Flavones are a class of flavonoids that are a subject of increasing interest because of their biological activities in vitro and in vivo. This article reviews the major sources of flavones and their ...concentrations in food and beverages, which vary widely between studies. It also covers the roles of flavones in plants, the influence of growing conditions on their concentrations, and their stability during food processing. The absorption and metabolism of flavones are also reviewed, in particular the intestinal absorption of both O- and C-glycosides. Pharmacokinetic studies in both animals and humans are described, comparing differences between species and the effects of glycosylation on bioavailability. Biological activity in animal models and human dietary intervention studies is also reviewed. A better understanding of flavone sources and bioavailability is needed to understand mechanisms of action and nutritional intervention.
Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of ...stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3–4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug–drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.
Purpose
The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed ...for mometasone furoate, budesonide and fluticasone propionate.
Methods
Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate
of in vivo
drug dissolution/absorption was predicted for the included ICSs from
in vitro
aerodynamic particle size distribution and
in vitro
drug solubility estimates measured in an
in vivo
predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an
in vitro
Transwell
®
based dissolution system.
Results
Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.
Conclusion
Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of
in vivo
predictions.
This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.
Eligible patients received ...increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients).
Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers.
Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.
ClinicalTrials.gov, NCT01058707.
Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is ...difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone. Doxorubicin (DOX) was loaded to hollow gold nanospheres (HAuNS) coated with polyethylene glycol (PEG). The pharmacokinetics and biodistribution of both DOX and HAuNS in the resulting nanoconstruct, DOX@PEG-HAuNS having different DOX:PEG:HAuNS ratios, were evaluated using dual isotope labeling techniques. The antitumor activity of DOX@PEG-HAuNS with DOX:PEG:HAuNS weight ratio of 1:3:1 (NP3) in combination with NIR laser was studied in vitro and in vivo using human MDA-MB-231 breast cancer and A2780 ovarian cancer cells. In vitro, NP3 mediated PTA of both cancer cells and DOX release upon NIR laser treatment. In vivo, NP3 showed slower clearance in blood and greater accumulation in tumors than free DOX. NP3-plus-NIR laser demonstrated greater antitumor activity than free DOX, NP3, or liposomal DOX. Moreover, NP3 displayed significantly decreased systemic toxicity compared to free DOX or liposomal DOX. Enhanced antitumor effect with NP3-plus-laser can be attributed to both the cytotoxic effect of DOX released from NP3 and the photothermal effect mediated by HAuNS. Slow release of DOX from NP3 in normal tissues contributed to reduced systemic toxicity. Photothermal-chemotherapy exemplified by a single-agent nanoconstruct NP3 is a promising approach to anticancer therapy.
Hollow gold nanospheres formed stable complexes with doxorubicin and mediated both photothermal ablation therapy and local release of the drug by near-infrared light. Display omitted
A series of poly(dimethysiloxane)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMS-b-PDMAEMA) block copolymers were synthesized with atom transfer radical polymerization (ATRP). In aqueous solution ...the polymers self-assembled into micelles with diameters between 80 and 300 nm, with the ability to encapsulate DOX. The polymer with the shortest PDMAEMA block (5 units) displayed excellent cell viability, while micelles containing longer PDMAEMA block lengths (13 and 22 units) led to increased cytotoxicity. The carriers released DOX in response to a decrease in pH from 7.4 to 5.5. Confocal laser scanning microscopy (CLSM) revealed that nanoparticles were taken up by endocytosis into acidic cell compartments. Furthermore, DOX-loaded nanocarriers exhibited intracellular pH-response as changes in cell morphology and drug release were observed within 24 h.
Aceclofenac-loaded alginate/gellan gum microspheres for prolonged aceclofenac release were prepared through maleic anhydride-induced unsaturated esterification. The drug entrapment efficiency of ...these microspheres was found 39.30±1.28% to 98.46±0.40% and their average particle sizes were 270–490μm. These microspheres were characterized by FTIR, DSC, P-XRD and SEM analysis. The in vitro dissolution indicated prolonged sustained release of aceclofenac over 6h, which also followed the Korsmeyer–Peppas model (R2=0.9571–0.9952). The microspheres prepared through 3% (w/v) maleic anhydride-induced esterification exhibited comparatively slower drug-release. Most of the microspheres were followed Fickian diffusion mechanism except the microspheres containing higher gellan gum content, which followed anomalous (non-Fickian) diffusion. The in vivo results showed sustained systemic absorption of aceclofenac in rabbits and excellent anti-inflammatory activity in carrageenan-induced rats after oral administration over prolonged period.
SCOPE: Flavan‐3‐ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of ...(‐)‐epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross‐over study in humans. METHODS AND RESULTS: Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC‐MS and GC‐MS/MS. Glucuronidated, sulfated, and methylated (‐)‐epicatechin and 5‐(3′,4′‐dihydroxyphenyl)‐valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4‐hydroxy‐5‐(3′,4′‐dihydroxyphenyl)valeric acid and their conjugated metabolites were detected. The formation of 5‐(3′,4′‐dihydroxyphenyl)‐valerolactone and 4‐hydroxy‐5‐(3′,4′‐dihydroxyphenyl)valeric acid varied largely between individuals as well as with the degree of polymerization of flavan‐3‐ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan‐3‐ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces. CONCLUSION: In addition to conjugated metabolites derived from the absorption of monomeric flavan‐3‐ols, 5‐(3′,4′‐dihydroxyphenyl)‐valerolactone represents an important in vivo metabolite of (‐)‐epicatechin and procyanidin B1 produced by the gut microbiota.
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