Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson’s disease (PD), a neurodegenerative disorder. Therefore, in the ...present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.
Oxidative stress is a major factor implicated in the degeneration of cholinergic neurons in Alzheimer's disease. Presently, cholinesterase inhibitors are the mainstay of therapy for Alzheimer's ...disease. However, the potential of cholinesterase inhibitors as antioxidants, an important aspect for neuroprotection, has not been properly investigated. Therefore, the present study was designed to investigate the influence of antidementia drugs, tacrine and donepezil, on biochemical markers of oxidative stress, glutathione (GSH) and malondialdehyde (MDA), and acetylcholinesterase activity in the brain in a streptozotocin-induced experimental model of dementia in mice. Intracerebral (i.c.) injection of streptozotocin at a dose of 0.5 mg/kg on 1st and 3rd days caused significant deficits in memory function, as evaluated in a passive avoidance test and Morris Water Maze (spatial memory) test 14 days after the 1st dose. Mice were treated with tacrine and donepezil at a dose of 5 mg/kg orally in separate groups. Both tacrine- and donepezil-treated mice showed a significant improvement of the streptozotocin (i.c.)-induced memory impairment. Streptozotocin (i.c.) administration caused a significant decrease in GSH and increase in MDA as compared to control, indicating a state of oxidative stress in the brain of streptozotocin (i.c.) amnesic mice. Treatment of streptozotocin (i.c.) amnesic mice with tacrine or donepezil did not cause significant changes in GSH and MDA levels in the brain as compared to control. Streptozotocin amnesic mice had raised acetylcholinesterase activity in the brain while there was a significant decrease in brain acetylcholinesterase activity in tacrine- and donepezil-treated streptozotocin (i.c.) mice. Thus, results indicate that tacrine and donepezil, beside inhibition of acetylcholinesterase, may also suppress oxidative stress.
Electrochemical sensors offer promising prospects for real-time pollutant monitoring. In this study, copper oxide-dispersed graphitic carbon nanofibers (CuO-CNFs) grown via chemical vapour deposition ...were employed as a robust platform for detecting a variety of environmental pollutants. This array-based sensor adeptly identifies three different classes of analytes, i. e., antibiotics (chloramphenicol (CP) and tylosin tartrate (TT)), heavy metals (cadmium (Cd) and lead (Pb)), and pesticides (quinalphos (QP) and imidacloprid (IP)). Electron collection is facilitated by a glassy carbon electrode, while various physico-electrochemical methods delve into the properties of CuO-CNFs. The CuO-CNF-modified GCE array rapidly discerns (<15 sec) a broad linear range: 1-20 ppm for CP, 1-13.33 ppm for TT, 0.66-11.66 ppm for Cd, 20-33.33 ppm for Pb, 1.6-11.6 ppm for QP, and 5-25 ppm for IP, boasting quantification limits of 1.0, 1.0, 0.66, 20.0, 1.6, and 5.0 ppm for CP, TT, Cd, Pb, QP, and IP, respectively. Notably, this sensor achieves simultaneous identification of mixed analytes, including CP and TT, Cd and Pb, and QP and IP, within real tap water. Furthermore, the electrochemical sensor exhibits robustness; heightened sensitivity, selectivity, and stability; a swift response; and impressive reproducibility in detecting CP, TT, Cd, Pb, QP, and IP within aqueous samples. Consequently, this array-based electrochemical sensor has emerged as a rapid and simultaneous detection tool for diverse pollutant residues in surface and groundwater samples.
Blood is one of the most assessable matrices for the determination of pesticide residue exposure in humans. Effective sample preparation/cleanup of biological samples is very important in the ...development of a sensitive, reproducible, and robust method. In the present study, a simple, cost-effective, and rapid gas chromatography–tandem mass spectrometry method has been developed and validated for simultaneous analysis of 31 multiclass (organophosphates, organochlorines, and synthetic pyrethroids) pesticide residues in human plasma by means of a mini QuEChERS (quick, easy, cheap, effective, rugged, and safe) method. We have adopted a modified version of the QuEChERS method, which is primarily used for pesticide residue analysis in food commodities. The QuEChERS method was optimized by use of different extraction solvents and different amounts and combinations of salts and sorbents (primary–secondary amines and C
18
) for the dispersive solid-phase extraction step. The results show that a combination of ethyl acetate with 2% acetic acid, magnesium sulfate (0.4 g), and solid-phase extraction for sample cleanup with primary–secondary amines (50 mg) per 1-mL volume of plasma is the most suitable for generating acceptable results with high recoveries for all multiclass pesticides from human plasma. The mean recovery ranged from 74% to 109% for all the analytes. The limit of quantification and limit of detection of the method ranged from 0.12 to 13.53 ng mL
-1
and from 0.04 to 4.10 ng mL
-1
respectively. The intraday precision and the interday precision of the method were 6% or less and 11% or less respectively. This method would be useful for the analysis of a wide range of pesticides of interest in a small volume of clinical and/or forensic samples to support biomonitoring and toxicological applications.
Graphical Abstract
Pesticide residues analysis in human plasma using mini QuEChERS method
•Formononetin and Biochanin A were found to be inhibitors of human and rat CYP1A2.•Formononetin is a competitive inhibitor of human CYP1A2 activity.•Biochanin A is a mixed-type inhibitor of rat ...CYP1A2 activity.•Minimal inhibitory effect of Formononetin and Biochanin A on other CYP isoforms.•Predicted in vivo interaction with CYP1A2 is significant at intestinal level.
Formononetin (FMN) and Biochanin A (BCA) are the principal isoflavones present in commercially available extracts of red clover that are widely been consumed for various health benefits. We investigated the in vitro effects of FMN and BCA on catalytic activity of human/rat cytochrome P450 enzymes to assess the drug interaction potential of red clover. IC50 and Ki values of FMN and BCA for CYPs were determined in human/rat liver microsomes. FMN and BCA showed concentration-dependent inhibition of CYP1A2 activity with IC50 values of 13.42 and 24.98μM in human liver microsomes and 38.57 and 11.86μM in rat liver microsomes, respectively. The mode of inhibition of human CYP1A2 by FMN was found to be competitive with apparent Ki value of 10.13±1.96μM. FMN also inhibited human CYP2D6. BCA exerted moderately inhibitory effects on human CYP2C9. The predicted in vivo inhibition for CYP1A2 was insignificant (R value <1.1) at hepatic level while at intestinal level, it was significant (R value >11). The inhibitory effects on other CYPs were found to be minimal. Red clover may be considered safe to be consumed along with co-prescribed medications; however, precaution must be taken while co-administering it with CYP1A2 substrates.
Isoformononetin (methoxy isoflavone) is a potent osteogenic isoflavone abundantly present in Butea monosperma, Pisum sativum, Mung bean, Machaerium villosum, Medicago sativa, and Glycine max. In the ...current study, an LC–ESI-MS/MS method for the simultaneous evaluation of isoformononetin (IFN), daidzein (DZN) and equol (EQL) was developed and validated in rat plasma using biochanin A as an internal standard. IFN, DZN, and EQL separation was achieved by using acetonitrile and acetic acid (0.1%) in the ratio of 90:10 (% v/v) as mobile phase under isocratic conditions at a flow rate of 0.6 mL/min on Atlantis C18 (4.6 × 250 mm, 5.0 μm) column. The achieved method was linear within the concentration range of 0.5–500 ng/mL. The method was effectively applied to investigate the permeability, protein binding estimation and pharmacokinetics studies of IFN in rats. The PAMPA permeability of IFN was found to be high at pH 4.0 and 7.0. The protein binding was found to be about 91% of IFN. The oral bioavailability of IFN was found to be poor (21.6%). IFN was found to have a moderate clearance (2.9 L/h/kg) and a large apparent volume of distribution (12.1 L/kg). The plasma half-life (t1/2) and maximum attainable concentration (Cmax) of IFN at systemic circulation was found to be 1.9 ± 0.6 h and 269.3 ± 0.4 after oral administration.
Display omitted
•A rapid simultaneous LC-MS/MS method of isoformononetin, daidzein and equol in rat plasma was developed.•The method was sensitive with 0.5 ng/mL as lower limit of quantification for all analytes.•Comprehensive preclinical in vitro and in vivo pharmacokinetics and permeability studies were investigated for first time.•Absolute bioavailability of isoformononetin was low (21.6%).
Display omitted
•Ce-CNFs are synthesized using CVD technique.•The average diameter of synthesized Ce-CNFs ranges from 20 nm to 40 nm.•The linear range and LOD of Cu (II) ions are 0.6–1.8 ppb and ...0.3 ppb respectively.•The linear range and LOD of Pb (II) ions are 0.9–2.1 ppb and 0.6 ppb respectively.
Chemical vapor deposition (CVD) grown cerium oxide catalyzed 1-D carbon nanofibers (Ce-CNFs) were synthesized first time via tip growth mechanism for the sensitive, selective and simultaneous determination of heavy metals/ions, i.e., Pb (II) and Cu (II). Acetylene and cerium oxide was used for growing the Ce-CNFs via CVD process as carbon source and catalyst for decomposing the acetylene respectively. Inexpensive polymethyl vinyl ether-alt-maleic anhydride (PMMVEA) was used as a binder rather than expensive Nafion solution. Ce-CNFs modified glassy carbon electrode was used as working electrode in three electrode assembly for simultaneous selective detection of Pb (II) and Cu (II) using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The fabricated Ce-CNF electrode exhibited a linear behavior with Pb (II) and Cu (II), and the limit of detection was found to be 0.6 ppb and 0.3 ppb respectively. The electrode material was efficaciously tested against real water sample (Gomti river, Lucknow, India), for checking its practical applications. The prepared Ce-CNFs modified electrode is relatively nontoxic and low-cost. Consequently, it could be directly employed as a real-time electrochemical sensor for simultaneous determination of Pb (II) and Cu (II) ions.
The inhibitory activities of eight cytochrome P450 (CYP) isoenzymes for representative or suspected inhibitors of CYPs, including pesticides, were evaluated simultaneously using an in vitro cocktail ...incubation method to demonstrate the importance of systematic evaluation of CYP inhibitory risks in drug interaction (DI). Potent inhibition of CYP2B6 was noticeable for some azoles, including voriconazole. When voriconazole and cyclophosphamide were co-administered in mice, cyclophosphamide-induced alopecia and leukopenia were significantly suppressed by approximately 50% with increased blood concentrations of cyclophosphamide. The formation of an active metabolite of cyclophosphamide was suppressed effectively by voriconazole in the mouse liver microsomes. Surveys of adverse event reporting databases in Japan (JADER) and the U.S. (FAERS) showed that the proportional reporting ratios of neutropenia, hemorrhagic cystitis, and alopecia for cyclophosphamide, which is principally activated by CYP2B6 in humans, were mostly reduced, or tended to be reduced when azoles, including voriconazole, were prescribed in combination. It is highly likely that DIs between cyclophosphamide and azoles occur in the clinical setting. This study also suggests that more proper consideration of CYP2B6-mediated DIs is warranted. The combination of the in vitro cocktail method and a survey of adverse event reporting databases was a useful method to comprehensively detect pharmacokinetic DIs.
A simple, sensitive and rapid method for the analysis of lumefantrine in rat plasma using liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) was developed. Detection was performed ...by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The method included a chromatographic run of 5
min using a C
18 analytical column and the calibration curve was linear over the concentration range of 2–500
ng/mL with a correlation coefficient (
r) of 0.996 or better. The intra- and inter-day assay precision ranged from 1.5 to 7.5% and 5.5 to 7.7%, respectively, and intra- and inter-day assay accuracy was between 91.3–109.7% and 97.0–104.7%, respectively. The method was successfully applied for the pharmacokinetic study in rats.
PDF
