Analysis of pharmaceutical impurities in the methamphetamine crystals seized for drug trafficking in Korea.

Some methamphetamine (MA) crystals contain pharmaceutical impurities. They often come from the co-ingredients of cold drugs used for extracting ephedrine or pseudoephedrine. Though these impurities are not so commonly encountered, they reflect the trends in precursor chemicals and manufacturing sources. As a result of monitoring impurities in the MA crystals seized in Korea during 2006-2011, 10 species of pharmaceutical impurities were identified by gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. They may be co-ingredients of the legal drugs used as a source of ephedrine or pseudoephedrine. In contrast, some of them are presumed to be adulterants added during or after clandestine synthesis. It is interesting that some of these have been identified in the MA crystals seized in other countries in the same year. Species of pharmaceutical impurities in the MA crystals increased particularly in 2010, indicating a change in precursor chemicals and/or manufacturing sources.

Simultaneous analysis of synthetic cannabinoids in the materials seized during drug trafficking using GC-MS.

A rapid and simple gas chromatography-mass spectrometry (GC-MS) method was developed and validated to identify and quantify synthetic cannabinoids in the materials seized during drug trafficking. Accuracy and reproducibility of the method were improved by using deuterated JWH-018 and JWH-073 as internal standards. Validation results of the GC-MS method showed that it was suitable for simultaneous qualitative and quantitative analyses of synthetic cannabinoids, and we analyzed synthetic cannabinoids in seized materials using the validated GC-MS method. As a result of the analysis, ten species of synthetic cannabinoids were identified in dried leaves (n = 40), bulk powders (n = 6), and tablets (n = 14) seized in Korea during 2009-2012, as a single ingredient or as a mixture with other active co-ingredients. JWH-018 and JWH-073 were the most frequently identified compounds in the seized materials. Synthetic cannabinoids in the dried leaves showed broad concentration ranges, which may cause unexpected toxicity to abusers. The bulk powders were considered as raw materials used to prepare legal highs, and they contained single ingredient of JWH-073, JWH-019, or JWH-250 with the purity over 70 %. In contrast, JWH-018 and JWH-073 contents in the tablets were 7.1-13.8 and 3.0-10.2 mg/g, respectively. Relatively low contents in the tablets suggest that the synthetic cannabinoids may have been added to the tablets as supplements to other active co-ingredients.

The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells.

BACKGROUND: Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity. METHODS: Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation. RESULTS: Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment. CONCLUSIONS: Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies. GENERAL SIGNIFICANCE: Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.

Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis.

Both natural and synthetic cannabinoids have been shown to suppress the growth of tumor cells in culture and in animal models by affecting key signaling pathways including angiogenesis, a pivotal step in tumor growth, invasion, and metastasis. In our search for cannabinoid-like anticancer agents devoid of psychoactive side effects, we synthesized and evaluated the anti-angiogenic effects of a novel series of hexahydrocannabinol analogs. Among these, two analogs LYR-7 [(9S)-3,6,6,9-tetramethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol] and LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-yl)ethanone)] were selected based on their anti-angiogenic activity and lack of binding affinity for cannabinoid receptors. Both LYR-7 and LYR-8 inhibited VEGF-induced proliferation, migration, and capillary-like tube formation of HUVECs in a concentration-dependent manner. The inhibitory effect of the compounds on cell proliferation was more selective in endothelial cells than in breast cancer cells (MCF-7 and tamoxifen-resistant MCF-7). We also noted effective inhibition of VEGF-induced new blood vessel formation by the compounds in the in vivo chick chorioallantoic membrane (CAM) assay. Furthermore, both LYR analogs potently inhibited VEGF production and NF-κB transcriptional activity in cancer cells. Additionally, LYR-7 or LYR-8 strongly inhibited breast cancer cell-induced angiogenesis and tumor growth. Together, these results suggest that novel synthetic hexahydrocannabinol analogs, LYR-7 and LYR-8, inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling in endothelial cells and suppressing VEGF production and cancer cell growth.