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Background: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting. Objectives: In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary according to dosing time and whether sex and feeding status interfere with the chronopharmacokinetics. Method: A single dosage of 5 mg/kg everolimus was administered orally to C57BL/6J male and female mice, in fed or fasted states at ZT1‐rest and ZT13‐activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24 h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined. Results: Females had a greater ileum AUC0–24h than males when fed (P = 0.043). Everolimus AUC0–24h in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (P = 0.001). Plasma Cmax, AUC0–24h, and AUCtotal were not statistically significant between the groups (P = 0.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (P = 0.029). Conclusion: Our findings imply that the pharmacokinetics of everolimus in mice may differ according to dosing time, sex, and feeding. Greater tissue distribution of everolimus at ZT1 may be associated with the worst tolerated time of everolimus. Our research suggests that oral chronomodulated everolimus therapy may be more effective and safer for cancer patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the human central nervous system. It is one of the most common neurological disorders around the world and there is still no complete cure for MS. Purification of a terpenoid from Capparis ovata was carried out and its structure was elucidated as stigmast-5,22-dien-3β-ol, myristate (3β,22E-stigmasteryl myristate; SDM) by NMR and mass spectral analyses. No information regarding its any health effect is available in the literature. In the present study, we have described its effects on inflammatory factors such as the expression levels of cytokines, chemokines and adhesion molecules as well as apoptosis/infiltration and myelination in SH-SY5Y cells. The expression levels of proinflammatory or inflammatory cytokines and chemokines such as NF-κB1, CCL5, CXCL9, CXCL10 and HIF1A along with T-cell activating cytokines such as IL-6 and TGFB1 were significantly downregulated with SDM treatment. Moreover, the expression levels of the main myelin proteins such as MBP, MAG and PLP that are essential for healthy myelin architecture were significantly up-regulated. The results presented in this study strongly suggest that the SDM offers a unique possibility to be used with autoimmune diseases, including MS due to its activity on the manipulation of cytokines and the promotion of myelin formation.

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma C max and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5′DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, C max and AUC0-6h values of 5′DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5′DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects. [ABSTRACT FROM AUTHOR]

In this study, the biotransformation of carvone and camphor by Aspergillus flavus and the products were investigated. The biotransformation reaction of carvone by A. flavus resulted in the production of neodihydrocarveol, dihydrocarvone, 2-cyclohexene-1-one,2-methyl-5-(1-methylethenyl), limonene-1,2-diol, trans-p-mentha-1(7),8-dien-2-ol, p-menth-8(10)-ene-2,9-diol, and the biotransformation reaction of camphor resulted in the production of 2 -campholenic acid, 2-cyclohexene-1-one,2-hydroxy-4,4,6,6-tetramethyl, α-campholene aldehyde. The naturally produced essential oils by biotransformation of carvone and camphor were observed to be cytotoxic to breast cancer cells while no significant inhibition was seen in the healthy cell line. Additionally, biotransformation products had the highest inhibition (74%) against aflatoxin B1. The bioactivities of biotransformation products are promising, and they can be further investigated for their therapeutic potential as active agents. [ABSTRACT FROM AUTHOR]

Nowadays, it is vital to have new, complete, and rapid methods to screen and follow pharmacotoxicological and forensic cases. In this context, an important role is undoubtedly played by liquid chromatography-tandem mass spectrometry (LC-MS/MS) thanks to its advanced features. This instrument configuration can offer comprehensive and complete analysis and is a very potent analytical tool in the hands of analysts for the correct identification and quantification of analytes. The present review paper discusses the applications of LC-MS/MS in pharmacotoxicological cases because it is impossible to ignore the importance of this powerful instrument for the rapid development of pharmacological and forensic advanced research in recent years. On one hand, pharmacology is fundamental for drug monitoring and helping people to find the so-called "personal therapy" or "personalized therapy". On the other hand, toxicological and forensic LC-MS/MS represents the most critical instrument configuration applied to the screening and research of drugs and illicit drugs, giving critical support to law enforcement. Often the two areas are stackable, and for this reason, many methods include analytes attributable to both fields of application. In this manuscript, drugs and illicit drugs were divided in separate sections, with particular attention paid in the first section to therapeutic drug monitoring (TDM) and clinical approaches with a focus on central nervous system (CNS). The second section is focused on the methods developed in recent years for the determination of illicit drugs, often in combination with CNS drugs. All references considered herein cover the last 3 years, except for some specific and peculiar applications for which some more dated but still recent articles have been considered. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) represent a class of organic compounds. Fish oil has been identified as one of the most important contributors to the level of persistent organic pollutants in foods. In fact, fish oils could contain elevated levels of lipophilic pollutants, such as PAHs due to the low metabolization capability of fish. The determination of PAHs in fish oils is complicated due to the fat matrix, which adversely affects both the extraction efficiency and analytical data quality. Target compounds were successfully extracted from nutritional supplements using fabric phase sorptive extraction (FPSE). For elution of the PAHs, the prepared sol-gel phenyl/polydimethylsiloxane (PDMS) coated fabric phase sorptive extraction membranes were back-extracted with acetonitrile and then eluted sample was analyzed by high-performance liquid chromatography (HPLC) with fluorescence detection. The PAHs were eluted on a C18 125 × 4 mm, 5 μm column, the oven temperature was 30 °C, and gradient elution was achieved with acetonitrile and water. The compounds were measured at wavelengths of 270 and 390 nm for pyrene and chrysene and 290 and 430 nm for benzo(a)pyrene. The method was validated in terms of linearity (2.5 to 75 ng/mL for pyrene and chrysene; 2.5 to 100 ng/mL for benzo(a)pyrene), precision and trueness (both intra- and inter-day), and recovery (from 63.2% to 102.3%). The obtained results by applying an innovative FPSE sampling/sample clean-up procedure which has recently shown its advantages in several applications for analysis of biological, environmental, cosmetic, and food matrices are presented in this work for the first time. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the chemical profile of Thymus nummularius by LC–MS/MS and GC/MS. Additionally, the methanol extract, essential oil and some individual main compounds of Thymus nummularius were tested for antioxidant, anticholinesterase and antimicrobial activities. Besides, HPLC–FLD was used to determine total aflatoxin in the plant material. Among the twenty-seven compounds studied by LC–MS/MS, rosmarinic acid (131,898.9 ± 6463.0 μg/g dry-extract) was found to be the most abundant compound in the methanol extract. On the other hand, thymol (60.38%) and terpinyl-acetate (10.49%) were found to be the major compounds of the essential oil. Both the essential oil and the methanol extract of T. nummularius exhibited strong antioxidant activity in the four tested methods. Furthermore, the essential oil showed high inhibitory activity against acetyl-,butyryl-cholinesterase enzymes and very strong antimicrobial activity against all tested microorganisms. Besides, T. nummularius can be used both as rosmarinic acid source and as food supplement due to its non-aflatoxin content and high antioxidant, anticholinesterase and antimicrobial activities. [ABSTRACT FROM AUTHOR]

Context: Capparis L. (Capparaceae) is grown worldwide. Caper has been used in traditional medicine to treat various diseases including rheumatism, kidney, liver, stomach, as well as headache and toothache., Objective: To isolate and elucidate of the secondary metabolites of the C. ovata extracts which are responsible for their anti-inflammatory activities., Materials and Methods: Buds, fruits, flowers, leaves and stems of C. ovata Desf. was dried, cut to pieces, then ground separately. From their dichloromethane/hexane (1:1) extracts, eight compounds were isolated and their structures were elucidated by NMR, mass spectroscopic techniques. The effects of compounds on the expression of inflammatory cytokines in SH-SY5Y cell lines were examined by qRT-PCR ranging from 4 to 96 µM. Cell viability was expressed as a percentage of the control, untreated cells., Results: This is a first report on isolation of triterpenoids and steroids from C. ovata with anti-inflammatory activity. One new triterpenoid ester olean-12-en-3β,28-diol, 3β-pentacosanoate ( 1 ) and two new natural steroids 5α,6α-epoxycholestan-3β-ol ( 5 ) and 5β,6β-epoxycholestan-3β-ol ( 6 ) were elucidated besides known compounds; oleanolic acid ( 2 ), ursolic acid ( 3 ), β-sitosterol ( 4 ), stigmast-5,22-dien-3β-myristate ( 7 ) and bismethyl-octylphthalate ( 8 ). mRNA expression levels as EC 10 of all the tested seven genes were decreased, particularly CXCL9 (19.36-fold), CXCL10 (8.14-fold), and TNF (18.69) by the treatment of 26 µM of compound 1 on SH-SY5Y cells., Discussion and Conclusions: Triterpenoids and steroids isolated from C. ovata were found to be moderate-strong anti-inflammatory compounds. Particularly, compounds 1 and 3 were found to be promising therapeutic agents in the treatment of inflammatory and autoimmune diseases.