scholarly journals Investigating the Potential of Transmucosal Delivery of Febuxostat from Oral Lyophilized Tablets Loaded with a Self-Nanoemulsifying Delivery System

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 534 ◽  
Author(s):  
Yasir A. Al-Amodi ◽  
Khaled M Hosny ◽  
Waleed S. Alharbi ◽  
Martin K. Safo ◽  
Khalid M El-Say
Keyword(s):  
Oral Bioavailability ◽  
Area Under The Curve ◽  
Stability Index ◽  
The United States ◽  
Maximum Plasma ◽  
Large Area ◽  
Healthy Human ◽  
Disintegration Time ◽  
Maximum Stability ◽  
Transmucosal Delivery

Gout is the most familiar inflammatory arthritis condition caused by the elevation of uric acid in the bloodstream. Febuxostat (FBX) is the latest drug approved by the United States Food and Drug Administration (US FDA) for the treatment of gout and hyperuricemia. FBX is characterized by low solubility resulting in poor gastrointestinal bioavailability. This study aimed at improving the oral bioavailability of FBX by its incorporation into self-nanoemulsifying delivery systems (SNEDS) with minimum globule size and maximum stability index. The SNEDS-incorporated FBX was loaded into a carrier substrate with a large surface area and lyophilized with other excipients to produce a fluffy, porous-like structure tablet for the transmucosal delivery of FBX. The solubility of FBX was studied in various oils, surfactants, and cosurfactants. Extreme vertices design was utilized to optimize FBX-SNEDS, and subsequently loaded into lyophilized tablets along with suitable excipients. The percentages of the main tablet excipients were optimized using a Box–Behnken design to develop self-nanoemulsifying lyophilized tablets (SNELTs) with minimum disintegration time and maximum drug release. The pharmacokinetics parameters of the optimized FBX-SNELTs were tested in healthy human volunteers in comparison with the marketed FBX tablets. The results revealed that the optimized FBX-SNELTs increased the maximum plasma concentration (Cmax) and decreased the time to reach Cmax (Tmax) with a large area under the curve (AUC) as a result of the enhanced relative oral bioavailability of 146.4%. The significant enhancement of FBX bioavailability is expected to lead to reduced side effects and frequency of administration during the treatment of gout.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Preeti D. Kulkarni ◽  
Neena D. Damle ◽  
Lal Hingorani ◽  
Vaidhun H. Bhaskar ◽  
Minal R. Ghante ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Bioavailability ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Maximum Plasma ◽  
Boswellic Acid ◽  
Healthy Human ◽  
Boswellia Serrata ◽  
Solid Lipid ◽  
Human Volunteers

Abstract Objectives The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. Methods The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. Results Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. Conclusions The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects

2021 ◽  
Vol 36 (3) ◽  
pp. 215-221
Author(s):  
Preeti D. Kulkarni ◽  
Neena D. Damle ◽  
Lal Hingorani ◽  
Vaidhun H. Bhaskar ◽  
Minal R. Ghante ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Bioavailability ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Maximum Plasma ◽  
Boswellic Acid ◽  
Healthy Human ◽  
Boswellia Serrata ◽  
Solid Lipid ◽  
Human Volunteers

Abstract Objectives The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. Methods The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. Results Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. Conclusions The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

scholarly journals Enhanced Water Dispersibility of Curcumin Encapsulated in Alginate-Polysorbate 80 Nano Particles and Bioavailability in Healthy Human Volunteers

2019 ◽  
Vol 7 (1) ◽  
pp. 39-56 ◽  
Author(s):  
Roopa Govindaraju ◽  
Roopa Karki ◽  
Jayanthi Chandrashekarappa ◽  
Mukunthan Santhanam ◽  
Akshay K.K. Shankar ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Aqueous Solubility ◽  
Nano Particles ◽  
Simulated Gastric Fluid ◽  
Maximum Plasma ◽  
Polysorbate 80 ◽  
Healthy Human ◽  
Ionotropic Gelation ◽  
Quality Life ◽  
Human Volunteers

Background: The turmeric (Curcuma longa) plant, a perennial herb of the ginger family, is an agronomic crop in the south and southeast tropical Asia. Turmeric an Indian yellow gold and universal spice is described in Ayurveda, an ancient treatise on longevity and quality life for the treatment of various inflammatory disorders. The oral bioavailability of curcumin is low due to poor aqueous solubility, alkaline instability and speedy elimination. Objective: The present study is designed to prepare alginate polysorbate 80 nanoparticles to enhance aqueous solubility/dispersibility, hence bioavailability. Method: Curcumin-loaded alginate - polysorbate 80 nanoparticles were prepared by ionotropic gelation technique. Results: The optimized nano particles exhibited higher encapsulation efficiency (95%), particle size of 383 nm and Zeta potential of +200 mV. Formulations exhibited very low dissolution in Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF), but the major portion released in SCF which is attributed to the digestibility of alginate in Simulated Colonic Fluid (SCF) under the influence of colonic micro flora. FTIR and DSC observations revealed the successful entrapment of curcumin in alginate polysorbate-80 nanoparticles. The nanoparticles were more spherical, discrete and homogeneous. In healthy human volunteers, the oral bioavailability (AUC) of curcumin increased 5-fold after the consumption of curcumin nanosuspension compared to curcumin suspension. Maximum plasma concentration Cmax- 636 ± 122 ng/ml was observed at tmax- 2h for nanosuspension, whereas Cmax-87.7 ± 17.9ng/ml at tmax- 4h for suspension. Conclusion: Curcumin-loaded alginate - polysorbate 80 nanoparticles prepared by ionotropic gelation method, successfully entrapped curcumin. Both curcumin suspension and curcumin nanosuspension were safe and well tolerated and may thus be useful in the prevention or treatment of various inflammatory diseases of mankind.

scholarly journals Toxicokinetic of phenothrin in rabbits

2021 ◽  
Vol 91 (5) ◽  
pp. 547-558
Author(s):  
Tarık Kaya ◽  
◽  
Gökhan Eraslan
Keyword(s):  
Residence Time ◽  
Mean Residence Time ◽  
Oral Bioavailability ◽  
Area Under The Curve ◽  
Maximum Plasma ◽  
Time Curve ◽  
Elimination Half ◽  
Group 2 ◽  
Compartment Open Model ◽  
Group 1

The toxicokinetics of single dose phenothrin were examined in rabbits. For this aim, a total of 14 New Zealand breed, 2 to 2.5 kg body weight, 6 month-old female rabbits were used. The animals were divided into two groups and each group had 7 animals. Phenothrin was administered intravenously to each animal in group 1, at a dose of 10 mg/kg b.w. and orally to each of the animals in group 2 at the same dose. Dimethyl sulfoxide was used as a solvent in application of phenothrin. Plasma phenothrin levels were measured by gas chromatography equipped with an ECD detector. Toxicokinetic evaluations were made according to the plasma phenothrin level-time curve. Phenothrin was found to be distributed according to the two-compartment open model. The values ​​of elimination half-life (t1/2β), mean residence time (MRT) and area under the curve (AUC0→∞) after intravenous phenothrin administration were 2.57 ± 0.10 h, 2.79 ± 0.09 h and 6893.05 ± 261.26 ng/h/mL, respectively. On the other hand, the maximum plasma concentration (Cmax), time to reach Cmax (tmax), t1/2β, MRT and AUC0→∞ after oral administration were 185.71 ± 8.21 ng/mL, 1.21 ± 0.20 h, 4.24 ± 0.39 h, 6.65 ± 0.54 h and 1054.04 ± 65.90 ng/h/mL, respectively. The oral bioavailability of phenothrin was calculated as 15.29%. Mean residence time was short and oral bioavailability was low. This may be one of the reasons why phenothrin is included in safe pesticides.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals Acacia Gum Is Well Tolerated While Increasing Satiety and Lowering Peak Blood Glucose Response in Healthy Human Subjects

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 618
Author(s):  
Riley Larson ◽  
Courtney Nelson ◽  
Renee Korczak ◽  
Holly Willis ◽  
Jennifer Erickson ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Human Subjects ◽  
Area Under The Curve ◽  
Soluble Fiber ◽  
Healthy Human ◽  
Glucose Response ◽  
Blood Glucose Response ◽  
Acacia Gum ◽  
Fiber Treatment ◽  
Healthy Human Subjects

Acacia gum (AG) is a non-viscous soluble fiber that is easily incorporated into beverages and foods. To determine its physiological effects in healthy human subjects, we fed 0, 20, and 40 g of acacia gum in orange juice along with a bagel and cream cheese after a 12 h fast and compared satiety, glycemic response, gastrointestinal tolerance, and food intake among treatments. Subjects (n = 48) reported less hunger and greater fullness at 15 min (p = 0.019 and 0.003, respectively) and 240 min (p = 0.036 and 0.05, respectively) after breakfast with the 40 g fiber treatment. They also reported being more satisfied at 15 min (p = 0.011) and less hungry with the 40 g fiber treatment at 30 min (p = 0.012). Subjects reported more bloating, flatulence, and GI rumbling on the 40 g fiber treatment compared to control, although values for GI tolerance were all low with AG treatment. No significant differences were found in area under the curve (AUC) or change from baseline for blood glucose response, although actual blood glucose with 20 g fiber at 30 min was significantly less than control. Individuals varied greatly in their postprandial glucose response to all treatments. AG improves satiety response and may lower peak glucose response at certain timepoints, and it is well tolerated in healthy human subjects. AG can be added to beverages and foods in doses that can help meet fiber recommendations.

scholarly journals Underneath Kyoto: Emerging Subnational Government Initiatives and Incipient Issue-Bundling Opportunities in China and the United States

2008 ◽  
Vol 8 (1) ◽  
pp. 53-77 ◽  
Author(s):  
Peter H. Koehn
Keyword(s):  
United States ◽  
Stress Reduction ◽  
Traffic Congestion ◽  
Local Level ◽  
National Level ◽  
Ghg Emissions ◽  
The United States ◽  
Healthy Human ◽  
Republic Of China ◽  
Stabilization Policies

At present, progress in mitigating global GHG emissions is impeded by political stalemate at the national level in the United States and the People's Republic of China. Through the conceptual lenses of multilevel governance and framing politics, the article analyzes emerging policy initiatives among subnational governments in both countries. Effective subnational emission-mitigating action requires framing climatic-stabilization policies in terms of local co-benefits associated with environmental protection, health promotion, and economic advantage. In an impressive group of US states and cities, and increasingly at the local level in China, public concerns about air pollution, consumption and waste management, traffic congestion, health threats, the ability to attract tourists, and/or diminishing resources are legitimizing policy developments that carry the co-benefit of controlling GHG emissions. A co-benefits framing strategy that links individual and community concerns for morbidity, mortality, stress reduction, and healthy human development for all with GHG-emission limitation/reduction is especially likely to resonate powerfully at the subnational level throughout China and the United States.

External Validation of the Cardiac Surgery Score in a Quaternary Hospital in the United States of America

2021 ◽  
pp. 088506662110668
Author(s):  
Asha Singh ◽  
Chen Liang ◽  
Stephanie L. Mick ◽  
Chiedozie Udeh
Keyword(s):  
United States ◽  
Cardiac Surgery ◽  
United States Of America ◽  
Predictive Accuracy ◽  
External Validation ◽  
Cleveland Clinic ◽  
Area Under The Curve ◽  
The United States ◽  
Mortality Data ◽  
The Usa

Background The Cardiac Surgery Score (CASUS) was developed to assist in predicting post-cardiac surgery mortality using parameters measured in the intensive care unit. It is calculated by assigning points to ten physiologic variables and adding them to obtain a score (additive CASUS), or by logistic regression to weight the variables and estimate the probability of mortality (logistic CASUS). Both additive and logistic CASUS have been externally validated elsewhere, but not yet in the United States of America (USA). This study aims to validate CASUS in a quaternary hospital in the USA and compare the predictive performance of additive to logistic CASUS in this setting. Methods Additive and logistic CASUS (postoperative days 1-5) were calculated for 7098 patients at Cleveland Clinic from January 2015 to February 2017. 30-day mortality data were abstracted from institutional records and the Death Registries for Ohio State and the Centers for Disease Control. Given a low event rate, model discrimination was assessed by area under the curve (AUROC), partial AUROC (pAUC), and average precision (AP). Calibration was assessed by curves and quantified using Harrell's Emax, and Integrated Calibration Index (ICI). Results 30-day mortality rate was 1.37%. For additive CASUS, odds ratio for mortality was 1.41 (1.35-1.46, P <0.001). Additive and logistic CASUS had comparable pAUC and AUROC (all >0.83). However, additive CASUS had greater AP, especially on postoperative day 1 (0.22 vs. 0.11). Additive CASUS had better calibration curves, and lower Emax, and ICI on all days. Conclusions Additive and logistic CASUS discriminated well for postoperative 30-day mortality in our quaternary center in the USA, however logistic CASUS under-predicted mortality in our cohort. Given its ease of calculation, and better predictive accuracy, additive CASUS may be the preferred model for postoperative use. Validation in more typical cardiac surgery centers in the USA is recommended.

Physicochemical Evaluation of Brands of Amlodipine Besylate Tablets.

2020 ◽  
Vol 1 (5) ◽  
pp. 24-33
Author(s):  
C.A. Anyanwu-Ndulewe ◽  
◽  
L.E. Mogbolu ◽  
M.A. Oladunni ◽  
A.A. Adepoju-Bello
Keyword(s):  
Hardness Test ◽  
Drug Market ◽  
The United States ◽  
Financial Strain ◽  
Average Weight ◽  
Dissolution Profile ◽  
Amlodipine Besylate ◽  
Disintegration Time ◽  
Physicochemical Evaluation ◽  
Dissolution Efficiency

Background: Hypertension is a chronic condition, and the cost of filling prescriptions has a potential of putting a financial strain on patients, hence the need for lower priced but bioequivalent generics. The Nigerian drug market is awash with generics of Amlodipine besylate, a first line drug in the treatment of hypertension, therefore, any prescribed alternative must be bioequivalent to the originator. Objectives: This study assessed the physicochemical properties of some brands in order to predict pharmaceutical and bioequivalence and invariably, the interchangeability with the innovator brand. Methods: Compendial parameters of average weight, friability, disintegration, drug content and dissolution profile of ten generic brands were evaluated using the United States Pharmacopeia (USP) as well as the non-official hardness test. Results: Two brands failed the test for hardness, while still keeping to the stipulated friability limit. All the brands met the required disintegration time, irrespective of the discordance of some brands in the breaking force and friability values. All brands were found to contain between 92.00 and 103.57% (w/w) of Amlodipine besylate. Two brands failed to achieve ≥75% dissolution expected at 30 minutes and this was reflected in the low f2 values of 35.06% and 28.73%. The dissolution curves displayed a similarity for two brands, which was also corroborated by the high percentage dissolution efficiency (DE) of 92.00%, as well as the f1 and f2 values, compared to the innovator brand. Conclusion: Although the parameters used may predict therapeutic equivalence, interchangeability with the comparator brand is subject to relevant bioequivalence studies.

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