7‑hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects

Mitragynina speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.</p

Removal of Hepatitis B virus surface HBsAg and core HBcAg antigens using microbial fuel cells producing electricity from human urine

© 2019, The Author(s). Microbial electrochemical technology is emerging as an alternative way of treating waste and converting this directly to electricity. Intensive research on these systems is ongoing but it currently lacks the evaluation of possible environmental transmission of enteric viruses originating from the waste stream. In this study, for the first time we investigated this aspect by assessing the removal efficiency of hepatitis B core and surface antigens in cascades of continuous flow microbial fuel cells. The log-reduction (LR) of surface antigen (HBsAg) reached a maximum value of 1.86 ± 0.20 (98.6% reduction), which was similar to the open circuit control and degraded regardless of the recorded current. Core antigen (HBcAg) was much more resistant to treatment and the maximal LR was equal to 0.229 ± 0.028 (41.0% reduction). The highest LR rate observed for HBsAg was 4.66 ± 0.19 h−1 and for HBcAg 0.10 ± 0.01 h−1. Regression analysis revealed correlation between hydraulic retention time, power and redox potential on inactivation efficiency, also indicating electroactive behaviour of biofilm in open circuit control through the snorkel-effect. The results indicate that microbial electrochemical technologies may be successfully applied to reduce the risk of environmental transmission of hepatitis B virus but also open up the possibility of testing other viruses for wider implementation

Material-Specific Investigations of Correlated Electron Systems

We present the results of numerical studies for selected materials with strongly correlated electrons using a combination of the local-density approximation and dynamical mean-field theory (DMFT). For the solution of the DMFT equations a continuous-time quantum Monte-Carlo algorithm was employed. All simulations were performed on the supercomputer HLRB II at the Leibniz Rechenzentrum in Munich. Specifically we have analyzed the pressure induced metal-insulator transitions in Fe2O3 and NiS2, the charge susceptibility of the fluctuating-valence elemental metal Yb, and the spectral properties of a covalent band-insulator model which includes local electronic correlations.Comment: 14 pages, 7 figures, to appear in "High Performance Computing in Science and Engineering, Garching 2009" (Springer

The Dynamical Cluster Approximation: Non-Local Dynamics of Correlated Electron Systems

We recently introduced the dynamical cluster approximation(DCA), a new technique that includes short-ranged dynamical correlations in addition to the local dynamics of the dynamical mean field approximation while preserving causality. The technique is based on an iterative self-consistency scheme on a finite size periodic cluster. The dynamical mean field approximation (exact result) is obtained by taking the cluster to a single site (the thermodynamic limit). Here, we provide details of our method, explicitly show that it is causal, systematic, $\Phi$-derivable, and that it becomes conserving as the cluster size increases. We demonstrate the DCA by applying it to a Quantum Monte Carlo and Exact Enumeration study of the two-dimensional Falicov-Kimball model. The resulting spectral functions preserve causality, and the spectra and the CDW transition temperature converge quickly and systematically to the thermodynamic limit as the cluster size increases.Comment: 19 pages, 13 postscript figures, revte

Charge-transfer metal-insulator transitions in the spin-one-half Falicov-Kimball model

The spin-one-half Falicov-Kimball model is solved exactly on an infinite-coordination-number Bethe lattice in the thermodynamic limit. This model is a paradigm for a charge-transfer metal-insulator transition where the occupancy of localized and delocalized electronic orbitals rapidly changes at the metal-insulator transition (rather than the character of the electronic states changing from insulating to metallic as in a Mott-Hubbard transition). The exact solution displays both continuous and discontinuous (first-order) transitions.Comment: 22 pages including 4 figures(eps), RevTe

Wannier-function description of the electronic polarization and infrared absorption of high-pressure hydrogen

We have constructed maximally-localized Wannier functions for prototype structures of solid molecular hydrogen under pressure, starting from LDA and tight-binding Bloch wave functions. Each occupied Wannier function can be associated with two paired protons, defining a ``Wannier molecule''. The sum of the dipole moments of these ``molecules'' always gives the correct macroscopic polarization, even under strong compression, when the overlap between nearby Wannier functions becomes significant. We find that at megabar pressures the contributions to the dipoles arising from the overlapping tails of the Wannier functions is very large. The strong vibron infrared absorption experimentally observed in phase III, above ~ 150 GPa, is analyzed in terms of the vibron-induced fluctuations of the Wannier dipoles. We decompose these fluctuations into ``static'' and ``dynamical'' contributions, and find that at such high densities the latter term, which increases much more steeply with pressure, is dominant.Comment: 17 pages, two-column style with 14 postscript figures embedded. Uses REVTEX and epsf macro