Simon P. Elliott

Bio: Simon P. Elliott is an academic researcher from King's College London. The author has contributed to research in topics: Poison control & Ketoacidosis. The author has an hindex of 26, co-authored 54 publications receiving 1886 citations.

The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis

Abstract: The search for synthetic opioids as alternatives to opium-based derivatives has provided an important impulse to drug development around the globe An important goal in the systematic evaluation of new drug candidates is the identification of compounds that provide a more favorable side-effect profile, which includes reduced dependence-producing properties and abuse liability A rich source of information about these research efforts can be found in the scientific literature However, the exploration of these important discoveries has also been increasingly mined by largescale producers of these materials, which are then offered for sale These so-called ‘research chemicals’ or new psychoactive substances (NPS)[1] have created challenges to policy makers, clinicians, and law enforcement around the world[2] Recent examples of synthetic opioids that emerged as NPS on the market, and which were associated with severe cases of adverse effects, include 3,4-dichloro-N- {[1-(dimethylamino)cyclohexyl]methyl}benzamide (AH-7921), 1-cyclohexyl-4-(1,2- diphenylethyl)piperazines (MT-45) and N-phenyl-N-[1-(2-phenylethyl)piperidin-4- yl]acetamide (acetylfentanyl), respectively (Figure 1) Following the recommendation provided by the World Health Organization’s Expert Committee on Drug Dependence (ECDD),[3] AH-7921 was placed in Schedule I of the 1961 Single Convention, as amended by the 1972 Protocol in 2015[4] Furthermore, ECDD’s recommendation to place MT-45 into Schedule I and acetylfentanyl in Schedules I and IV of the same Convention[5] have been recently confirmed by the Commission on Narcotic Drugs[6] -Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) (Figure 1) has recently emerged on the market and can be purchased from various Internet retailers and is a structural isomer of AH-7921 (Figure 1) The preparation of U- 47700 and other derivatives was disclosed by the Upjohn Company in the 1970s[7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself[8,9] The presence of two chiral centres gives rise to a cis- and trans- racemic mixture with the trans-form being advertised for sale Binding studies also revealed that U-47700 displayed an appreciable selectivity for the μ-opioid receptor over the −opioid receptor[10,11] A variety of cyclohexyl trans-1,2-diamines have been found to be potent analgesics and the vicinal 1,2-diamine pattern has provided access to a large range of substances with diverse biological activities[12-14] Since U-47700 did not progress to clinical trials, there is no direct clinical information pertaining to its effects Keeping in mind the various limitations that may be associated with descriptions obtained from self-reporting users, its effects have been described with various positive and negative symptoms but appeared to be essentially comparable to other opioids Specifically, euphoria was reported in individuals, sometimes being short-lived, as well as general lift in mood with these desired effects being experienced in waves The negative effects were also opioid based, including nausea with some users describing respiratory depression For some users, U-47700 had a shorter duration of action and the urge to keep re-dosing was stated as being very high

Investigation of the first deaths in the United Kingdom involving the detection and quantitation of the piperazines BZP and 3-TFMPP.

Abstract: Piperazines such as 1-benzylpiperazine (BZP), 1-(3-trifluromethylphenyl)piperazine (3-TFMPP), and 1-(3-chlorophenyl)piperazine (3-CPP) have become recent drugs of abuse. With stimulant effects comparable to amphetamines but with a lower potency and differential global scheduling status, they have been sold as a supposed legal alternative to "Ecstasy". A few non-fatal and fatal cases where BZP has been detected have been published and typically involve other drugs. However, toxicity involving BZP alone has also been reported. No case data currently exist for 3-TFMPP. The toxicological situation is complicated by the existence of positional isomers of TFMPP and CPP. This paper includes ultraviolet (UV) and liquid chromatography-mass spectrometry data for these isomers and indicates an advantage in using UV spectra to distinguish the structures. Consequently, the presence of BZP and 3-TFMPP has been confirmed in three fatalities (road traffic deaths and a fatal fall), with two cases involving both drugs. These are the first reported cases of 3-TFMPP in postmortem fluid. In all cases, other drugs and/or ethanol were found. BZP was found at concentrations of 0.71, < 0.50, and 1.39 mg/L and 3-TFMPP was found at concentrations of 0.05 and 0.15 mg/L in postmortem blood. Concentrations were also measured in urine. Although BZP and 3-TFMPP were not the direct cause of death, the toxicological findings presented in this paper may assist the interpretation of future cases involving these drugs where their significance may be more apparent.

Current awareness of piperazines: pharmacology and toxicology.

Abstract: Although many piperazine derivatives exist, only a limited number have been studied, whereby they have been found to be generally stimulant in nature resulting from dopaminergic, noradrenergic, and predominantly serotoninergic effects in the brain. Reported toxic effects include agitation, anxiety, cardiac symptoms (e.g. tachycardia) and sometimes seizures. As for many drugs, they are primarily metabolized by cytochrome P450 with subsequent possible glucuronidation and/or sulfation. Their abuse has been relatively recently observed in the last decade with only a few identified in biological fluid (primarily 1-benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (3-TFMPP)) despite publications of a number of analytical methods. Even when detected, however, the toxicological significance of their presence is often difficult to ascertain as many cases involve other drugs as well as a wide and overlapping range of concentrations found in blood (both in life and after death). This paper reviews the current pharmacological and toxicological information for piperazine derivatives and also includes new ante-mortem and post-mortem blood data. Copyright © 2011 John Wiley & Sons, Ltd.

Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol

Abstract: 1,4-Butanediol (BDO) is an important commodity chemical used to manufacture over 2.5 million tons annually of valuable polymers, and it is currently produced exclusively through feedstocks derived from oil and natural gas. Herein we report what are to our knowledge the first direct biocatalytic routes to BDO from renewable carbohydrate feedstocks, leading to a strain of Escherichia coli capable of producing 18 g l(-1) of this highly reduced, non-natural chemical. A pathway-identification algorithm elucidated multiple pathways for the biosynthesis of BDO from common metabolic intermediates. Guided by a genome-scale metabolic model, we engineered the E. coli host to enhance anaerobic operation of the oxidative tricarboxylic acid cycle, thereby generating reducing power to drive the BDO pathway. The organism produced BDO from glucose, xylose, sucrose and biomass-derived mixed sugar streams. This work demonstrates a systems-based metabolic engineering approach to strain design and development that can enable new bioprocesses for commodity chemicals that are not naturally produced by living cells.

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

Abstract: The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

The harmful health effects of recreational ecstasy: a systematic review of observational evidence

Abstract: Objectives: To provide an evidence-based perspective on the prognostic value of novel markers in localised prostate cancer and to identify the best prognostic model including the three classical markers and investigate whether models incorporating novel markers are better. Data sources: Eight electronic bibliographic databases were searched during March–April 2007. The reference lists of relevant articles were checked and various health services research-related resources consulted via the internet. The search was restricted to publications from 1970 onwards in the English language. Methods: Selected studies were assessed, data extracted using a standard template, and quality assessed using an adaptation of published criteria. Because of the heterogeneity regarding populations, outcomes and study type, meta-analyses were not undertaken and the results are presented in tabulated format with a narrative synthesis of the results. Results: In total 30 papers met the inclusion criteria, of which 28 reported on prognostic novel markers and five on prognostic models. A total of 21 novel markers were identified from the 28 novel marker studies. There was considerable variability in the results reported, the quality of the studies was generally poor and there was a shortage of studies in some categories. The marker with the strongest evidence for its prognostic significance was prostate-specific antigen (PSA) velocity (or doubling time). There was a particularly strong association between PSA velocity and prostate cancer death in both clinical and pathological models. In the clinical model the hazard ratio for death from prostate cancer was 9.8 (95% CI 2.8–34.3, pE

Here Today, Gone Tomorrow…and Back Again? A Review of Herbal Marijuana Alternatives (K2, Spice), Synthetic Cathinones (Bath Salts), Kratom, Salvia divinorum, Methoxetamine, and Piperazines

Abstract: Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called “bath salts,” have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as “legal ketamine.” Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as “legal Ecstasy.” These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.