Enhanced Oral Bioavailability of Paclitaxel in Presence of P-gp Blockers: Smart Extraction Procedure, Antitumor and Side Effects Study in Mice

Abstract Background The resistance of V600E-BRAF to the vemurafenib and the side effects of the identified inhibitors trigger the research for a novel and more potent anti-melanoma agents. In this study, virtual docking screening along with pharmacokinetics ADMET and drug-likeness predictions were combined to evaluate some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors. Results Some of the selected compounds exhibited better binding scores and favorable interaction with the V600E-BRAF enzyme. Out of the screened compounds, two most potent (5 and 9) having good Rerank scores (− 128.011 and − 126.258) emerged as effective and potent V600E-BRAF inhibitors that outperformed the FDA-approved V600E-BRAF inhibitor (vemurafenib, − 118.607). Thus, the molecular docking studies revealed that the studied compounds showed competing for inhibition of V600E-BRAF with vemurafenib at the binding site and possessed better pharmacological parameters based on the drug-likeness rules filters for the oral bioavailability, and ADMET risk parameters. Conclusion The docking analysis, drug-likeness rules filters, and ADMET study identified compounds (5 and 9) as the best hits against V600E-BRAF kinase with enhanced pharmacological properties. This recommends that these compounds may be developed as potent anti-melanoma agents.

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An insight into cochleates, a potential drug delivery system

RSC Advances ◽

10.1039/c5ra08550k ◽

2015 ◽

Vol 5 (99) ◽

pp. 81188-81202 ◽

Cited By ~ 17

Author(s):

Atmaram Pawar ◽

C. Bothiraja ◽

Karimunnisa Shaikh ◽

Ashwin Mali

Keyword(s):

Drug Delivery ◽

Side Effects ◽

Drug Delivery System ◽

Lipid Bilayer ◽

Aqueous Phase ◽

Oral Bioavailability ◽

Spiral Structure ◽

Potential Drug ◽

System P ◽

Insight Into

Cochleates are solid particulates made up of large continuous lipid bilayer sheets rolled up in a spiral structure with little or no internal aqueous phase. Cochleates improve the oral bioavailability and efficacy of the drugs by decreasing side effects.

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Preparation and Characterization of a Novel Swellable and Floating Gastroretentive Drug Delivery System (sfGRDDS) for Enhanced Oral Bioavailability of Nilotinib

Pharmaceutics ◽

10.3390/pharmaceutics12020137 ◽

2020 ◽

Vol 12 (2) ◽

pp. 137 ◽

Cited By ~ 2

Author(s):

Hong-Liang Lin ◽

Ling-Chun Chen ◽

Wen-Ting Cheng ◽

Wei-Jie Cheng ◽

Hsiu-O Ho ◽

...

Keyword(s):

Drug Delivery ◽

Side Effects ◽

Drug Delivery System ◽

Delivery System ◽

Oral Bioavailability ◽

Optimal Dose ◽

Pharmacokinetic Profile ◽

Medical Need ◽

Tablet Hardness

Regarding compliance and minimization of side effects of nilotinib therapy, there is a medical need to have a gastroretentive drug delivery system (GRDDS) to enhance the oral bioavailability that is able to administer an optimal dose in a quaque die (QD) or daily manner. In this study, the influence on a swelling and floating (sf) GRDDS composed of a polymeric excipient (HPMC 90SH 100K, HEC 250HHX, or PEO 7000K) and Kollidon® SR was examined. Results demonstrated that PEO 7000K/Kollidon SR (P/K) at a 7/3 ratio was determined to be a basic GRDDS formulation with optimal swelling and floating abilities. MCC PH102 or HPCsssl,SFP was further added at a 50% content to this basic formulation to increase the tablet hardness and release all of the drug within 24 h. Also, the caplet form and capsule form containing the same formulation demonstrated higher hardness for the former and enhanced floating ability for the latter. A pharmacokinetic study on rabbits with pH values in stomach and intestine similar to human confirmed that the enhanced oral bioavailability ranged from 2.65–8.39-fold with respect to Tasigna, a commercially available form of nilotinib. In conclusion, the multiple of enhancement of the oral bioavailability of nilotinib with sfGRDDS could offer a pharmacokinetic profile with therapeutic effectiveness for the QD administration of a reasonable dose of nilotinib, thereby increasing compliance and minimizing side effects.

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Quetiapine fumarate loaded nanostructure lipid carrier for enhancing oral bioavailability: Design, development and pharmacokinetic assessment

Current Drug Delivery ◽

10.2174/1567201817999200728135119 ◽

2020 ◽

Vol 17 ◽

Author(s):

Shweta Agarwal ◽

S.L HariKumar ◽

Poonam Negi ◽

Navneet Upadhyay ◽

Rajeev Garg

Keyword(s):

Side Effects ◽

Oral Bioavailability ◽

In Vitro Release ◽

Amorphous State ◽

Entrapment Efficiency ◽

Treated Group ◽

Design Development ◽

Lymphatic Absorption ◽

Quetiapine Fumarate

Aim: The study aimed at developing and characterizing nanostructure lipid carriers (NLC) of Quetiapine fumarate (QF) by Design of Experiment (DoE) for enhancement of bioavailability. Background:QF, an anti-psychotic drug, has oral bioavailability of 9% due to hepatic first pass metabolism necessitating use of high doses. Its side effects are dose related and enhancement in bioavailability would result in minimization of side effects. Objective: The objective of the study was enhancement of bioavailability of NLC of QF by preferential lymphatic uptake. Methods: Hot emulsification-ultrasonication was the method of formulation using PrecirolATO5 and Oleic acid as solid and liquid lipid respectively. Poloxamer188 and Phospholipon90G were used as surfactant and stabilizer respectively. Solid:liquid lipid ratio and Phospholipon90G amount were independent variables and percent entrapment efficiency (%EE), particle size (PS) dependent variables during optimization by Central Composite Design. Results: The optimized formulation showed %EE of 77.21%, PS of 140.2nm and surface charge of -19.9mV. Higuchi kinetic model was followed during in-vitro release. TEM revealed spherical, smooth nanoparticles. X-ray diffraction study con-firmed presence of drug in amorphous state in NLC. Pharmacokinetic study in rats showed AUC0-∞ of QF-NLC to be 3.93 times that of QF in suspension suggesting significant enhancement in bioavailability. An increase in AUC0-∞ in cyclo-heximide untreated rats group of QF loaded NLC by 2.43 times ascompared to cycloheximide treated group, confirmed lymphatic absorption of QF-NLC. Conclusion: The results validated DoE as an appropriate tool for developing QF loaded NLC and proved NLC to be a promising delivery system for enhancement of oral bioavailability of QF.

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Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry

Journal of Chromatography B ◽

10.1016/j.jchromb.2003.08.003 ◽

2003 ◽

Vol 796 (1) ◽

pp. 71-86 ◽

Cited By ~ 40

Author(s):

L MALLIS ◽

A SARKAHIAN ◽

H HARRIS ◽

M ZHANG ◽

O MCCONNELL

Keyword(s):

Mass Spectrometry ◽

Tandem Mass Spectrometry ◽

Oral Bioavailability ◽

Extraction Procedure ◽

Tandem Mass ◽

Electrospray Tandem Mass Spectrometry ◽

Column Extraction

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Gastric Ulcers Produced by Cisplatin

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100099337 ◽

1981 ◽

Vol 39 ◽

pp. 582-583

Author(s):

S.K. Aggarwal ◽

J. San Antonio

Keyword(s):

Electron Microscopy ◽

Single Dose ◽

Side Effects ◽

Antitumor Agent ◽

Gastric Ulcers ◽

Enzyme Cytochemistry ◽

Intestinal Toxicity ◽

Ovarian Cancers ◽

Inner Surface

Cisplatin (cis-dichlorodiammineplatinum(II)) a potent antitumor agent is now available for the treatment of testicular and ovarian cancers. It is however, not free from its serious side effects including nephrotoxicity, gastro intestinal toxicity, myelosuppression, and ototoxicity. Here we now report that the drug produces peculiar bloating of the stomach in rats and induces acute ulceration.Wistar-derived rats weighing 200-250 g were administered cisplatin(9 mg/kg) ip as a single dose in 0.15 M NaCl. After 3 days the animals were sacrificed by decapitation. The stomachs were removed, the contents analyzed for pepsin and acidity. The inner surface was examined with a dissecting microscope after a moderate stretching for ulcers. Affected areas were fixed and processed for routine electron microscopy and enzyme cytochemistry.The drug treated animals kept on food and water consistently showed bloating and lesions (Fig. 1) with a frequency of 6-70 ulcers in the rumen section of the stomachs.

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Effects of cisplatin treatment on the rat neurohypophysis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100142256 ◽

1986 ◽

Vol 44 ◽

pp. 122-123

Author(s):

J.M. Fadool ◽

P.J. Boyer ◽

S.K. Aggarwal

Keyword(s):

Side Effects ◽

Urine Output ◽

Morphological Changes ◽

Limiting Factor ◽

Antineoplastic Drugs

Cisplatin (CDDP) is currently one of the most valuable antineoplastic drugs available. However, it has severe toxic side effects of which nephrotoxicity is the major dose limiting factor in its use. It induces morphological changes in the kidney with hampered urine output. The present study is an effort to determine the influence of the drug on the neurohypophysis for any antidiuretic effects on the kidney.

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Severe Drooling and Treatment With Botulinum Toxin

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd21.1.15 ◽

2012 ◽

Vol 21 (1) ◽

pp. 15-21

Author(s):

Merete Bakke ◽

Allan Bardow ◽

Eigild Møller

Keyword(s):

Botulinum Toxin ◽

Side Effects ◽

Health Risk ◽

Flow Rate ◽

Clinical Evidence ◽

Acetylcholine Release ◽

Psychosocial Problems ◽

Rate Reduction ◽

Local Inhibition ◽

Surgical Treatments

Severe drooling is associated with discomfort and psychosocial problems and may constitute a health risk. A variety of different surgical and non-surgical treatments have been used to diminish drooling, some of them with little or uncertain effect and others more effective but irreversible or with side effects. Based on clinical evidence, injection with botulinum toxin (BTX) into the parotid and submandibular glands is a useful treatment option, because it is local, reversible, and with few side effects, although it has to be repeated. The mechanism of BTX is a local inhibition of acetylcholine release, which diminishes receptor-coupled secretion and results in a flow rate reduction of 25–50% for 2–7 months.

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