scholarly journals Celecoxib Loaded In-Situ Provesicular Powder and Its In-Vitro Cytotoxic Effect for Cancer Therapy: Fabrication, Characterization, Optimization and Pharmacokinetic Evaluation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1157
Author(s):  
Ali M. Nasr ◽  
Sameh S. Elhady ◽  
Shady A. Swidan ◽  
Noha M. Badawi
Keyword(s):  
Fatty Alcohol ◽  
Desirability Function ◽  
Area Under The Curve ◽  
Free Form ◽  
Pharmacokinetic Parameters ◽  
Anticancer Efficacy ◽  
Cox 2

Introduction: Several recent studies have shown that the role of cyclooxygenase 2 (COX-2) in carcinogenesis has become more evident. It affects angiogenesis, apoptosis, and invasion, and plays a key role in the production of carcinogens. It has also been reported that COX-2 inhibitors such as celecoxib (CLX) might play an effective role in preventing cancer formation and progression. Formulation of CLX into nanovesicles is a promising technique to improve its bioavailability and anticancer efficacy. Aim: The aim of this study is to optimize and evaluate the anticancer efficacy of CLX-loaded in-situ provesicular powder composed of surfactants and fatty alcohol-based novel nanovesicles in-vitro and determine its pharmacokinetic parameters in-vivo. Methods: The novel provesicular powders were prepared by the slurry method and optimized by 32 full factorial design using the desirability function. Results: Small mean particle size was achieved by the formed vesicles with value of 351.7 ± 1.76 nm and high entrapment efficacy of CLX in the formed vesicles of 97.53 ± 0.84%. Solid state characterization of the optimized formulation showed that the powder was free flowing, showed no incompatibilities between drug and excipients and showed smooth texture. The cytotoxic study of the optimized formula on HCT-116, HepG-2, A-549, PC-3 and MCF-7 cell lines showed significant increase in activity of CLX compared to its free form. The pharmacokinetic study on albino rabbits after oral administration showed significant increase in the area under the curve (AUC)0–24 h and significantly higher oral relative bioavailability of the optimized formulation compared to Celebrex® 100 mg market product (p < 0.05). Conclusion: All findings of this study suggest the potential improvement of efficacy and bioavailability of CLX when formulated in the form of in-situ provesicular powder composed of surfactants and fatty alcohol-based novel nanovesicles for its repositioned use as an anticancer agent.

scholarly journals Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing

2001 ◽  
Vol 45 (1) ◽  
pp. 30-37 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Daniel S. Stein
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Dose Range ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Protease Enzyme ◽  
Immunodeficiency Virus

ABSTRACT In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (C max,ss,C min,ss, and C avg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0→∞ decreased linearly with dose and correlated significantly with treatment-associated decreases in α1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 μg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 μg/ml), even after adjustment for protein binding. The median amprenavir C min,sswas also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 μg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C max. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

scholarly journals Preparation, characterization, and in vivo pharmacokinetics of thermosensitive in situ nasal gel of donepezil hydrochloride

2020 ◽  
Vol 70 (3) ◽  
pp. 411-422 ◽  
Author(s):  
Fugen Gu ◽  
Huimin Fan ◽  
Zhixin Cong ◽  
Shuang Li ◽  
Yi Wang ◽  
...  
Keyword(s):  
Ph Value ◽  
Relative Bioavailability ◽  
Nasal Delivery ◽  
Poloxamer 407 ◽  
Nasal Administration ◽  
Pharmacokinetic Parameters ◽  
Donepezil Hydrochloride

AbstractDonepezil hydrochloride thermosensitive in situ gel for nasal delivery was prepared by using Poloxamer 407 and Poloxamer 188 as thermoreversible polymers, hydroxypropyl-β-cyclodextrin and ethylparaben as permeation enhancer and preservative, respectively. The gelation temperature and time, pH value of the gel formulation were found to meet the requirements for nasal administration. The in vitro erosion and in vitro release tests exhibited obvious drug sustained release behavior. Meantime, main pharmacokinetic parameters such as tmax, cmax and AUC in plasma as well as in brain were significantly different between the nasal gel formulation and intragastric drug solution in rats (p < 0.01). The relative bioavailability and drug targeting efficiency of the gel formulation were calculated to be 385.6 and 151.2 %, respectively. Thus, the drug gel formulation might be a potential new delivery system for treatment of Alzheimer’s disease due to its higher bioavailability and better distribution to brain when compared to oral route.

scholarly journals Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

2020 ◽  
Vol 94 (8) ◽  
pp. 2637-2661 ◽  
Author(s):  
E. E. J. Kasteel ◽  
K. Darney ◽  
N. I. Kramer ◽  
J. L. C. M. Dorne ◽  
L. S. Lautz
Keyword(s):  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Extensive Literature ◽  
Interindividual Differences ◽  
Uncertainty Factors ◽  
Chemical Risk Assessment ◽  
Acute And Chronic Exposure

Abstract UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro–in vivo extrapolations in chemical risk assessment are discussed.

In vitro and in vivo polysaccharides assembly: ultrastructural and cytochemical study of growing plant cell wall components.

1978 ◽  
Vol 36 (2) ◽  
pp. 434-435
Author(s):  
D. Reis ◽  
B. Vian ◽  
J. C. Roland
Keyword(s):  
Cell Wall ◽  
Self Assembly ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Three Dimensional ◽  
Cytochemical Study ◽  
Wall Components

Wall morphogenesis in higher plants is a problem still open to controversy. Until now the possibility of a transmembrane control and the involvement of microtubules were mostly envisaged. Self-assembly processes have been observed in the case of walls of Chlamydomonas and bacteria. Spontaneous gelling interactions between xanthan and galactomannan from Ceratonia have been analyzed very recently. The present work provides indications that some processes of spontaneous aggregation could occur in higher plants during the formation and expansion of cell wall.Observations were performed on hypocotyl of mung bean (Phaseolus aureus) for which growth characteristics and wall composition have been previously defined.In situ, the walls of actively growing cells (primary walls) show an ordered three-dimensional organization (fig. 1). The wall is typically polylamellate with multifibrillar layers alternately transverse and longitudinal. Between these layers intermediate strata exist in which the orientation of microfibrils progressively rotates. Thus a progressive change in the morphogenetic activity occurs.

Effect of Depolymerized Holothurian Glycosaminoglycan (DHG) on Tissue Factor Pathway Inhibitor: In Vitro and In Vivo Studies

1997 ◽  
Vol 78 (02) ◽  
pp. 864-870 ◽  
Author(s):  
Hideki Nagase ◽  
Kei-ichi Enjyoji ◽  
Yu-ichi Kamikubo ◽  
Keiko T Kitazato ◽  
Kenji Kitazato ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Factor Xa ◽  
Free Form ◽  
Initial Reaction ◽  
Extrinsic Pathway ◽  
Factor Xa Inhibition ◽  
Tissue Factor Pathway

SummaryDepolymerized holothurian glycosaminoglycan (DHG) is a glycosaminoglycan extracted from the sea cucumber Stichopus japonicusSelenka. In previous studies, we demonstrated that DHG has antithrombotic and anticoagulant activities that are distinguishable from those of heparin and dermatan sulfate. In the present study, we examined the effect of DHG on the tissue factor pathway inhibitor (TFPI), which inhibits the initial reaction of the tissue factor (TF)-mediated coagulation pathway. We first examined the effect of DHG on factor Xa inhibition by TFPI and the inhibition of TF-factor Vila by TFPI-factor Xa in in vitro experiments using human purified proteins. DHG increased the rate of factor Xa inhibition by TFPI, which was abolished either with a synthetic C-terminal peptide or with a synthetic K3 domain peptide of TFPI. In contrast, DHG reduced the rate of TF-factor Vila inhibition by TFPI-factor Xa. Therefore, the effect of DHG on in vitroactivity of TFPI appears to be contradictory. We then examined the effect of DHG on TFPI in cynomolgus monkeys and compared it with that of unfractionated heparin. DHG induced an increase in the circulating level of free-form TFPI in plasma about 20-fold when administered i.v. at 1 mg/kg. The prothrombin time (PT) in monkey plasma after DHG administration was longer than that estimated from the plasma concentrations of DHG. Therefore, free-form TFPI released by DHG seems to play an additive role in the anticoagulant mechanisms of DHG through the extrinsic pathway in vivo. From the results shown in the present work and in previous studies, we conclude that DHG shows anticoagulant activity at various stages of coagulation reactions, i.e., by inhibiting the initial reaction of the extrinsic pathway, by inhibiting the intrinsic Xase, and by inhibiting thrombin.

Evaluation of Structure-Controlled Silk Fibroin Coatings for Orthopedic Infection and In-Situ Osteogenesis: In Vitro and In Vivo

2020 ◽  
Author(s):  
Wenhao Zhou ◽  
Teng Zhang ◽  
Jianglong Yan ◽  
QiYao Li ◽  
Panpan Xiong ◽  
...  
Keyword(s):  
Silk Fibroin ◽  
Orthopedic Infection

scholarly journals Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 904
Author(s):  
Irin Tanaudommongkon ◽  
Asama Tanaudommongkon ◽  
Xiaowei Dong
Keyword(s):  
Sustained Release ◽  
Trough Concentration ◽  
Self Assembly ◽  
Subcutaneous Injection ◽  
Drug Loading ◽  
Entrapment Efficiency ◽  
Long Acting

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

scholarly journals Establishment of MHHi001-A-5, a GCaMP6f and RedStar dual reporter human iPSC line for in vitro and in vivo characterization and in situ tracing of iPSC derivatives

2021 ◽  
Vol 52 ◽  
pp. 102206
Author(s):  
Alexandra Haase ◽  
Tim Kohrn ◽  
Veronika Fricke ◽  
Maria Elena Ricci Signorini ◽  
Merlin Witte ◽  
...  
Keyword(s):  
Ipsc Line ◽  
Dual Reporter ◽  
In Vivo Characterization ◽  
Human Ipsc

scholarly journals Experimental and theoretical explorations of nanocarriers’ multistep delivery performance for rational design and anticancer prediction

2021 ◽  
Vol 7 (6) ◽  
pp. eaba2458
Author(s):  
Weier Bao ◽  
Falin Tian ◽  
Chengliang Lyu ◽  
Bin Liu ◽  
Bin Li ◽  
...  
Keyword(s):  
Physical Properties ◽  
Rational Design ◽  
Theoretical Models ◽  
Cell Uptake ◽  
Anticancer Efficacy ◽  
Delivery Performance ◽  
Simulation Based ◽  
Multistep Process

The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.

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