Comparative Pharmacokinetic Assessment of Innovative Sublingual, Rectal and Vaporizer Cannabis Products Versus Approved Cannabis Products in Healthy Volunteers.

Background: Over the last years, there is a dramatic increase in the use of medical cannabis products for an expanding range of clinical indications. The type of the drug product and its administration route affect substantially the rate and the extent of absorption of cannabinoids and the effects induced by them in the patients. The current challenge for the cannabis pharmaceutical industry is to develop formulations that allow predictable and stable absorption of cannabinoids. This article reports the results of the clinical trial that investigated the pharmacokinetics (PKs) of innovative cannabis products in healthy volunteers. Materials and Methods: This was a single-center study with a single-dose, randomized, crossover, partially blinded controlled design. Each of the 12 healthy volunteers received 8 different products, of the 10 products that were assessed in this trial: novel sublingual (SL) tablet, vaporizer, and rectal products, comparator products (Sativex® and oil-based oromucosal products), and placebo products. Serial blood samples were collected, plasma concentrations of the THC, 11-OH-THC, and CBD were quantified and subjected to noncompartmental PK analysis. Results: Novel medical cannabis products that were investigated in the study induced substantial exposure of the volunteers to the active ingredients, had more rapid absorption, and in some cases also less variable absorption of THC and CBD, in comparison with the approved comparison products. The bioavailability of the novel SL tablet-based and suppositories products was somewhat lower than that of the oromucosal products. The vaporizer provided immediate systemic absorption with highest maximal concentration. The safety profile of the novel cannabis products, namely vaporizer, SL tablets, and suppositories, was not inferior to the Sativex and oil-based oromucosal formulations. Conclusions: The novel cannabis products that were assessed in this study have PK properties that may be advantageous for management of specific medical conditions or in specific subgroups of patients that are prescribed medical cannabis.

Novel design principles enable specific targeting of imaging and therapeutic agents to necrotic domains in breast tumors.

INTRODUCTION: Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis. It is commonly identified by means of invasive histopathology, which often correlates with morbidity and potential tumor cell dissemination, and limits the reconstruction of the whole necrotic domain. In this study we hypothesized that non covalent association to serum albumin (SA) and covalent binding to ligands for tumor-abundant cell receptors should synergistically drive selective accumulation and prolonged retention of imaging and therapeutic agents in breast tumor necrotic domains enabling in vivo identification, imaging and possibly treatment of such tumors. METHODS: Cyclo-Arg-Gly-Asp-D-Phe-Lys (c(RGDfK)) were conjugated to bacteriochlorophyll-derivatives (Bchl-Ds), previously developed as photodynamic agents, fluorescent probes and metal chelators in our lab. The c(RGDfK) component drives ligation to alphaVbeta3 integrin receptors over-expressed by tumor cells and neo-vessels, and the Bchl-D component associates to SA in a non-covalent manner. STL-6014, a c(RGDfK)-Bchl-D representative, was i.v. injected to CD-1, nude female mice bearing necrotic and non-necrotic human MDA-MB-231-RFP breast cancer tumors. The fluorescence signals of the Bchl-Ds and RFP were monitored over days after treatment, by quantitative whole body imaging and excised tumor/tissue samples derived thereof. Complementary experiments included competitive inhibition of STL-6014 uptake by free c(RGDfK), comparative pharmacokinetics of nonconjugated c(RGDfK) Bchl-D (STL-7012) and of two human serum albumin (HSA) conjugates: HSA-STL-7012 and HSA-STL-6014. RESULTS: STL-6014 and STL-7012 formed complexes with HSA (HSA/STL-6014, HSA/STL-7012). STL-6014, HSA-STL-7012 and HSA-STL-6014, selectively accumulated at similar rates, in tumor viable regions over the first 8 h post administration. They then migrated into the necrotic tumor domain and presented tumor half lifetimes (T1/2) in the range of days where T1/2 for HSA-STL-6014 > STL-6014 > HSA-STL-7012. No accumulation of STL-7012 was observed. Pre-injection of c(RGDfK) excess, prevented the uptake of STL-6014 in the small, but not in the large tumors. CONCLUSIONS: Non-covalent association to SA and covalent binding to c(RGDfK), synergistically enable the accumulation and prolonged retention of Bchl-Ds in the necrotic regions of tumors. These findings provide novel guidelines and strategy for imaging and treatment of necrotic tumors.

The effect of resolution-dependent global shape modifications on rigid-body protein-protein docking.

Docking unbound molecules presents a challenge in the case where no prior biological or bioinformatic knowledge exists. This is mainly due to differences between the structures of the molecules when in a complex and in the free state. Presumably, these differences interfere with the ability of protein-protein docking algorithms, which rely on a dominant shape descriptor, to identify the correct solution and rank it higher than false solutions. In this study we verify the notion that small discords in the molecular fit can be eliminated by using appropriately designed low-resolution shape descriptors, thereby improving the docking results. We exploit the inherent gradual resolution dependency of Fourier transforms and formulate a resolution-dependent shape descriptor by truncating selected Fourier transform terms. Thus, different levels of shape modification are attained, affecting the degree of detail in the depiction of the molecular surface. We applied the modified descriptor to a selection of 23 protein-protein systems, using the unbound structures where possible. The docking results obtained with the new geometric descriptor were considerably superior to former results, improving the ranks of nearly correct solutions for 17 systems. Unification of the results of scans in which different resolutions were employed further improved the ranks of nearly correct solutions to less than 100 for 12 of the 23 systems and less than 300 for 20 systems. The new geometric descriptor can be combined with other descriptors, which typify the electrostatic or hydrophobic character of the molecular surface, and with external experimental or bioinformatic data.

Modeling oligomers with Cn or Dn symmetry: application to CAPRI target 10.

The abundance of oligomeric proteins makes them a frequent target for structure prediction. However, homologous proteins sometimes adopt different oligomerization states, rendering the prediction of structures of whole oligomers beyond the scope of comparative modeling. This obstacle can be overcome by combining comparative modeling of the single subunit of an oligomer with docking techniques, designed for predicting subunit-subunit interfaces. We present here algorithms for predicting the structures of homo-oligomers with C(n) or D(n) (n > 2) symmetry. The prediction procedure includes a symmetry-restricted docking step followed by a C(n) or D(n) oligomer-forming step, in which the dimers from the docking step are assembled to oligomers. The procedure is applied to each of the crystallographically independent subunits in 8 C(n) and 3 D(n) oligomers, producing very accurate predictions. It is further applied to a single monomer of the tick-borne encephalitis virus coat protein E (Target 10 of the CAPRI experiment). The predicted trimer ranked 30, obtained via rigid-body geometric-hydrophobic docking followed by C(n) oligomer formation, is very similar to the experimentally observed trimer formed by domain II of this protein. Furthermore, the predicted trimer formed from the separated domain I is also close to the experimental structure.