Physicochemical Characteristics of Sunitinib Malate and its Process-Related Impurities

In this article, details of crystal and molecular structures of sunitinib malate (SUM), an anticancer therapeutic, and its key synthetic intermediate are presented. Both these compounds were also characterized spectroscopically and thermally. SUM crystallizes in the monoclinic P2₁ space group with two molecules in the asymmetric part of the unit cell, whereas the intermediate crystallises in the triclinic P-1 space group with four independent molecules in the asymmetric unit. The three-dimensional structure of SUM consists of two different layers of molecules. The first one is built of the malic anions, whereas the other layer consists of more hydrophobic sunitinib molecules. This layer is formed by two types of molecules creating a herring bond-like pattern with pairs of neighboring cations forming the V-shape arrangement of molecules. The V-shaped pairs of molecules form ribbons by fitting into two neighboring V shapes. The characteristic V-shape assemble of the moieties is hold together with three C-H…F weak interactions. Besides, process-related impurities of SUM were identified and their structures confirmed by separate synthesis. These impurities were fully characterized by spectroscopic and crystallographic methods as well as by differential scanning calorimetry and thermogravimetric analysis. The H-, ¹³C-, and ¹⁵N-nuclear magnetic resonance signals were fully assigned structurally and the resulting structures were confirmed by Fourier-transformed infrared spectroscopy. It was the herein elaborated synthesis of impurity-free SUM that allowed for growing of its single crystals suitable for X-ray crystallographic studies. Comparison of the powder X-ray diffraction pattern for SUM with that derived from single-crystal X-ray crystallographic analysis indicated that SUM formed the polymorph I crystal phase, which is also encountered in its pharmaceutical formulation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:706–716, 2013     

Synthesis and Biological Evaluation of Novel 1,2,3‐Triazolonucleotides

A general procedure for the preparation of 1,2,3‐triazole analogs of nucleosides from diethyl 2‐azidoethoxymethyl‐ and 2‐azidoethoxyethylphosphonates was elaborated. The application of microwave irradiation shortened the reaction time to 10 min in comparison to ca. 48 h when 1,3‐dipolar cycloadditions were performed under standard conditions. All compounds were evaluated in vitro for inhibitory activity against a broad variety of DNA and RNA viruses. None of the compounds were antivirally active at subtoxic concentrations. Compound 17k exhibited moderate inhibitory effects on the proliferation of human T‐lymphocyte cells (IC₅₀ = 64 µM for CEM).     

Influence of the Undercut Anchor Head Angle on the Propagation of the Failure Zone of the Rock Medium—Part II

Problems concerning the influence of the geometric parameters of an undercutting anchor on the range of the failure zone of rock medium during the pulling out of the anchor constitute one of the aspects that arouse the interest of authors due to attempts to use undercutting anchors in the process of rock lump separation. This method is considered an alternative to the existing methods of separation, especially in special cases of mining technologies. This article presents the results of numerical investigations into the effect of changes in the head geometry that occur as a result of wear on the conical part of the undercutting anchor and the extent of failure of the rock medium during its pulling out. This is an extension of considerations presented in previous work, where special attention was paid to the influence of potential errors in anchor installation, leading to changes in head geometry and, consequently, to changes in the extent of the failure zone of the rock medium. As a result, significant changes in the volume of the detached rock masses are observed. This study shows that the increasing surface friction of the stripping anchor head leads to a decrease in the angle of the undercutting head. As a result, the extent of the failure zone measured on the free rock surface increases, the value of the angle of the failure cone at the initial stage of the stripping decreases, and the deformation of rock in the plane perpendicular to the anchor axis increases.     

Research into the Disintegration of Abrasive Materials in the Abrasive Water Jet Machining Process

The size and distribution of abrasive particles have a significant influence on the effectiveness of the cutting process by the high-speed abrasive water jet (AWJ). This paper deals with the disintegration intensity of abrasive materials in AWJ cutting during the creation of the abrasive jet. An evaluation of the abrasive materials was performed after forming in the cutting head was carried out and grain distribution was evaluated using the geometric and logarithmic Folk and Ward method. The influence of the abrasive concentration of abrasive materials such as alluvial garnet, recycled garnet, corundum, and olivine on grain distribution was studied. A recovery analysis was also carried out and the recycling coefficient was determined for each abrasive material tested.     

Changes in antioxidant capacity of blood due to mutual action of electromagnetic field (1800 MHz) and opioid drug (tramadol) in animal model of persistent inflammatory state

BackgroundThe biological effects and health implications of electromagnetic field (EMF) associated with cellular mobile telephones and related wireless systems and devices have become a focus of international scientific interest and world-wide public concern. It has also been proved that EMF influences the production of reactive oxygen species (ROS) in different tissues.MethodsExperiments were performed in healthy rats and in rats with persistent inflammatory state induced by Complete Freund's Adjuvant (CFA) injection, which was given 24 h before EMF exposure and drug application. Rats were injected with CFA or the same volume of paraffin oil into the plantar surface of the left hind paw. Animals were exposed to the far-field range of an antenna at 1800 MHz with the additional modulation which was identical to that generated by mobile phone GSM 1800. Rats were given 15 min exposure, or were sham-exposed with no voltage applied to the field generator in control groups. Immediately before EMF exposure, rats were injected intraperitoneally with tramadol in the 20 mg/kg dose or vehicle in the 1 ml/kg volume.ResultsOur study revealed that single EMF exposure in 1800 MHz frequency significantly reduced antioxidant capacity both in healthy animals and those with paw inflammation. A certain synergic mode of action between applied electromagnetic fields and administered tramadol in rats treated with CFA was observed.ConclusionsThe aim of the study was to examine the possible, parallel/combined effects of electromagnetic radiation, artificially induced inflammation and a centrally-acting synthetic opioid analgesic drug, tramadol, (used in the treatment of severe pain) on the antioxidant capacity of blood of rats. The antioxidant capacity of blood of healthy rats was higher than that of rats which received only tramadol and were exposed to electromagnetic fields.     

Identification of Dmt-D-Lys-Phe-Phe-OH as a highly antinociceptive tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20

BackgroundRecently, we presented a novel compound (PK20, Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH) that targets single entity opioid and neurotensin pharmacophores. This endomorphin-2-like opioid peptide was introduced as a highly active analgesic because it elicited a strong dose- and time-dependent antinociceptive response when administered centrally and peripherally. Its pain-relieving activity was observed as rapidly as 5 min after drug injection. Such promising results led us to perform further studies, such as determining the resistance to enzymatic degradation, which resulted in obtaining a very stable opioid pharmacore PK20 metabolite.MethodsThe synthesis of PK20 and its N-terminal tetrapeptide fragment has been accomplished using solid phase peptide chemistry. The biological stability of peptides has been measured in human serum and analyzed by HPLC/MS. Peptides were pharmacologically characterized in in vitro MOP and DOP receptor binding as well as [³⁵S]GTPγS receptor binding assays. Antinociceptive properties of compounds were measured by in vivo assays in C₅₇Bl₆ mice after intravenous or intrathecal applications.ResultsDmt-D-Lys-Phe-Phe-OH (PK20M), an N-terminal tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20, is characterized by a long duration of action, as demonstrated by a preserved, long-lasting analgesic effect even 2 h post-injection (average % MPE = 69.33). In rat brain membranes, PK20M efficiently displaced both the MOP and DOP receptor selective radioprobes [³H]DAMGO and [³H]DIDI (pKi of 9.52 and 7.86, respectively) and potently stimulated [³⁵S]GTPγS binding, proving full agonism at both receptor types. In the [³⁵S]GTPγS assay, which measured the agonist-mediated G protein activation, PK20M together with PK20 and Met-enkephalin were potent stimulators of the regulatory G proteins. The relative affinities of PK20M for the μ and δ receptor subtypes revealed μ-receptor selectivity.ConclusionThe novel MOP receptor selective metabolite has been shown to possess opioid subtype receptor selectivity, high potency, and effective analgesic activities as measured in various bioassays.     

Potential neurotoxic effect of ethylene glycol ethers mixtures

BackgroundEthylene glycol ethers (EGEs) are widely used as mixtures in various industrial processes and in many household products. 2-Methoxyethanol and 2-ethoxyethanol primarily exert gonadotoxic effect, while 2-butoxyethanol and 2-isopropoxyethanol have potent hemolytic activity. EGEs can cross the blood-brain barrier, but their potential neurodegenerative action in vivo has not been investigated, yet. In the present work, we examined potential adverse effects of EGEs on some selected brain structures.MethodsA mixture of two compounds: one with stronger hydrophilic properties (2-methoxyethanol or 2-ethoxyethanol) and the second more lipophilic (2-butoxyethanol or 2-isopropoxyethanol) were administered sc for 4 weeks. Total antioxidant capacity, lipid peroxidation and caspase-3 activity were determined in the frontal cortex and hippocampus.ResultsIt has been found that 4-week administration of a mixture of two EGEs, with various intensity, decreased total antioxidant capacity, enhanced lipid peroxidation and increased caspase-3 activity in the frontal cortex and hippocampus of Wistar rat.ConclusionThe obtained results suggested that EGEs exerted adverse effects on the CNS cells and may contribute in pathogenesis of neurodegenerative disorders.     

Ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel blocker) elevates the threshold for maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effect of ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel (HCN) blocker) on the threshold for maximal electroshock (MEST)-induced tonic seizures in mice.MethodsElectroconvulsionswere produced inmice bymeans of a current (sine-wave, 50Hz,maximum500V, strength from3–10mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint).ResultsIvabradine administered intraperitoneally (ip), 60 min before the MEST test, at doses of 5 and 10 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (p < 0.05 and p < 0.001, respectively). Linear regression analysis of ivabradine doses and their corresponding threshold increases allowed determination of the threshold increasing doses by 20 and 50% (TID₂₀ and TID₅₀ values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID₂₀ and TID₅₀ values for ivabradine were 8.70 and 18.29 mg/kg, respectively.ConclusionsBased on this preclinical study, one can ascertain that ivabradine dose-dependently increased the threshold for MEST-induced seizures, suggesting the antiseizure activity of the compound in this seizure model in mice.