Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM‐775)

Lysergic acid diethylamide (LSD) is perhaps one of the best‐known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as ‘research chemicals’ or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM‐775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM‐775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM‐775. A powdered sample of LSM‐775 was characterized by X‐ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC–MS), high mass accuracy electrospray MS/MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid‐state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM‐775 acts as a nonselective agonist at 5‐HT_1A and 5‐HT_2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM‐775 activates 5‐HT_2A receptors and produces hallucinogen‐like effects in vivo. LSM‐775 did not induce the head twitch response unless 5‐HT_1A receptors were blocked by pretreatment with the antagonist WAY‐100,635 (1 mg/kg, subcutaneous). These findings suggest that 5‐HT_1A activation by LSM‐775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM‐775 is only capable of producing weak LSD‐like effects in humans.     

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials,utilizing polymer‐supported reagents

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in‐house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer‐supported reagents starting from 2‐amino‐2'‐chloro‐5‐nitrobenzophenone (clonazolam) and 2‐amino‐5‐nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4‐triazole ring moiety was performed within a gas chromatography–mass spectrometry (GC–MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by‐product profiles for both the micro and the preparative scale syntheses are also presented.     

Synthesis,analytical characterization,and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.     

Patients’ and parents’ views about lower limb orthopaedic surgery for ambulant children and young people with cerebral palsy: a qualitative evidence synthesis

PurposeThe article identifies the aspects of health and outcomes that are considered important from the perspective of ambulatory children with cerebral palsy (CP) and their parents regarding lower limb orthopaedic surgery and explores how they experience surgical interventions.MethodsFour databases (Embase, MEDLINE (Ovid), CINAHL and PsycINFO) were searched from inception to 11 April 2020. Studies were included if they: 1) they involved children or young adults diagnosed with ambulant CP or their family, 2) participants had experience with lower limb orthopaedic surgery and 3) studies employed qualitative research methods. The Critical Appraisal Skills Programme was used to appraise identified studies. The ‘Best-fit framework’ synthesis approach was used by applying the International Classification of Functioning-Children and Youth (ICF–CY) linking rules and thematic synthesis. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.ResultsSix studies were included. Four themes were generated which were linked to the ICF–CY framework: Body function and structure, Activity and participation, Environmental factors, Personal factors, as well as non-ICF–CY themes including Emotional well-being and Goal setting. Important surgical outcomes identified were pain, fatigue, movement-related function, mobility, walking ability, community life, emotional well-being, and adequate provision of public and health services.ConclusionThese findings are important for understanding patient-centred outcomes in lower limb ortho-paedics surgery and providing focus for future interventional studies aimed at improving outcomes of importance to children with CP. These findings highlight the importance of long-term support to help people negotiate the challenge of surgical regimes and to achieve good outcomes after orthopaedic surgery. The outcomes identified will contribute to the development of a core outcome set in this field.Level of evidenceIII     

Treatments of unilateral neglect: a review

OBJECTIVES: To review the existing literature on treatments of unilateral neglect, to synthesize findings, and to offer recommendations for future studies. DATA SOURCES: Computerized databases including MEDLINE and PsychINFO. STUDY SELECTION: All studies investigating treatment(s) of unilateral neglect. DATA EXTRACTION: Authors reviewed design and other methodologic issues. DATA SYNTHESIS: Unilateral neglect is a common consequence of right-hemisphere stroke. It is well recognized that the disorder is heterogeneous and has numerous subtypes. There have been numerous studies showing that arousal, hemispheric activation, and spatial attention treatments may all improve neglect, at least transiently. Despite these promising outcomes, little consensus exists as to whether 1 treatment is more efficacious than others, in part because cross-study differences in methodology render meta-analyses difficult, and in part because many studies fail to document duration of treatment effects or generalization to daily activities. One possibility is that these varied and diverse treatments may all be effective, reflecting redundancy in neural circuits devoted to attention and action in space, and consequent flexibility of the spatial processing system. It remains possible, however, that different subtypes of neglect may respond differentially to treatment of various sorts. Most existing studies of neglect have relied on very small populations of neglect patients, whose neglect is characterized only generally. CONCLUSION: Methodologic shortcomings hinder assessment of the efficacy of various types of neglect treatment. In the future, these shortcomings could be addressed with larger studies of well-characterized patients that evaluate duration of treatment effects and include functional measures. In addition, the role of overarching variables, such as reduced arousal, requires consideration. The ultimate goal of these studies might be the development of triaging strategies wherein neglect patients are assigned to treatments of most likely benefit on the basis of neuroanatomic and behavioral profiles.     

Factors associated with receipt of residential rehabilitation by opiate users indicate that these clients are more amenable to drug treatment

Aims: Residential rehabilitation (RR) is relatively expensive and is received by a minority of drug users seeking treatment. It is perceived to be particularly effective, but those entering RR may be more amenable to treatment than those treated in other modalities. The objective of this study was to explore ways in which opiate users treated in a residential setting differ, at treatment entry, from those treated in a community setting. Methods: Opiate users (N?=?406) who received either RR or community substitute prescribing (CSP) were sampled from the UK Drug Treatment Outcomes Research Study (DTORS). A logistic regression analysis, controlling for Drug Action Team, was used to predict the occurrence of RR versus CSP for the treatment of opiate dependence. Measures included self-reported levels of drug use, offending, social measures and health. Findings: RR clients were different to CSP clients in a number of respects that may positively influence treatment outcome; most importantly, their reasons for seeking treatment were different and they were better motivated. Conclusions: Higher treatment motivation may be one factor that explains why RR is a more effective treatment for clients with complex drug-related problems.     

Structure-Based and Rational Design of a Hepatitis C Virus Vaccine

A hepatitis C virus (HCV) vaccine is a critical yet unfulfilled step in addressing the global disease burden of HCV. While decades of research have led to numerous clinical and pre-clinical vaccine candidates, these efforts have been hindered by factors including HCV antigenic variability and immune evasion. Structure-based and rational vaccine design approaches have capitalized on insights regarding the immune response to HCV and the structures of antibody-bound envelope glycoproteins. Despite successes with other viruses, designing an immunogen based on HCV glycoproteins that can elicit broadly protective immunity against HCV infection is an ongoing challenge. Here, we describe HCV vaccine design approaches where immunogens were selected and optimized through analysis of available structures, identification of conserved epitopes targeted by neutralizing antibodies, or both. Several designs have elicited immune responses against HCV in vivo, revealing correlates of HCV antigen immunogenicity and breadth of induced responses. Recent studies have elucidated the functional, dynamic and immunological features of key regions of the viral envelope glycoproteins, which can inform next-generation immunogen design efforts. These insights and design strategies represent promising pathways to HCV vaccine development, which can be further informed by successful immunogen designs generated for other viruses.