Pharmacies as potential providers of harm reduction services: A preliminary online survey

Background Recreational drug use is a major cause of disease, injury, physical and mental impairment and death in developed countries such as the United Kingdom and the United States. Alcohol, tobacco, cannabis, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybe mushrooms are recreational drugs with capacity to cause harm. Cannabis, MDMA and psilocybin have reported therapeutic applications. Objectives The primary purpose of this study was to determine which of the three types of vendor (pharmacy, shop and the black market) are perceived to be the most suitable for selling the substances discussed according to a general population sample. Methods A sample of 105 UK nationals was selected for the survey. Participants were presented information regarding reported relative dangers of alcohol, tobacco, cannabis, MDMA and psilocybin and potential therapeutic applications. Participants were then asked to review harm reduction strategies. Results It was found that participants concluded that pharmacists with available NHS support from GPs and mental health workers are the most suitable vendors of cannabis, MDMA and psilocybin as opposed to regulated shops or the black market (p &lt; 0.001). There was a high level of support for selling cannabis in pharmacies both for therapeutic use and for harm reduction purposes with a mean score of 7.0 out of 10. Participants (60) with a university education were found to be more in favour of the substances being sold primarily in pharmacies (alcohol 5.6, tobacco 6.7, cannabis 7.6, MDMA 6.5 and psilocybin 6.5) than participants (45) with no university qualification (alcohol 5.0, tobacco 4.8, cannabis 6.3, MDMA 5.0 and psilocybin 5.1). Conclusions The data suggest that the university-educated participants are supportive of treating recreational drug use as a health issue with GPs, mental health workers and pharmacists taking on roles. </jats:sec

Repurposing old carbon monoxide-releasing molecules towards the anti-angiogenic therapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is defined by the lack of expression of the oestrogen and progesterone receptors and HER-2. Recently, carbon monoxide (CO) was found to behave as an important endogenous signalling molecule and to suppress VEGF receptor-2 (VEGFR-2) and protein kinase B phosphorylation. Given that anti-angiogenic drugs exist as one of the few available targeted therapies against TNBC, the aim of this project was to study the effects of CO-releasing molecules (CORMs) on TNBC cell lines and the associated endothelial cells and characterise their anti-angiogenic properties that can be used for the reduction of cancer-driven angiogenesis. Four commercially available CORMs were screened for their cytotoxicity, their effects on cell metabolism, migration, VEGF expression, tube formation and VEGFR-2 activation. The most important result was the reduction in VEGF levels expressed by CORM-treated TNBC cells, along with the inhibition of phosphorylation of VEGFR2 and downstream proteins. The migration and tube formation ability of endothelial cells was also decreased by CORMs, justifying a potential re-purposing of old CORMs towards the anti-angiogenic therapy of TNBC. The additional favourable low cytotoxicity, reduction in the glycolysis levels and downregulation of haem oxygenase-1 in TNBC cells enhance the potential of CORMs against TNBC. In this study, CORM-2 remained the most effective CORM and we propose that CORM-2 may be pursued further as an additional agent in combination with existing anti-angiogenic therapies for a more successful targeting of malignant angiogenesis in TNBC

The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer

Breast cancer is the second most common cancer worldwide, accounting for 25% of all female cancers. Although the survival rate has increased significantly in the past few decades, patients who develop secondary site metastasis as well as those diagnosed with triple negative breast cancer still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK-VEGFR3 signalling. More recently, C4 is reported to have SASH1 inducing properties. However, C4 exerts its antitumour and antiangiogenic effects at high micromolar concentrations (>100 μm) that would not be compatible with further drug development against invasive breast cancer driven by FAK signalling. In this study, molecular modelling guided structural modifications have been introduced to the chloropyramine C4 scaffold to improve its activity in breast cancer cell lines. Seventeen compounds were designed and synthesized, and their antiproliferative activity was evaluated against three human breast cancer lines (MDA-MB-231, BT474 and T47D). Compound 5c was identified to display an average activity of IC50 = 23.5–31.3 μm, which represents a significant improvement of C4 activity in the same assay model. Molecular modelling and pharmacokinetic studies provided more promising insights into the mechanistic features of this new series

Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors

Series of 4-amino-6-(arylamino)-1,3,5-triazine-2-carbohydrazides (3a-e) and N'-phenyl-4,6-bis(arylamino)-1,3,5-triazine-2-carbohydrazides (6a-e), for ease of readership, we will abbreviate our compound names as “ new triazines”, have been synthesized, based on the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ9 and 4-amino-N'-phenyl-6-(arylamino)-1,3,5-triazine-2-carbohydrazides. Synthesis of the target compounds was readily accomplished in two steps from either bis-aryl/aryl biguanides via reaction of phenylhydrazine or hydrazinehydrate with key 4-amino-6-bis(arylamino)/(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were evaluated for their abilities to inhibit Rad6B ubiquitin conjugation and in vitro anticancer activity against several human cancer cell lines: ovarian (OV90 and A2780), lung (H1299and A549), breast (MCF-7 and MDA-MB231) and colon (HT29) cancer cells by MTS assays. All the 10 new triazines exhibited superior Rad6B inhibitory activities in comparison to selective Rad6 inhibitor TZ9 that was reported previously. Similarly, new triazines also showed better IC50 values in survival assays of various tumor cell lines. Particularly, new triazines 6a-c, exhibited lower IC50 (3.3 to 22M) values compared to TZ

Online survey into the development of a model legal framework for a cannabis market in the United Kingdom

Background Despite rescheduling of cannabis to Schedule 2 and amendments to the law permitting legal availability of cannabis for the treatment of medical conditions, access to cannabis for medical use remains challenging for patients in the United Kingdom (UK). Recreational use is widespread despite laws stating users can be sentenced to prison for up to 5 years for possession. Objective The aim of the study was to develop a model for a legal cannabis market in the UK building upon the results of a preceding study in which a UK population sample determined that pharmacies are the most suitable primary legal vendor of cannabis as opposed to regulated shops or the black market. Methods An online survey was developed using Qualtrics software and advertised via the Multidisciplinary Association for Psychedelic Studies’ Facebook, Twitter and Instagram social media accounts and monthly newsletter. Results Three hundred and ninety seven individuals, a majority having used cannabis at least once, consented to participate in the study. The participants concluded that there is enough evidence for cannabis to be prescribed to treat a range of medical conditions. In addition to pharmacies providing cannabis to patients with a prescription, a majority of participants supported cannabis being sold in pharmacies for harm reduction purposes and allowing access to medicinal cannabis in cases where supporting evidence is insufficient to merit a prescription. Participants supported greater integration between dispensing pharmacies and mental health services. Overall, the participants did not oppose a consultation or screening for potential cannabis users prior to obtaining access from licensed vendors. UK participants were supportive of the concept of a cannabis card, which users can present to licensed vendors such as pharmacies, with specific recommendations (such as strains relevant to a patient’s medical condition) being coded into the card. A majority of participants supported the existence of shisha-type bars for the purchase and onsite consumption of cannabis and determined that such vendors should not be part of a pharmacy chain of stores or regulated by pharmacy regulators. The participants generally preferred that laws regarding public consumption are in line with existing smoking legislation. Participants determined that it should be legally permitted to grow cannabis at home for personal medical and non-medical purposes but not to sell for profit. Conclusion The results are suggestive of a regulatory system that medical and non-medical cannabis users can use which aims to maximise therapeutic applications, minimise harms and respect individual liberty

Protein-protein interactions as targets for small-molecule therapeutics in cancer

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer

Structure-based virtual screening, synthesis and biological evaluation of potential FAK-FAT domain inhibitors for treatment of metastatic cancer

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series