Small Molecule Drugs That Inhibit Phagocytosis.

In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity. We recently screened a chemical library of 80 compounds containing pyrazole/isoxazole/pyrrole core structures and found four hit molecules for further follow-up, all having the pyrazole core structure. Subsequent evaluation via MTT viability, LDH release, and apoptosis, led to the selection of two lead compounds with negligible toxicity and high efficacy. In an in vitro assay for inhibition of phagocytosis, their IC50 values were 2-4 µM. The rational development of these discoveries from hit to lead molecule stage, viz. independent synthesis/scale up of hit molecules, and in vivo activities in mouse models of autoimmune disease, will result in the selection of a lead compound(s) for further pre-clinical evaluation.

Extractions of Medical Cannabis Cultivars and the Role of Decarboxylation in Optimal Receptor Responses.

Introduction: Phytocannabinoids, characteristic compounds produced by medical cannabis, interact with cannabinoid (CB) receptors (CB1 and CB2) as well as other receptor systems to exhibit their corresponding pharmacological effects. In their natural form, CBs such as Δ9-tetrahydrocannabinolic acid and cannabidiolic acid are inactive at these receptors, while their decarboxylated forms (Δ9-tetrahydrocannabinol and cannabidiol, respectively) are potent ligands at CB receptors. Thus, extraction and processing of medical cannabis for active constituents are important. Purpose and Methods: Patients consuming medical cannabis often have limited alternative treatment options and in recent years, medical cannabis extracts have been popular as a substitute for dried cannabis plants, despite limited studies on these derivatives. We investigated three disparate cannabis cultivars and compared four chemical extraction methods head to head, viz. Soxhlet, ultrasound-assisted supercritical fluid, and microwave-assisted extractions, for their efficiency. We further characterized the chemical compositions of these extracts. Results: Microwave extraction consistently produced completely decarboxylated phytocannabinoid extracts. Factors such as temperature and exposure time play important roles in the decarboxylation of phytocannabinoids, thereby generating pharmacologically active CBs, and these conditions may differ for each cannabis cultivar. Conclusion: Chemical consistency and potency due to active compounds are in turn important in producing consistent and reliable medical cannabis extracts and their derivatives. These processes must be subject to higher levels of scientific rigor as the patient population around the world are seeking the help of such extracts for various clinical conditions, and as medical cannabis industry is receiving acceptance in various countries.