Smoking Mull: a grounded theory model on the dynamics of combined tobacco and cannabis use among men

Issue addressed: Australians’ use of cannabis has been increasing. Over a third of Australians (35.4%) have used cannabis at some time in their lives and 10.3% are recent users. Almost two-thirds of cannabis users combine cannabis with tobacco. The aim of this study was to understand the process of mulling – smoking tobacco and cannabis together – using a grounded theory approach. Methods: Twenty-one in-depth semi structured interviews were conducted with men aged 25–34 and living on the North Coast of New South Wales. Interviews explored participants’ smoking practices, histories and cessation attempts. Results: A model describing mulling behaviour and the dynamics of smoking cannabis and tobacco was developed. It provides an explanatory framework that demonstrates the flexibility in smoking practices, including substance substitution – participants changed the type of cannabis they smoked, the amount of tobacco they mixed with it and the devices they used to smoke according to the situations they were in and the effects sought. Conclusion: Understanding these dynamic smoking practices and the importance of situations and effects, as well as the specific role of tobacco in mulling, may allow health workers to design more relevant and appropriate interventions. So what?: Combining tobacco with cannabis is the most common way of smoking cannabis in Australia. However, tobacco cessation programmes rarely address cannabis use. Further research to develop evidence-based approaches for mull use would improve cessation outcomes. Keywords: concomitant use, marijuana, mulling, nicotineNHMR

Integrating research- and relationship-based approaches in Australian health promotion practice

We examine the perspectives of health promotion practitioners on their approaches to determining health promotion practice, in particular on the role of research and relationships in this process. Using Grounded Theory methods, we analysed 58 semi-structured interviews with 54 health promotion practitioners in New South Wales, Australia. Practitioners differentiated between relationship-based and research-based approaches as two sources of knowledge to guide health promotion practice. We identify several tensions in seeking to combine these approaches in practice and describe the strategies that participants adopted to manage these tensions. The strategies included working in an evidence-informed rather than evidence-based way, creating new evidence about relationship-based processes and outcomes, adopting ‘relationship-based’ research and evaluation methods, making research and evaluation useful for communities, building research and evaluation skills and improving collaboration between research & evaluation and program implementation staff. We conclude by highlighting three systemic factors which could further support the integration of researchbased and relationship-based health promotion practices: (1) expanding conceptions of health promotion evidence, (2) developing 'relationship-based' research methods that enable practitioners to measure complex social processes and outcomes and to facilitate community participation and benefit, and (3) developing organisational capacity. KEYWORDS: qualitative research, health promotion practice, community participation, research & evaluationNHMR

Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer

Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.P50 GM067041 - NIGMS NIH HHS; R01 GM099920 - NIGMS NIH HHS; GM-067041 - NIGMS NIH HHS; GM-099920 - NIGMS NIH HH

Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies

Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics