Pharmacokinetics of Orally Applied Cannabinoids and Medical Marijuana Extracts in Mouse Nervous Tissue and Plasma: Relevance for Pain Treatment.

Cannabis sativa plants contain a multitude of bioactive substances, which show broad variability between different plant strains. Of the more than a hundred naturally occurring phytocannabinoids, Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been the most extensively studied, but whether and how the lesser investigated compounds in plant extracts affect bioavailability or biological effects of Δ9-THC or CBD is not known. We therefore performed a first pilot study to assess THC concentrations in plasma, spinal cord and brain after oral administration of THC compared to medical marijuana extracts rich in THC or depleted of THC. Δ9-THC levels were higher in mice receiving the THC-rich extract. Surprisingly, only orally applied CBD but not THC alleviated mechanical hypersensitivity in the mouse spared nerve injury model, favoring CBD as an analgesic compound for which fewer unwanted psychoactive effects are to be expected.

Systemic inflammatory markers in patients with polyneuropathies.

Introduction: In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods: To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results: While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion: In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.

Food Interactions Observed in a Pharmacokinetic Investigation Comparing Two Marketed Cold Preparations (BNO1016 and ELOM-080) after Administration to Beagle Dogs - A Pilot Study.

Sinupret extract (BNO 1016) and Gelomyrtol forte (ELOM-080) represent the two top-selling cold remedies in Germany nowadays. Whereas BNO 1016 is a typical immediate release coated tablet, ELOM-080 is an enteric-coated soft gelatin capsule. The latter formulation, however, is at risk of pharmacokinetic interactions affecting absorption, especially in cases of concomitant food intake. In the present pilot study, we investigated the risk of a possible food effect in three male beagle dogs. Single doses of BNO 1016 and ELOM-80 were administered under fasting and fed conditions. Blood was sampled up to 30 h post-administration and plasma concentrations of the characteristic ingredients of BNO 1016 as well as ELOM-080 analytes were determined. Pharmacokinetic parameters focusing on the rate and extent of absorption were derived. BNO 1016 analytes demonstrated a similar course in both the fasted and fed states. ELOM-080 analytes also showed a similar picture in the fasted state. However, lag times (time from administration to first quantifiable time point in plasma) of up to 2 h post-administration with corresponding time to reach maximum concentration (obtained directly from the measured concentration) values of 3 to 4 h were observed, reflecting a longer gastric residence time. In the fed state, ELOM-080 showed significant pharmacokinetic characteristics, suggesting a clear food effect. A major observation was a double peak phenomenon that could be observed in two of three dogs. Furthermore, lag times of some analytes, up to 3 - 4 h, and corresponding time to reach maximum concentration values, up to 6 - 8 h, occurred. In contrast to BNO 1016, these findings suggest that, as with other enteric-coated formulations, there may also be a significant risk for food effects with ELOM-080 in humans.

The LIM-homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes.

LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies, but their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. Microarray analysis using a tetracycline-inducible LMX1B expression system in HeLa cells revealed that a subset of NF-kappaB target genes, including IL-6 and IL-8, are upregulated in LMX1B-expressing cells. Inhibition of NF-kappaB activity by short interfering RNA-mediated knock-down of p65 impairs, while activation of NF-kappaB activity by TNF-alpha synergizes induction of NF-kappaB target genes by LMX1B. Chromatin immunoprecipitation demonstrated that LMX1B binds to the proximal promoter of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappaB site, and that LMX1B recruitment correlates with increased NF-kappaB DNA association. IL-6 promoter-reporter assays showed that the kappaB site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of NF-kappaB target genes is affected in the kidney of Lmx1b(-/-) knock-out mice, thus supporting the biological relevance of our findings. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappaB target genes in cooperation with nuclear p50/p65 NF-kappaB.