Cannabinoids in the treatment of epilepsy: current status and future prospects

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures

Quantum Homodyne Tomography as an Informationally Complete Positive Operator Valued Measure

We define a positive operator valued measure $E$ on $[0,2\pi]\times R$ describing the measurement of randomly sampled quadratures in quantum homodyne tomography, and we study its probabilistic properties. Moreover, we give a mathematical analysis of the relation between the description of a state in terms of $E$ and the description provided by its Wigner transform.Comment: 9 page

Vibrational spectrum of solid picene (C_22H_14)

Recently, Mitsuhashi et al., have observed superconductivity with transition temperature up to 18 K in potassium doped picene (C22H14), a polycyclic aromatic hydrocarbon compound [Nature 464 (2010) 76]. Theoretical analysis indicate the importance of electron-phonon coupling in the superconducting mechanisms of these systems, with different emphasis on inter- and intra-molecular vibrations, depending on the approximations used. Here we present a combined experimental and ab-initio study of the Raman and infrared spectrum of undoped solid picene, which allows us to unanbiguously assign the vibrational modes. This combined study enables the identification of the modes which couple strongly to electrons and hence can play an important role in the superconducting properties of the doped samples

Quantum tomography, phase space observables, and generalized Markov kernels

We construct a generalized Markov kernel which transforms the observable associated with the homodyne tomography into a covariant phase space observable with a regular kernel state. Illustrative examples are given in the cases of a 'Schrodinger cat' kernel state and the Cahill-Glauber s-parametrized distributions. Also we consider an example of a kernel state when the generalized Markov kernel cannot be constructed.Comment: 20 pages, 3 figure

Surface activated chemical ionization - Electrospray mass spectrometry in the analysis of urinary thiodiglycolic acid

RATIONALE Thiodiglycolic acid (TDGA) is a urinary metabolite of the oxazaphosphorine class of chemotherapeutics, in particular of ifosfamide. Ifosfamide metabolism generates chloroacetaldehyde (CAA), a toxic compound associated with neurotoxicity, nephrotoxicity, urotoxicity and cardiotoxicity. CAA, in turn, interacts with cellular thiol groups leading to GSH depletion, cell death and generation of thiodiglycolic acid (TDGA), as a final product. TDGA is mainly excreted in the urine. The ability to accurately measure TDGA in urine, therefore, will be a useful way of monitoring the ifosfamide exposure during chemotherapy. METHODS TDGA in urine samples was measured with liquid chromatograpy coupled to mass spectrometry (LC-MS) by means of a novel Surface Activated Chemical Ionization - Electrospray (SACI-ESI) or a classical ESI ion source alone. RESULTS The SACI - ESI and ESI alone based methods for analysis of urinary TDGA were optimized and compared. A strong reduction in matrix effect together with enhanced quantification performances was obtained with the SACI \u2013 ESI when compared with the ESI. In particular, an increase in quantification precision (from 85 to 95%) and accuracy (from 59 to 90%) were observed, which allowed for optimal detection of TDGA. CONCLUSIONS The LC-SACI-ESI-MS approach provides a very sensitive and quantitative method for the analysis of TDGA. Thanks to sensitivity enhancement and matrix effect reduction, the SACI \u2013 ESI enables the use of a relatively low cost ion-trap mass spectrometer in the analysis of this toxicity biomarker in urine. Due to these characteristics, this approach would constitutes an invaluable tool in the clinical laboratory, for measuring TDGA and other toxicity related biomarkers of chemotherapy with proper sensitivity and accuracy

Mathematical modelling of the spread of contamination during fires in forests exposed to radioactive contamination

The paper suggested in the context of the general mathematical model of forest fires [1] gives a new mathematical setting and method of numerical solution of a problem of a radioactive spread above the forest region. Numerical solution of problems of radioactive smoke spread during crown fire in exemplified heat energy release in the forest fire front was found. Heat energy release in the forest fire front was found to cause further radioactive particles spread by the action of wind. In the absence of wind, radioactive smoke particles deposit again on the underlying surface after a time. As a wind velocity increases, these particles are transferred in the ground layer over distances proportional to a wind velocity

The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel