Characterization of the Penetration of the Blood–Brain Barrier by High-Performance Liquid Chromatography (HPLC) Using a Stationary Phase with an Immobilized Artificial Membrane

The biological activity of drugs on organisms is associated with the pharmacokinetic properties, such as the ability to penetrate through environments of varying polarity such as cellular organelles. In this area, particular attention is turned to the physicochemical properties that determine the potential of drugs to pass across the blood–brain barrier and thus to act on the central nervous system. In this study, special effort has been devoted to the simulation of passive diffusion of seven drugs (propranolol, ibuprofen, atenolol, promazine, chlorpromazine, imipramine, and desipramine) through the blood–brain barrier by high-performance liquid chromatography (HPLC) using a column with an immobilized artificial membrane. Gradient reverse elution was used to develop a linear correlation model for the capacity factors k_IAM and the in vivo logarithmic values of brain-to-blood drug concentration ratios (log BB) with R of 0.9851. Eleven additional pharmaceuticals were determined by the same method to predict their potential to penetrate the blood–brain barrier. The reported analytical method represents an alternative tool for rapid and noninvasive assessment of the absorption properties of chemicals, especially for the development of novel drugs. The retention of the studied compounds on the immobilized artificial membrane column was also compared with three other C18-based stationary phases. Herein, the results of the HPLC determination of drugs using an immobilized artificial membrane are briefly discussed with respect to a general application of the method for evaluating a broader spectrum of pharmaceutical compounds.     

Glass transition of semi-crystalline PLLA with different morphologies as studied by dynamic mechanical analysis

Poly(l-lactic acid) was crystallized from the glassy state at different temperatures to produce fully transformed semi-crystalline specimens exhibiting different lamellar morphologies. The materials were tested by dynamic mechanical analysis, where a T _g decrease was found with an increasing crystallization temperature. Considering a three-phase model, this tendency was related to the corresponding increase in the thickness of the rigid amorphous phase. It is suggested that this phase could, in some extent, accommodate through local translational/rotational motions the cooperative motions taking place within the mobile amorphous phase. This could be due to the non-compact structure of the cooperatively rearranging regions, which can present a string-like or fractal structure in their edges. The width of the loss factor peak associated to the glass transition increases with increasing crystallization temperature, suggesting an increase in the broadness of the distribution of relaxation times. The drop in the storage modulus across T _g varies systematically with the crystallization temperature in the different materials and could be correlated with the crystalline content. Above T _g, the loss factor exhibits a plateau-like behaviour at significantly high values, which seems to be a rather general behaviour in semi-crystalline systems that could be related to the contribution of pure irreversible flow in the overall viscoelastic behaviour.     

Tangent Euler Top in General Relativity

We define the tangent Euler top in General Relativity through a constrained Lagrangian on the orthonormal frame bundle. The corresponding motions are studied to various degrees of approximation, the lowest of which is shown to yield the Mathisson-Papapetrou equations.     

Coordination of the natural ligand lapachol to iron(II): synthesis,theoretical study and antiproliferative activity

Transition Metal Chemistry - Lapachol is a natural naphthoquinone known for having a variety of biological properties, and in recent years, it has been used in the synthesis of metal complexes with...     

Deformations of calibrated subbundles of Euclidean spaces via twisting by special sections

We extend the ‘bundle constructions’ of calibrated submanifolds, due to Harvey–Lawson in the special Lagrangian case, and to Ionel–Karigiannis–Min-Oo in the cases of exceptional calibrations, by ‘twisting’ the bundles by a special (harmonic, holomorphic, or parallel) section of a complementary bundle. The existence of such deformations shows that the moduli space of calibrated deformations of these ‘calibrated subbundles’ includes deformations which destroy the linear structure of the fibre.     

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.