1,721,074 research outputs found
Photodegradation of Drugs of Abuse in Hair
No full textHair analysis is a valuable tool in clinical and forensic toxicology to demonstrate drug exposure when cases of chronic intoxication, use, abuse, or single dose consumption need to be diagnosed in the context of facilitated crimes, withdrawal controls, doping controls, or workplace drug testing, with a large window from weeks to months/years for drug detection. However, scalp hair is exposed to sunlight and/or artificial light for many hours per day; hence, the action of light on hair could alter the content of drugs/illicit drugs and/or metabolites and the xenobiotics can gradually disappear from the hair shaft or be transformed into other compounds having a different structure from the parent molecule. Thus, light exposure should be considered as a potential confounder in studies investigating xenobiotics in hair giving rise to reduced drug concentrations or even false negative results. On the other hand, the formation of new photodegradation products could lead to the identification of new markers of abuse useful in forensic evaluations. Although the importance of the potentially detrimental effect of light on the exogenous molecules present in the hair shaft is being recognized, very few studies are actually present in the literature about the photodecomposition of illicit drugs in this valuable biological specimen
The neuroleptic drug Fluphenazine induces a significant UVA-mediated cytotoxic effect on three human cancer cell lines through apoptosis
No full textThe cytotoxic activity of fluphenazine (FPZ) in combination with UVA light was evaluated on three human tumor cell lines, HeLa, MSTO-211H and A431. The photobiological effect was determined following irradiation treatment in the presence of/or after the removal of incubated FPZ. Under both conditions, FPZ proved to be very effective in killing tumor cells, with GI50 values in the micromolar range. However, when FPZ was present during irradiation, the photocytotoxicity was at least two times higher than that after its removal suggesting the contribution of the drug both outside and inside the cells. The uptake of FPZ was very fast and, after only 15 minutes of incubation, the compound was accumulated inside lysosomes, as evidenced through fluorescence microscopy. FPZ distribution covered also the nucleus and the cytoplasm without significant plasma membrane association. After irradiation, the membrane of lysosomes in which FPZ was accumulated lost its integrity suggesting that the released lysosomal enzymes played an important role in cell death, and mitochondria were damaged as well, following apoptosis. Indeed, cytofluorimetric studies demonstrated that apoptosis was the main mechanism of cell death. Finally, an extremely high production of ROS was found, indicating a significant photodynamic mechanism involved in the photocytotoxic effect of FPZ. Taken together, our data show that FPZ following UVA irradiation behaves as an effective photoantiproliferative compound inducing apoptosis on various human tumor cells
4,6,4’-Trimethylthioangelicin, a new furocoumarin derivative with potential photochemotherapeutic proprieties.
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PBL (PSORALENS + BLUE LIGHT): BLUE LIGHT ACTIVATES 8-MOP AND TMA TRIGGERING PROSTATE (DU145) AND VESICAL (T24) TUMOR CELL APOPTOSIS AND DEATH
No full textBACKGROUND. Psoralens and angelicins (furocoumarins) are natural and synthetic compounds with high antiproliferative potency under UVA irradiation mainly used for the treatment of skin diseases (PUVA therapy) or immunological disorders in extracorporeal photopheresis (ECP). To improve their activity against psoriasis or vitiligo and avoid severe side effects mainly related to the formation of interstrand crosslinks (XLs) with DNA pyrimidine bases, a variety of derivatives, hopefully monofunctional, have been synthesized. Although angelicins, due to their angular geometry, do not generally form XLs, some of them, i.e. (TMA), can crosslink folded DNA upon UVA. Furthermore, furocoumarins produce ROS that impair cellular functions through lipid peroxidation, oxidation of guanine and strand breaks in nucleic acids, oxidation of proteins and inactivation of enzymes.
To photoactivate 8- MOP and 4,6,4'-trimetylangelicin (TMA) towards human prostate (DU145 PCa) and bladder (T24) cancer cell lines, a new approach based on less toxic and more penetrating visible radiation (BL, 420 nm) is proposed.
RESULTS. TMA and 8-MOP showed high antiproliferative activity towards both cancer cell lines, through induction of apoptosis. Besides ROS generation (less efficient under BL than UVA), the proapoptotic effect seemed related to the activation of p38 and inhibition of p44/42 phosphorylation. Moreover, no phosphorylation of the histone H2AX, nuclear β -catenin and GSK3β occurred. Moreover, Cyclin D1, c-Myc and CD44v6 expression were reduced through inhibition of the Wnt pathway. Overall, DU145 cells appeared more sensitive to PBL than T24, showing a specificity of the test compounds towards different tumor cell lines. The strong photocytotoxicity of TMA and 8-MOP can be related to the kind and number of DNA lesions. Under BL, no mutagenic crosslinks, no photocleavage nor photooxidative lesions were detected on isolated DNA by TMA phototreatment, but only MAs can form. However, generation of XLs still remained for 8-MOP under BL but in a lower amount than under UVA.
CONCLUSIONS. Overall, our results indicate that 8-MOP, and particularly TMA, can be efficiently activated by BL and may be considered good candidates for targeted PBL of prostate and bladder cancers and possibly for other solid tumors
Novel method for fast trabectedin quantification using hydrophilic interaction liquid chromatography and tandem mass spectrometry for human pharmacokinetic studies
No full textFew time-consuming bioanalytical methods are currently available for trabectedin quantification in clinical investigations. Here we present a novel, fast and sensitive method for trabectedin determination in human plasma based on hydrophilic interaction liquid chromatography and tandem mass spectrometry (HILIC-MS/MS). Plasma samples are treated with acetonitrile–0.1 % formic acid and the solvent extract is directly injected into an Acquity BEH Amide column (2.1 × 100 mm, 1.7 μm) operating in HILIC mode at 0.2 mL/min with 80:20 acetonitrile–0.1 % formic acid in water. The analyte is separated by an organic solvent gradient and quantified by an Agilent Ultivo triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode. The quantitative MRM transitions were m/z 762→234 and m/z 765→234 for trabectedin and its d3-labeled derivative, respectively. The lower limit of quantification (LLOQ) was 0.01 ng/mL and the assay was linear up to 2.5 ng/mL. The intra- and inter-day relative error ranged from 1.19 % to 8.52 %, while the relative standard deviation was less than 12.35 %. The method was used to determine the pharmacokinetic profiles of trabectedin in 26 patients with soft tissue sarcoma, showing that this new HILIC-MS/MS method is suitable for use in clinical research
PBL (Psoralens + Blue light): how blue light activates furocoumarin derivatives triggering tumor cell apoptosis
No full textBACKGROUND. Furocoumarins are natural and synthetic compounds with high chemotherapeutic potency under UVA irradiation. To improve their activity and avoid severe side effects likely mainly related to the formation of interstrand crosslinks (XLs) with DNA pyrimidine bases, a variety of derivatives, hopefully monofunctionals, have been synthesized. Although angelicins, due to their angular geometry, do not generally form XLs, some of them, i.e. (TMA), can crosslink folded DNA upon UVA. The UVA photobiological effects of furocoumarins are mainly related to their capacity to photoreact with DNA. Furthermore, furocoumarins produce ROS that impair cellular functions through lipid peroxidation, oxidation of guanine and strand breaks in nucleic acids, oxidation of proteins and inactivation of enzymes.
To photoactivate 8- MOP and 4,6,4'-trimetylangelicin (TMA) towards human prostate (DU145 PCa) and bladder (T24) cancer cell lines, a new approach based on less toxic and more penetrating visible radiation (BL, 420 nm) is presented.
RESULTS. TMA and 8-MOP show high antiproliferative activity towards cancer cells, through induction of apoptosis. Besides ROS generation (less efficient under BL than UVA), the proapoptotic effect seems related to the activation of p38 and inhibition of p44/42 phosphorylation. Interestingly, the decrease of β nuclear-catenin is coupled with dropping of CD44-positive cells. The strong photocytotoxicity of TMA and 8-MOP can be related to the kind and number of DNA lesions. Under BL, no mutagenic crosslinks, no photocleavage nor photooxidative lesions are detected on isolated DNA by TMA treatment, but only MAs form. However, formation of XLs still remains for 8-MOP under BL but in a lower amount than UVA.
CONCLUSIONS. Overall, our results indicate that 8-MOP, and particularly TMA, can be efficiently activated by BL and may be considered good compounds for targeted phototherapy of prostate and bladder cancers and possibly for other solid tumors
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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