Patient‐centred tobacco management

Patient‐centred tobacco management approaches tobacco smoking as a chronic disease and can be offered to all smokers irrespective of their attitude to quitting. Maintaining a long‐term relationship with smokers enables the adoption of flexible solutions and shared goals. It is argued that patient‐centred tobacco management potentially heightens the chances of eventual abstinence for smokers who are unable, or not yet ready to quit. [Gould, GS. Patient‐centred tobacco management. Drug Alcohol Rev 2014;33:93–98]     

Syntheses,analytical and pharmacological characterizations of the ‘legal high’ 4‐[1‐(3‐methoxyphenyl)cyclohexyl]morpholine (3‐MeO‐PCMo) and analogues

New psychoactive substances (NPS) are commonly referred to as ‘research chemicals’, ‘designer drugs’ or ‘legal highs’. One NPS class is represented by dissociative anesthetics, which include analogues of the arylcyclohexylamine phencyclidine (PCP), ketamine and diphenidine. A recent addition to the NPS market was 4‐[1‐(3‐methoxyphenyl)cyclohexyl]morpholine (3‐MeO‐PCMo), a morpholine analogue of 3‐MeO‐PCP. Although suspected to have dissociative effects in users, information about its pharmacological profile is not available. From clinical and forensic perspectives, detailed analytical data are needed for identification, especially when facing the presence of positional isomers, as these are frequently unavailable commercially. This study presents the analytical and pharmacological characterization of 3‐MeO‐PCMo along with five additional analogues, namely the 2‐ and 4‐MeO‐PCMo isomers, 3,4‐methylenedioxy‐PCMo (3,4‐MD‐PCMo), 3‐Me‐PCMo and PCMo. All six arylcyclohexylmorpholines were synthesized and characterized using chromatographic, mass spectrometric and spectroscopic techniques. The three positional isomers could be differentiated and the identity of 3‐MeO‐PCMo obtained from an internet vendor was verified. All six compounds were also evaluated for affinity at 46 central nervous system receptors including the N‐methyl‐d ‐aspartate receptor (NMDAR), an important target for dissociative anesthetics such as PCP and ketamine. In vitro binding studies using (+)‐[3‐³H]‐MK‐801 in rat forebrain preparations revealed moderate affinity for NMDAR in the rank order of 3‐Me >3‐MeO > PCMo >3,4‐MD > 2‐MeO > 4‐MeO‐PCMo. 3‐MeO‐PCMo was found to have moderate affinity for NMDAR comparable to that of ketamine, and had an approximate 12‐fold lower affinity than PCP. These results support the anecdotal reports of dissociative effects from 3‐MeO‐PCMo in humans.     

An unusual detection of tert‐butyl‐4‐anilinopiperidine‐1‐carboxylate in seizures of falsified ‘Xanax’ tablets and in items in a suspected heroin seizure submitted by Irish law enforcement

The identification of tert‐butyl‐4‐anilinopiperidine‐1‐carboxylate (4‐anilinopiperdine‐t‐BOC or 4‐AP‐t‐BOC) in many seized falsified ‘Xanax’ tablets has been reported after being encountered in forensic casework in late 2019 and early 2020 in Ireland. This substance was also detected in a pink powder submitted for analysis in March 2020. The pink powder was part of a larger seizure comprising brown powders which contained morphine or diamorphine (heroin) or a type of counterfeit heroin or heroin adulterant (known as ‘bash’). Novel benzodiazepines and other substances are being detected as ingredients in falsified benzodiazepine tablets more frequently on the illicit market. The detection of 4‐AP‐t‐BOC in benzodiazepine tablets is noteworthy and 4‐AP‐t‐BOC is added to the list of adulterants found in benzodiazepine tablets emerging in Europe. The presence of 4‐AP‐t‐BOC in both falsified ‘Xanax’ and powdered seizures is unusual, and analytical data are presented to assist with the identification of this compound in suspected illicit substances. The presence of 4‐AP‐t‐BOC in the tablets was confirmed using gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses, and spectral fragmentation pathways were suggested. To the authors' best knowledge, information about the biological activity of 4‐AP‐t‐BOC is not available. The removal of the t‐BOC protecting group yields 4‐anilinopiperidine which has been reported to be involved in the synthesis of fentanyl.     

‘100 years of peptide synthesis’: ligation methods for peptide and protein synthesis with applications to β‐peptide assemblies*

Abstract: A brief survey of the history of peptide chemistry from Theodore Curtius to Emil Fischer to Bruce Merrifield is first presented. The discovery and development of peptide ligation, i.e. of actual chemical synthesis of proteins are described. In the main chapter, ‘ Synthesis of Proteins by Chemical Ligation ’ a detailed discussion of the principles, reactivities and mechanisms involved in the various coupling strategies now applied (ligation, chemical ligation, native chemical ligation) is given. These include coupling sites with cysteine and methionine (as well as the seleno analogs), histidine, glycine and pseudo‐prolines, ‘unrestricted’ amino‐acid residues (using the Staudinger reaction), as well as solid‐phase segment coupling by thioligation of unprotected peptides. In another section, ‘ Synthesis of β‐peptides by Thioligation ’, couplings involving β²‐ and β³‐peptides are described (with experimental details).     

The terms ‘autacoid’, ‘hormone’ and ‘chalone’ and how they have shifted with time

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Can in‐depth research interviews have a ‘therapeutic’ effect for participants?

Objective The study's objective was to explore whether there was any discernible ‘therapeutic’ effect upon participants after an in‐depth research interview, which focused upon their experiences of hypertension and its management. Method A questionnaire comprising 13 questions (open and closed) was posted to patients with hypertension (n = 30), three to eight months after participating in face‐to‐face in‐depth interviews, which explored their experiences of chronic illness and its management. Key findings The data from 25 respondents (83%) suggested that in‐depth research interviews could have a therapeutic benefit for some participants. This benefit was described by some as encouraging them to take more control over their lifestyle; specifically, consideration of their diet and/or increasing the time involved in regular exercise or relaxation. For others, it was the recognition of the need for both additional information on hypertension and the available treatment options, and for healthcare professionals to talk with them and to discuss their condition and its management. Conclusions Participating in an in‐depth interview can have a therapeutic effect. This effect may encompass not only changes in the interviewee's perceptions and behaviour, but also the possible development of a more meaningful appreciation and understanding of their condition.     

‘At the moment it is just a couple of eccentrics doing it’: concordance in day‐to‐day practice

Objectives To assess the feasibility and acceptability of concordance in pharmacy practice through examination of communication between customers and pharmacists in two community pharmacies in consultations for over‐the‐counter medicines. Method A qualitative pilot study involving data drawn from six sources: audiotaped training session with all the pharmacists involved, observational field work in the pharmacies, audiotaped consultations with pharmacists and customers, debriefing interviews with pharmacists after the consultation, and semi‐structured interviews with customers a few days after their consultation. Setting Two community pharmacies that concentrate their services on medicine advice and dispensing, one in a deprived inner‐city area, the other in a more affluent suburban area of London. Key findings The pharmacists developed a personal understanding of concordance which informed their practice. Customers reported a high level of satisfaction with services they received from the respective pharmacists. Their accounts of the consultations verified the pharmacists' patient‐centredness in their day‐to‐day practice. Conclusion The implementation of a concordance model was possible through the development of a personalised, patient‐centred model which drew on the model of concordance but was adapted in accordance with both structural constraints as well as the personal style of the pharmacists involved.     

‘Smoking’ mephedrone: The identification of the pyrolysis products of 4‐methylmethcathinone hydrochloride

The ring‐substituted cathinone – mephedrone – has gained popularity among recreational drug users over the past several years. It is generally consumed orally or by snorting but reports indicate that it is also ingested by vaporization/inhalation. This study examines the pyrolysis products produced by heating mephedrone under using simulated ‘meth pipe’ conditions. Thirteen pyrolysis products were identified, the major ones being iso‐mephedrone, 4‐methylpropiophenone, 4‐methylphenylacetone, two pyrazine derivatives formed by dimerization of mephedrone, N‐methylated mephedrone (N,N,4‐trimethylcatinone), two hydroxylated oxidation products and a diketone. Other minor products formed were identified as 4‐methylacetophenone, two α‐chloro ketones and N‐methylated iso‐mephedrone. Copyright © 2012 John Wiley & Sons, Ltd.     

Isotope labeled ‘HEA/HEE’ moiety in the synthesis of labeled HIV‐protease inhibitors—Part II

[²H₅]‐Amprenavir and [²H ₅]‐saquinavir have been prepared from a common labeled precursor (1S, 2S)‐(1‐oxiranyl‐2‐[²H₅]phenylethyl)‐carbamic acid tert‐butyl ester, 1 . Both of these compounds are in the ‘HEA’ class of HIV protease inhibitors. [²H₅]‐Indinavir, a representative of the ‘HEE’ group of protease inhibitors, has also been synthesized. In the case of indinavir, 1S‐(2,2‐dimethyl‐8, 8a‐dihydro‐3aH‐indeno‐[1,2‐d]‐oxazol‐3R‐yl)‐2‐oxiranylmethyl‐3‐[²H₅]phenylpropan‐1‐one, 11 , provided the [phenyl‐²H₅]‐HEE core structure for synthesis of the desired labeled compound. Copyright © 2005 John Wiley & Sons, Ltd.     

Investigating Mammalian Tyrosine Phosphatase Inhibitors as Potential ‘Piggyback’ Leads to Target Trypanosoma brucei Transmission

African trypanosomiasis is a neglected tropical disease affecting humans and animals across 36 sub‐Saharan African countries. We have investigated the potential to exploit a ‘piggyback’ approach to inhibit Trypanosoma brucei transmission by targeting the key developmental regulator of transmission, T. brucei protein tyrosine phosphatase 1. This strategy took advantage of the extensive investment in inhibitors for human protein tyrosine phosphatase 1B, a key target for pharmaceutical companies for the treatment of obesity and diabetes. Structural predictions for human and trypanosome tyrosine phosphatases revealed the overall conservation of important functional motifs, validating the potential for exploiting cross specific compounds. Thereafter, nineteen inhibitors were evaluated; seventeen from a protein tyrosine phosphatase 1B‐targeted inhibitor library and two from literature analysis – oleanolic acid and suramin, the latter of which is a front line drug against African trypanosomiasis. The compounds tested displayed similar inhibitory activities against the human and trypanosome enzymes, mostly behaving as noncompetitive inhibitors. However, their activity against T. brucei in culture was low, necessitating further chemical modification to improve their efficacy and specificity. Nonetheless, the results validate the potential to explore a ‘piggyback’ strategy targeting T. brucei protein tyrosine phosphatase 1 through exploiting the large pharmacological investment in therapies for obesity targeting protein tyrosine phosphatase 1B.     

Indications of ‘atopic bowel’ in patients with self‐reported food hypersensitivity

Aliment Pharmacol Ther 31 , 1112–1122

Summary

Background An association between atopic disease and gastrointestinal complaints has been suggested. Aim To explore the association between atopic disease, gastrointestinal symptoms, and possible gastrointestinal manifestations of atopic disease in patients with self‐reported food hypersensitivity. Methods Symptoms, skin prick tests, serum markers of allergy and intestinal permeability were recorded in 71 adult patients. Eosinophils, tryptase‐ and IgE‐positive cells were counted in duodenal biopsies. Results Sixty‐six (93%) patients had irritable bowel syndrome (IBS) and 43 (61%) had atopic disease, predominantly rhinoconjunctivitis. All 43 were sensitized to inhalant allergens, 29 (41%) to food allergens, but food challenges were negative. Serum total IgE and duodenal IgE‐positive cell counts were significantly correlated (P < 0.0001) and both were significantly higher in atopic than in non‐atopic patients (P < 0.0001 and P = 0.003 respectively). IgE‐positive cells appeared to be ‘armed’ mast cells. Intestinal permeability was significantly elevated in atopic compared with non‐atopic patients (P = 0.02). Gastrointestinal symptoms and numbers of tryptase‐positive mast cells and eosinophils did not differ between groups. Conclusions Patients with self‐reported food hypersensitivity had a high prevalence of IBS and atopic disease. Atopic patients had increased intestinal permeability and density of IgE‐bearing cells compared with non‐atopic patients, but gastrointestinal symptoms did not differ between groups.     

Issues with monitoring the safety of psychoactive products under a legal regulated market for new psychoactive substances (‘legal highs’) in New Zealand

Introduction . New Zealand's Psychoactive Substances Act (2013) established the world's first regulated market for ‘low risk’ psychoactive products (‘legal highs’). Under an interim PSA regime, 47 existing products were permitted to be continued to be sold. Aim. To explore issues with the implementation of regulatory systems to monitor the safety of products on the legal market under the interim Psychoactive Substances Act regime. Methods. Semi‐structured interviews with 30 key stakeholders, including industry, government agency, health and drug service professionals were conducted, transcribed and analysed thematically. Results. In retrospect stakeholders questioned the decision to approve strong synthetic cannabinoid smoking products, noting their health risks because of product formulation, inconsistent manufacturing practices and smoking as the means of administration. Industry actors claimed the decision to approve synthetic cannabinoid smokeable products prevented potentially safer products from gaining market share. The system for withdrawing approved products which were subsequently found to be harmful was criticised for the poor quality of data available, limited engagement with health professionals and the slowness of product withdrawal. Many of the problems with the regime were attributed to the urgency under which the legal market under the interim Psychoactive Substances Act was established and implemented. Conclusions. The selection of ‘safer’ products, implementation of the product monitoring system, and engagement with health professionals may have benefited from more time and resources. An incremental approach to establishing the new market may have made the regulatory management of the new regime more workable. [Rychert M, Wilkins C, Witten K. Issues with monitoring the safety of psychoactive products under a legal regulated market for new psychoactive substances (‘legal highs’) in New Zealand. Drug Alcohol Rev 2017;00:000‐000]     

What products are considered psychoactive under New Zealand's legal market for new psychoactive substances (NPS, ‘legal highs’)? Implications for law enforcement and penalties

The problem of defining what psychoactive products and substances should be covered by legislation aimed at controlling new psychoactive substances (NPS; ‘legal highs’) is central to the current debate on designing new legislative responses to NPS. In New Zealand, implementation of the Psychoactive Substances Act 2013 (PSA) revealed uncertainties about which psychoactive products are covered by the new regime, with important implications for legal penalties. We reviewed five pieces of legislation which can cover substances with psychoactive properties: PSA, Misuse of Drugs Act (MODA), Food Act, Dietary Supplements Regulations and Medicines Act. Our analysis revealed that a number of psychoactive substances which are not MODA‐scheduled may potentially fall under more than one regulatory regime, including kava, Salvia divinorum, nitrous oxide, 25I‐NBOMe, and 1,3‐dimethylbutylamine (DMBA). For example, kava may be classified as a food, a dietary supplement, a herbal remedy, or a psychoactive substance, depending on how it is presented (including advertising and labelling). There are considerable differences in penalties and regulatory requirements between the different legislative regimes and these may result in unnecessary prosecutions or ‘gaming’ of the system. We discuss a number of ways to more clearly categorize products, including a public schedule of psychoactive substances and products, demarcation criteria based on the quantity of the active ingredient, and demarcation based on ‘discernible intoxication’. Routine use of forensic testing is essential to ensure appropriate prosecutions and penalties. Robust safety standards are also required in legislative regimes exempted from psychoactive substances regime to prevent ‘creative compliance’. Copyright © 2016 John Wiley & Sons, Ltd.     

Analyses of second‐generation ‘legal highs’ in the UK: Initial findings

In the UK, mephedrone and other so‐called ‘legal high’ derivatives have recently been classified as Class B, Schedule I under the Misuse of Drugs Act 1971. Since then, alternative products have been advertised on a number of websites. In order to obtain an immediate snapshot of the situation, 24 products were purchased online from 18 UK‐based websites over a period of 6 weeks following the ban in April 2010. Qualitative analyses were carried out by gas chromatography ion trap mass spectrometry using electron‐ and chemical ionization modes, nuclear magnetic resonance spectroscopy, and comparison with reference standards. Overall, the purchased products consisted of single cathinones or cathinone mixtures including mephedrone, butylone, 4‐methyl‐N‐ethylcathinone, flephedrone (4‐fluoromethcathinone) and MDPV (3,4‐methylenedioxypyrovalerone), respectively. Benzocaine, caffeine, lidocaine, and procaine were also detected. The emphasis was placed on ‘Energy 1’ (NRG‐1), a product advertised as a legal replacement for mephedrone‐type derivatives usually claiming to contain naphyrone (naphthylpyrovalerone, O‐2482). It was found that 70% of NRG‐1 and NRG‐2 products appeared to contain a mixture of cathinones banned in April 2010 and rebranded as ‘new’ legal highs, rather than legal chemicals such as naphyrone as claimed by the retailers. Only one out of 13 NRG‐1 samples appeared to show analytical data consistent with naphyrone. These findings also suggest that both consumers and online sellers (unlike manufacturers and wholesalers) are, most likely unknowingly, confronted with the risk of criminalization and potential harm. Copyright © 2010 John Wiley & Sons, Ltd.     

The effect of training and service provision on the self‐assessed competence of community pharmacists

Objective The purpose of this study was to explore self‐assessed competence of community pharmacists who had completed additional clinical pharmacy training at certificate level and were accredited to provide a clinical medication review service to primary care patients (the ‘trained’ group). The self‐assessed competence of these pharmacists was compared with others who had not undertaken the training (the ‘untrained’ group). Method A postal questionnaire was sent to 179 community pharmacists in both groups across four primary care trusts in the east of London. The questionnaire comprised two parts: characteristics of the respondents; and 81 behavioural statements divided into four competency clusters. Key findings The response rate was 50% (n = 90). While pharmacists who possessed a postgraduate qualification were more likely to assess themselves to be more competent in the ‘Delivery of patient care’ competency cluster, there was no difference in self‐assessed competence between ‘trained’ and ‘untrained’ groups. Conclusion Training and experience in providing clinical medication reviews did not seem to influence the self‐assessed competence of community pharmacists: indeed, the ‘trained’ pharmacists seemed to have become more aware of their competence gaps. As the roles of community pharmacists expand, pharmacists need greater targeted support to face new challenges and to deliver the new services in chronic medicines management.     

Synthesis of a new fluorine‐18 glycosylated ‘click’ cyanoquinoline for the imaging of epidermal growth factor receptor

This study reports the radiosynthesis of a new fluorine‐18 glycosylated ‘click’ cyanoquinoline [¹⁸F]5 for positron emission tomography imaging of epidermal growth factor receptor (EGFR). The tracer was obtained in 47.7 ± 7.5% (n = 3) decay‐corrected radiochemical yield from 2‐[¹⁸F]fluoro‐2‐deoxy‐β‐d ‐glucopyranosyl azide, and the overall nondecay‐corrected radiochemical yield from aqueous fluoride was 8.6 ± 2.3% (n = 3). An in vitro preliminary cellular uptake study showed selectivity of the tracer for EGFR‐positive A431 cell lines versus EGFR‐negative MCF‐7 cell lines. [¹⁸F]5 tracer uptake in A431 cells was significantly reduced by addition of the cold isotope analogue compound 5.     

Return of the lysergamides. Part II: Analytical and behavioural characterization of N6‐allyl‐6‐norlysergic acid diethylamide (AL‐LAD) and (2’S,4’S)‐lysergic acid 2,4‐dimethylazetidide (LSZ)

Lysergic acid N ,N ‐diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to varying extents in previous decades. In 2013, N ⁶‐allyl‐6‐norlysergic acid diethylamide (AL‐LAD) and (2’S ,4’S )‐lysergic acid 2,4‐dimethylazetidide (LSZ) appeared on the ‘research chemicals’/new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL‐LAD and LSZ tartrate samples and their semi‐quantitative determination on blotter paper. Included in this study was the use of nuclear magnetic resonance (NMR) spectroscopy, gas chromatography‐mass spectrometry (GC‐MS), low and high mass accuracy electrospray MS(/MS), high performance liquid chromatography diode array detection and GC solid‐state infrared analysis. One feature shared by serotonergic psychedelics, such as LSD, is the ability to mediate behavioural responses via activation of 5‐HT_2A receptors. Both AL‐LAD and LSZ displayed LSD‐like responses in male C57BL/6 J mice when employing the head‐twitch response (HTR) assay. AL‐LAD and LSZ produced nearly identical inverted‐U‐shaped dose‐dependent effects, with the maximal responses occurring at 200 µg/kg. Analysis of the dose responses by nonlinear regression confirmed that LSZ (ED₅₀ = 114.2 nmol/kg) was equipotent to LSD (ED₅₀ = 132.8 nmol/kg) in mice, whereas AL‐LAD was slightly less potent (ED₅₀ = 174.9 nmol/kg). The extent to which a comparison in potency can be translated directly to humans requires further investigation. Chemical and pharmacological data obtained from NPS may assist research communities that are interested in various aspects related to substance use and forensic identification. Copyright © 2016 John Wiley & Sons, Ltd.