as proposed for enzyme enhancement therapy (EET). This paper demonstrates that a novel iminosugar, DLHex-DGJ, has potent effects as competitive inhibitor of human acid beta-galactosidase in vitro, and describes its effects on activity, protein expression, maturation and intracellular transport in vivo in 13 fibroblasts lines with GLB1 mutations. Beside p.R201C and p.R201H, two further alleles, p.C230R and p.G438E, displayed significant sensitivity against DLHex-DGJ, with an increase of catalytic activity, and a normalization of transport and lysosomal processing of beta-Gal precursors., (Copyright 2010 Elsevier Inc. All rights reserved.)