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Quercetin (3,3Ј,4Ј,5,7-pentahydroxyflavone) is a widely distributed secondary metabolite in plants. Human beings regularly consume quercetin in various fruits, vegetables or herbal medicines; such as apple, onion, and sophora flower. Quercetin has been found to have various biological activities including antiproliferative effects on several cancer cells, [1][2][3] anti-inflammatory and anti-allergic effects, 4) anti-oxidative activity, 5) and atherosclerosis-preventing effect. 6) In clinical study, supplementation of quercetin in hypertensive patients for 28 d significantly reduced blood pressure. 7) However, orally administered quercetin is poorly absorbed, and the bioavailability of quercetin administered in capsule form to human beings was reported to be less than 1%. 8) Therefore, several trials have been conducted to increase the bioavailability of quercetin by optimizing its formulation. For example, a pharmacokinetic study in rats revealed that bioavailability of quercetin was increased 5.7-fold by administration using a solid lipid nanoparticle as an oral delivery carrier compared with that administered as a quercetin suspension. 9)Quercetin is generally accumulated in plants as glycosides such as glucosides, rutinosides and xylosides. These quercetin glycosides show higher solubility in water than quercetin due to the hydrophilicity of the sugar moieties. Indeed, quercetin-4Ј-O-b-D-glucopyranoside has higher bioavailability than its aglycone in human beings, suggesting that conjugation with glucose would enhance quercetin absorption in the small intestine. 10,11) Glucosyl conjugation of lipophilic small molecules leads to an increase in their water solubility.12) Several glucosides of quercetin have been prepared by enzymatic synthesis to enhance the water solubility, as exemplified by a-monoglucosyl rutin (aMR), 13) a-oligoglucosyl rutin (aOR), 14) and "enzymatically modified isoquercitrin" (EMIQ).15) In Japan, EMIQ has been approved as a food additive, 16) and in U.S.A., FDA declared EMIQ generally regarded as safe (GRAS) for use in multiple food categories. However, how glucosyl conjugation affects the pharmacokinetic behavior of quercetin remains unknown except that aMR exhibited 4.5-fold higher area under the plasma concentration-time curve (AUC ) value than quercetin after oral administration as a suspension in carboxymethylcellulose (CMC) solution in rats. 13) In the present investigation, we examined the intestinal absorption and bioavailability of quercetin after oral administration of various quercetin glucosides, and revealed that glucosyl conjugation of isoquercitrin (IQC) with a-glucosidic linkages is quite effective for improving the bioavailability. We also showed that hydrolysis of the glycosidic linkage prior to the absorption through small intestinal epithelium is essential. We further suggest that the collaborative action of two glucosidases, mucosal maltose-glucoamylase (MGAM) and lactase-phlorozin hydrolase (LPH), both anchoring in the mucosal membrane of the epithelial tissue, pla...

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Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n  = 50) and multiple (part 2, n  = 33) ascending oral doses.

An 11-year-old Japanese boy with Olmsted syndrome was seen at our clinic. He had a sharply marginated, painful keratoderma with a red border on his palms and soles. Flexion contractures of the fingers were also observed. Hyperkeratotic plaques were present below the lower lip, on the elbows and knees, and in the sacral area. Localized alopecia, leukokeratosis on the tongue, shortness of stature, and laxity of the large joints corresponded to the clinical features of Olmsted syndrome. Treatment with etretinate was effective for the palms and fingers, but resulted in no improvement of the keratoderma of the soles. Because of periosteal thickening of the tibia, presumably caused by etretinate, therapy was terminated one year after it began.

Quercetin, a flavonol distributed widely in edible and medicinal plants, has beneficial biological activities in vitro. However, the low water solubility of quercetin limits its bioavailability to exhibit activity in vivo. We evaluated the anti-allergic effects of quercetin, quercetin 3-O-glucoside (isoquercitrin, IQC), α-oligoglucosyl rutin (αOR), and enzymatically modified isoquercitrin (α-oligoglucosyl isoquercitrin; EMIQ) in the murine ear passive cutaneous anaphylaxis (PCA) reaction using ovalbumin as an antigen. The substances to be tested were dissolved or suspended in water, and administered orally to mice (4 mmol 10 ml⁻¹ kg⁻¹). EMIQ exhibited a significant inhibitory effect on the PCA reaction. We detected 600 μM IQC and 95.1 μM Q3Glcn in the plasma of mice 30 min after EMIQ treatment, suggesting that IQC and Q3Glcn might be the genuine active compounds mediating the anti-allergic effects of EMIQ. Oral treatments of quercetin and αOR at this dosage exhibited no anti-allergic effect, and IQC showed less effect than EMIQ. Since IQC and quercetin cannot completely dissolve in water at this concentration, the water solubilities of these substances might affect their biological activities. αOR dissolved well in water at the concentration used but plasma concentrations of quercetin metabolites in mice orally treated with αOR were low, suggesting that αOR might not be converted to IQC or quercetin by the enzymes in small intestine and thus not exhibit any activity. Glycosyl conjugation of quercetin with specific sugar motifs is an effective strategy to improve the biological activity of quercetin in vivo.

SUMMARY A microfluidic system using electrochemical biosensor for continuous lactic acid (LA) monitoring at the skin's surface was fabricated and tested. The system consists of a micro flow‐cell for sampling LA at the skin's surface and a microfluidic LA biosensor based on a redox reaction of osmium wired horseradish peroxidase. Our system measures excreted LA by dissolving whole secretion in phosphate buffered saline (PBS), which was supplied into the microchannel as carrier flow. The measurement system was utilized in the real‐time monitoring of LA secretion during stationary bike exercises. Exercise intensities were regulated by heart rates (HRs) and the sampling device was attached on the right upper arm of the volunteer. During the exercise, PBS was circulated into the measurement system. As a result, change of LA levels correlated with the volunteer's physiological status was confirmed. Secretion of LA was estimated to be 4.50 μg/cm2/min when the intensity of exercise was high (HR: 160 bpm) and the signal decreased to the initial level after the exercise. This indicates that our system is suitable for not only the assessment of exercise intensity, but also useful in evaluation of metabolic activity.

BackgroundPatients with thrombocytopenia associated with chronic liver disease (CLD) are at greater risk of bleeding during invasive procedures. This study characterized the pharmacokinetic/pharmacodynamic (PK/PD) profile of lusutrombopag, a novel thrombopoietin-receptor agonist, using modelling and simulation, and evaluated the appropriate dose regimen for treatment of thrombocytopenia in CLD patients undergoing invasive procedures.MethodsA population PK/PD model was developed using plasma lusutrombopag concentrations from 78 healthy subjects and 349 CLD patients, as well as platelet counts from 347 of these 349 patients. Covariates were explored from subject characteristics. Monte-Carlo simulations were performed to assess a dose response for efficacy (platelet counts ≥ 50,000/μL) and a risk for platelet overshooting (platelet counts > 200,000/μL).ResultsVisual predictive checks indicated the developed models described the PK/PD profile of lusutrombopag well. In the simulations, without stopping criteria, lusutrombopag 3 mg once daily for 7 days before scheduled invasive procedures provided effective platelet response (85.2% probability for efficacy). The probability of platelet overshooting was 1.2%, indicating that platelet monitoring is not necessary. Although body weight was an influential covariate on the pharmacokinetics of lusutrombopag, individually estimated peak platelet counts overlapped among the body weight groups, suggesting no clinically significant effect on body weight.ConclusionThe modelling and simulation support lusutrombopag 3 mg once daily for 7 days without platelet monitoring.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00770-4) contains supplementary material, which is available to authorized users.