Quantification and Brain Targeting of Eugenol-Loaded Surface Modified Nanoparticles Through Intranasal Route in the Treatment of Cerebral Ischemia

Drug Research ◽  
2018 ◽  
Vol 68 (10) ◽  
pp. 584-595 ◽  
Author(s):  
Niyaz Ahmad ◽  
Rizwan Ahmad ◽  
Md Alam ◽  
Farhan Ahmad
Keyword(s):  
Cerebral Ischemia ◽  
Rat Brain ◽  
Dynamic Range ◽  
Internal Standard ◽  
Drug Uptake ◽  
Brain Targeting ◽  
Pharmacokinetic Studies ◽  
Drug Bioavailability ◽  
Elution Time

Abstract Objective To enhance brain bioavailability for intranasally administered Eugenol-encapsulated-chitosan-coated-PCL-Nanoparticles (CS-EUG-PCL-NPs). Methods Chitosan-coated-PCL-Nanoparticles (CS-PCL-NPs) were developed through double emulsification-solvent evaporation technique and further characterized for particle size, zeta potential, size distribution, encapsulation efficiency as well as in vitro drug release. UPLC-PDA method was developed to evaluate brain-drug uptake for optimized CS-EUG-PCL-NPs and to determine it’s pharmacokinetic in rat’s brain as well as plasma. Results Mean particles size (224.5±5.31), polydispersity index (PDI) i. e. (0.216±0.020) and entrapment efficiency (68.13±5.03) was determined for developed NPs. UPLC-PDA-eλ study showed a significantly high mucoadhesive potential of CS-EUG-PCL-NPs and least for conventional and homogenized nanoformulation; elution time for EUG and internal standard (IS) thymoquinone as 3.50 and 3.61 min were observed respectively. Furthermore, intra and inter-assay (%CV) of 0.25–1.57, %accuracy (97.11-99.00%) as well as a linear dynamic range (100.00 ng/mL–2500.0 ng/mL), was observed. Pharmacokinetic studies in Wistar rat brain and plasma exhibited a high AUC0-24 alongwith an amplified Cmax (p**<0.01) as compared to i. v. treated group. Conclusions Intranasal administration of developed CS-coated-EUG-loaded-PCL-NPs enhanced the drug bioavailability in rat brain and thus preparation of Eugenol-NPs may help treat cerebral ischemia effectively. The toxicity studies performed at the end revealed safe nature of optimized nanoformulation.

Quantification and Evaluation of Glycyrrhizic Acid-loaded Surface Decorated Nanoparticles by UHPLC-MS/MS and used in the Treatment of Cerebral Ischemia

2019 ◽  
Vol 16 (1) ◽  
pp. 24-39 ◽  
Author(s):  
Niyaz Ahmad ◽  
Rizwan Ahmad ◽  
Md Aftab Alam ◽  
Farhan Jalees Ahmad ◽  
Rehan Abdur Rub
Keyword(s):  
Cerebral Ischemia ◽  
Rat Brain ◽  
Glycyrrhizic Acid ◽  
Dynamic Range ◽  
Internal Standard ◽  
Water Soluble ◽  
Drug Uptake ◽  
Pharmacokinetic Studies ◽  
Triple Quadrupole ◽  
Drug Bioavailability

Background: Glycyrrhizic Acid (GRA), a potent antioxidant triterpene saponin glycoside and neuroprotective properties exhibits an important role in the treatment of neurological disorders i.e. cerebral ischemia. GRA is water soluble, therefore it’s have low bioavailability in the brain. Objective: To enhance brain bioavailability for intranasally administered Glycyrrhizic Acidencapsulated- chitosan-coated-PCL-Nanoparticles (CS-GRA-PCL-NPs). Methods: Chitosan-coated-PCL-Nanoparticles (CS-PCL-NPs) were developed through double emulsification- solvent evaporation technique and further characterized for particle size, zeta potential, size distribution, encapsulation efficiency as well as in vitro drug release. UPLC triple quadrupole Qtrap MS/MS method was developed to evaluate brain-drug uptake for optimized CS-GRA-PCL-NPs and to determine its pharmacokinetic in rat’s brain as well as plasma. Results: Mean particles size (231.47±7.82), polydispersity index (PDI) i.e. (0.216±0.030) and entrapment efficiency (65.69±5.68) was determined for developed NPs. UPLC triple quadrupole Qtrap MS/MS method study showed a significantly high mucoadhesive potential of CS-GRA-PCL-NPs and least for conventional and homogenized nanoformulation; elution time for GRA and internal standard (IS) Hydrocortisone as 0.37 and 1.94 min at m/z 821.49/113.41 and 363.45/121.40 were observed, respectively. Furthermore, intra and inter-assay (%CV) of 0.49-5.48, %accuracy (90.00-99.09%) as well as a linear dynamic range (10.00 ng/mL -2000.0 ng/mL), was observed. Pharmacokinetic studies in Wistar rat brain exhibited a high AUC0-24 alongwith an amplified Cmax (p** < 0.01) as compared to i.v. treated group. Conclusion: Intranasal administration of developed CS-coated-GRA-loaded-PCL-NPs enhanced the drug bioavailability in rat brain along with successfully UPLC-MS/MS method and thus preparation of GRA-NPs may help treat cerebral ischemia effectively. The toxicity studies performed at the end revealed safe nature of optimized nanoformulation.

scholarly journals Quantification of Antimalarial Bisthiazolium Compounds and Their Neutral Bioprecursors in Plasma by Liquid Chromatography-Electrospray Mass Spectrometry

2005 ◽  
Vol 51 (3) ◽  
pp. 593-602 ◽  
Author(s):  
Olivier Nicolas ◽  
Christine Farenc ◽  
Michèle Calas ◽  
Henri J Vial ◽  
Françoise Bressolle
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Solid Phase ◽  
Internal Standard ◽  
Pharmacokinetic Studies ◽  
Ionization Mass ◽  
Limit Of Quantification ◽  
Lipophilic Prodrug

Abstract Background: A new class of antimalarial drugs targeting membrane biogenesis during intraerythrocytic Plasmodium falciparum development has been identified. The bisthiazolium salts T3 and T4 have superior in vitro and in vivo parasite-killing properties and need to be monitored. Methods: We used a liquid chromatography–electrospray ionization mass spectrometry method (positive mode) to quantify two bisthiazolium compounds (T3 and T4) and a related prodrug (TE4c) in human and rat plasma. Verapamil was used as internal standard. Verapamil and the TE4c compound were characterized by protonated molecules at m/z 455.7 and m/z 725.7, respectively. T3 and T4 were detected through two ions [M2+/2] at m/z 227.7 and m/z 241.8 and by their adducts with trifluoroacetic acid [M+TFA]+ at m/z 568 and m/z 596, respectively. The sample clean-up procedure involved solid-phase extraction. HPLC separation was performed on a reversed-phase column, using a water–acetonitrile gradient, with both solvents containing TFA. Stability under various conditions was also investigated. Results: The peak-area ratios (drugs/internal standard) were linked to concentrations (6.4–1282 μg/L for T3; 6.5–1309.8 μg/L for T4; 20–2000 μg/L for TE4c) according to a quadratic equation. The accuracy ranged from 85% to 113.1%, and the imprecision from 2.2% to 15%. The mean extraction recoveries were 87%, 98%, and 80% for T3, T4, and TE4c, respectively. The lower limit of quantification was 6.4 μg/L for the two bisthiazolium compounds, whereas it was 20 μg/L for TE4c, the related lipophilic prodrug. Conclusion: This highly specific and sensitive method is suitable for analyzing samples collected during preclinical pharmacokinetic studies in rats and to determine the percentage binding of T3 and T4 to human plasma proteins.

scholarly journals ANALYSIS OF LYNESTRENOL IN HUMAN PLASMA IN VITRO BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY UV-VIS: EUROPEAN MEDICINES AGENCY GUIDELINE

2020 ◽  
pp. 80-84
Author(s):  
NURFITRIYANA NURFITRIYANA ◽  
HARMITA HARMITA ◽  
ISKANDARSYAH ISKANDARSYAH
Keyword(s):  
Blood Plasma ◽  
Human Plasma ◽  
High Performance ◽  
Dynamic Range ◽  
Internal Standard ◽  
Hplc Method ◽  
European Medicines Agency ◽  
Rp Hplc ◽  
In Blood Plasma

Objective: Development and validation of reverse phase high performance liquid chromatographic (RP-HPLC) method with UV-Vis detector for in vitro determination of lynestrenol with levonorgestrel as an internal standard in human plasma. Methods: The RP-HPLC method was developed using a C18 Sunfire© waters column with a mobile phase of acetonitrile containing 0.1% formic acid in water (60:40), respectively, at a flow rate of 1.0 ml/min and was detected at a wavelength of 204 nm. Lynestrenol and levonorgestrel were extracted from human plasma using pentane with protein precipitation method. Results: The RP-HPLC method was able to selectively quantify lynestrenol in blood plasma on 40 ng/ml. The assay exhibited a linear dynamic range 40-1000 ng/ml for lynestrenol with retention time 4.0 second, and the coefficient correlation (r) was 0.9994. Accuracy (% diff) of this method was-10.81% to 8.72% with precision (CV) being 3.84% to 8.12%, and complete recovery was established to be 98.27% to 106.49%. The method was sensitive, selective, and has simple sample preparation extraction lynestrenol in plasma with pentane was successfully developed. Conclusion: The method can be used to analyze lynestrenol in blood plasma, with a simple pretreatment procedure using pentane.

scholarly journals Preparation and characterization of simvastatin/DMβCD complex and its pharmacokinetics in rats

2018 ◽  
Vol 68 (2) ◽  
pp. 145-157
Author(s):  
Fugen Gu ◽  
Jia Ning ◽  
Huimin Fan ◽  
Chunzhi Wu ◽  
Yi Wang
Keyword(s):  
Dissolution Rate ◽  
Free Drug ◽  
Pharmacokinetic Parameters ◽  
Complexing Agent ◽  
Phase Solubility ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Drug Bioavailability ◽  
Scanning Calorimetry

Abstract Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several β-cyclodextrin (βCD) derivatives such as HPβCD, SBEβCD and DMβCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each βCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above βCD derivatives DMβCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMβCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMβCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax) and the time to reach it (tmax) were 21.86 μg mL−1 and 1.4 h for the drug complex, 8.25 μg mL−1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01) between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %.

scholarly journals Robust and Sensitive High-Performance Liquid Chromatographic-UV Detection Technique for the Determination of Tigecycline in Rabbit Plasma

2011 ◽  
Vol 94 (3) ◽  
pp. 847-856 ◽  
Author(s):  
Kostas M Zorpas ◽  
Georgia N Valsami ◽  
Evangelos V Vryonis ◽  
Athanasios T Skoutelis ◽  
Helen A Archontaki
Keyword(s):  
High Performance ◽  
Internal Standard ◽  
Pharmacokinetic Profile ◽  
High Performance Liquid Chromatographic ◽  
Hplc Method ◽  
Pharmacokinetic Studies ◽  
Rabbit Plasma ◽  
Elution Time ◽  
Liquid Chromatographic

Abstract An isocratic HPLC method with detection at 248 nm was developed and fully validated for the determination of tigecycline in rabbit plasma. Minocycline was used as an internal standard. A Hypersil BDS RP-C18 column (250 × 4.6 mm, 5 μm particle size) was used with the mobile phase phosphate buffer (pH 7.10, 0.070 M)–acetonitrile (76 + 24, v/v) at a flow rate of 1.0 mL/min. The elution time of tigecycline and minocycline was approximately 8.1 and 9.9 min, respectively. Calibration curves of tigecycline were linear in the concentration range of 0.021–3.15 μg/mL in plasma. The LOD and LOQ in plasma were estimated as 7 and 21 ng/mL, respectively. The intraday and interday precision values of the method were in the range of 5.0–7.1 and 5.6–9.1%, while the corresponding accuracy values were in the ranges of 92.8–111.1 and 97.6–102.3%, respectively. At the LOQ, the intraday precision was 18.7%, while intraday and interday accuracy values were 97.3 and 98.0%, respectively. Robustness of the proposed method was studied using a Plackett-Burman experimental design. A pharmacokinetic profile is presented for confirmation of the applicability of the method to pharmacokinetic studies.

Brain Targeting of anti-HIV Nucleosides: Ether Prodrugs of 3′-Azido-2′,3′-Dideoxyuridine (AZdU) and 3′-Azido-3′-Deoxythymidine (AZT)

1993 ◽  
Vol 4 (5) ◽  
pp. 263-269 ◽  
Author(s):  
K. J. Doshi ◽  
Q. Islam ◽  
J. M. Gallo ◽  
F. D. Boudinot ◽  
L. Hsieh ◽  
...  
Keyword(s):  
Liver Homogenate ◽  
Parent Drug ◽  
Brain Targeting ◽  
Mouse Serum ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Drug Concentrations ◽  
Anti Hiv

In an effort to increase the brain delivery of anti-HIV nucleosides, 5-0-benzyl and glucose derivatives of 3′-azido-2′,3′-dideoxyuridine (AZdU or CS-87) and 3′-azido-3′-deoxythymidine (AZT) were synthesized. In vitro stability and pharmacokinetic studies in mice were conducted with benzyl AZdU (BzlAZdU), benzyl AZT (BzlAZT), and glucose AZdU (GAZdU) prodrugs. In vitro studies indicated that the prodrugs were stable in phosphate buffer (pH 7.4), human serum and mouse serum. In mouse brain homogenate, the degradation half-lives for BzlAZdU, BzlAZT, and GAZdU were 1.66, 2.06, and 0.98 h, respectively, and in liver homogenate the degradation half-lives were 0.49, 0.29, and 1.97h, respectively. Following intravenous administration of BzlAZdU, BzlAZT, or GAZdU to mice, prodrug and parent drug concentrations were measured in serum and brain by HPLC, and pharmacokinetic parameters determined. The brain:serum area under the concentration time-curve (AUC) ratio, a parameter indicative of prodrug uptake into brain, was 0.55 for BzlAZdU and 0.56 for BzlAZT, compared to 0.05–0.08 when the parent drugs AZdU and AZT were administered intravenously. GAZdU had poor brain penetration, achieving brain concentrations of only 5% of the serum concentrations. Parent drug concentrations in brain were, for the most part, not detected after administration of any of the prodrugs. Consistent with in vitro data, it is apparent that the prodrugs were converted to metabolites other than the parent drug species.

scholarly journals GC-MS Method for Quantification and Pharmacokinetic Study of Four Volatile Compounds in Rat Plasma after Oral Administration of Commiphora myrrh (Nees) Engl. Resin and In Vitro Cytotoxic Evaluation

Separations ◽  
2021 ◽  
Vol 8 (12) ◽  
pp. 239
Author(s):  
Ali S. Alqahtani ◽  
Rashed N. Herqash ◽  
Faleh Alqahtani ◽  
Syed Rizwan Ahamad ◽  
Fahd A. Nasr ◽  
...  
Keyword(s):  
Oral Administration ◽  
Volatile Compounds ◽  
Antiproliferative Activity ◽  
Extraction Procedure ◽  
Internal Standard ◽  
Rat Plasma ◽  
Lovo Cell ◽  
Pharmacokinetic Studies ◽  
Ic50 Values

A rapid, simple, and sensitive gas chromatography–tandem mass spectrometry (GC–MS) method was established and validated for simultaneous determination of four volatile compounds, namely curzerene, methoxyfuranodiene, β-elemene, and α-pinene in rat plasma samples after oral administration of the resin extract of Commiphora myrrh using limonene as an internal standard (IS). Liquid-liquid extraction using hexane and ethyl acetate (1:1) mixture as an extracting agent was used for the samples extraction procedure. The GC–MS system was operated under selective ion monitoring (SIM) mode using Perkin Elmer Elite 5MS column (30 m × 0.25 mm × 0.25 µm film thickness). Specificity, linearity, precision, accuracy, extraction recovery, and stability were used to validate the developed method. The assay showed good linearity (r2 ≥ 0.998), and the lowest limits of quantification (LLOQ) were 3.97–21.38 ng/mL for the four analytes. This assay was successfully applied to pharmacokinetic studies of the four volatile compounds in rat plasma. The antiproliferative activity of these volatile compounds was evaluated against lung carcinoma (A549) and colon (LoVo) cell lines, were each compound caused variable inhibition on cells proliferation and methoxyfuranodiene exerted the strong antiproliferative activity against both cell line according to IC50 values.

Mitomycin C skin toxicity studies in mice: reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide.

1986 ◽  
Vol 4 (9) ◽  
pp. 1399-1404 ◽  
Author(s):  
R T Dorr ◽  
M J Soble ◽  
J D Liddil ◽  
J H Keller
Keyword(s):  
Dimethyl Sulfoxide ◽  
Mitomycin C ◽  
Area Under The Curve ◽  
Mouse Skin ◽  
Skin Toxicity ◽  
Drug Uptake ◽  
Skin Tissue ◽  
Pharmacokinetic Studies ◽  
Skin Ulcers

A series of toxicologic and pharmacokinetic studies were performed in BALB/c mice administered intradermal (ID) mitomycin C (MMC) at doses of .015 to 0.25 mg. Dose-dependent skin ulcers were produced at clinically relevant MMC dose levels of .05 and .075 mg (3.6 to 10.7 mg/m2). These doses produced peak ulcers of 0.15 to 0.22 cm2, respectively, one to five days after injection. The integrated ulcer area X time values (area under the curve [AUC] ulceration) were 0.89 and 3.11 cm2 X d. A large number of local pharmacologic adjuvants were found to be ineffective at reducing MMC ulceration after proximal ID injection. These included diphenhydramine, catalase, heparin, hyaluronidase, hydrocortisone, cysteine, N-acetylcysteine, lidocaine, vitamin E, and superoxide dismutase. Also, neither topical heating nor cooling of skin reduced MMC ulcerations. In contrast, a single topical application of a 100% dimethyl sulfoxide (DMSO) solution completely prevented 0.025 mg MMC-induced skin ulceration and significantly reduced .075 mg MMC ulceration (P less than .05 by multiple range tests). Topical DMSO also altered the disposition of ID MMC in mouse skin but not in plasma. Unexpectedly, the DMSO applications slowed MMC elimination from the skin. DMSO significantly increased the AUC for MMC in skin from 0.89 to 2.25 ng/h/mL of tissue (P less than .05). DMSO did not alter the degree of protein binding in skin tissue nor the in vitro chemical stability of MMC in skin tissue homogenates. These results show that experimental MMC-induced skin ulcers in mice can be ameliorated with an immediate application of topical DMSO. This effect is not due to enhanced systemic drug uptake, but may be due to reduced reactivity of MMC with target cellular nucleophiles.

scholarly journals Two-Dimensional Gas Chromatography/Electron-Impact Mass Spectrometry with Cryofocusing for Simultaneous Quantification of MDMA, MDA, HMMA, HMA, and MDEA in Human Plasma

2008 ◽  
Vol 54 (2) ◽  
pp. 379-387 ◽  
Author(s):  
Erin A Kolbrich ◽  
Ross H Lowe ◽  
Marilyn A Huestis
Keyword(s):  
Human Plasma ◽  
Electron Impact ◽  
Dynamic Range ◽  
Solid Phase ◽  
Internal Standard ◽  
Drug Analysis ◽  
Pharmacokinetic Studies ◽  
Chromatographic Technique ◽  
Two Dimensional ◽  
Selected Ion Monitoring

Abstract Background: 3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is a popular recreational drug. Analysis of MDMA and metabolites in human plasma, particularly in pharmacokinetic studies, requires low limits of quantification. Two-dimensional GC/MS with cryofocusing is a chromatographic technique recognized for its increased selectivity and resolution. Methods: This method simultaneously quantifies 3,4-methylenedioxyethylamphetamine (MDEA), MDMA, and its metabolites, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) in human plasma. With hydrochloric acid, we hydrolyzed 1 mL plasma, fortified with internal standard. Analytes were subjected to solid-phase extraction, derivatized with heptafluorobutyric acid anhydride, and quantified using cryofocused 2-dimensional GC/MS operated in electron-impact selected ion-monitoring mode. Results: Limits of quantification were 1.0 μg/L for MDA and 2.5 μg/L for MDEA, MDMA, HMMA, and HMA. Calibration curves were linear to 100 μg/L for MDA and HMA and to 400 μg/L for MDEA, MDMA, and HMMA, with r2 &gt; 0.997. At 3 concentrations spanning the linear dynamic range of the assay, mean overall extraction efficiencies from plasma were ≥85% for all compounds of interest. Recoveries were 85.6% to 107.2% of target, and intra- and interassay imprecision (CV) was &lt;8.5% for all drugs at 3 concentrations within the range of the assay. None of the 66 exogenous compounds tested interfered with analyte quantification. Conclusions: This GC/MS assay provides low limits of quantification for simultaneous determination of MDEA, MDMA, and metabolites MDA, HMMA, and HMA in human plasma. The 2D chromatographic system should be suitable for application to other analytes and to other complex matrices.

Sign in / Sign up

Export Citation Format

Share Document