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BackgroundThrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD.MethodsIn this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated.ResultsThe proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set.ConclusionsLusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count.Clinical trial registrationThe study is registered at JapicCTI-121944.

The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

The health-promoting effects of phenolic compounds depend on their bioaccessibility from the food matrix and their consequent bioavailability. We carried out a randomized crossover pilot clinical trial to evaluate the matrix effect (raw flesh and juice) of ‘Ataulfo’ mango on the bioavailability of its phenolic compounds. Twelve healthy male subjects consumed a dose of mango flesh or juice. Blood was collected for six hours after consumption, and urine for 24 h. Plasma and urine phenolics were analyzed by electrochemical detection coupled to high performance liquid chromatography (HPLC-ECD). Five compounds were identified and quantified in plasma. Six phenolic compounds, plus a microbial metabolite (pyrogallol) were quantified in urine, suggesting colonic metabolism. The maximum plasma concentration (Cmax) occurred 2–4 h after consumption; excretion rates were maximum at 8–24 h. Mango flesh contributed to greater protocatechuic acid absorption (49%), mango juice contributed to higher chlorogenic acid absorption (62%). Our data suggests that the bioavailability and antioxidant capacity of mango phenolics is preserved, and may be increased when the flesh is processed into juice.

Aim We evaluated the efficacy and safety of Nuvastatic™ (C5OSEW5050ESA) in improving cancer-related fatigue (CRF) among cancer patients. Methods This multicenter randomized double-blind placebo-controlled phase 2 trial included 110 solid malignant tumor patients (stage II–IV) undergoing chemotherapy. They were randomly selected and provided oral Nuvastatic™ 1000 mg ( N  = 56) or placebo ( N  = 54) thrice daily for 9 weeks. The primary outcomes were fatigue (Brief Fatigue Inventory (BFI)) and Visual Analog Scale for Fatigue (VAS-F)) scores measured before and after intervention at baseline and weeks 3, 6, and 9. The secondary outcomes were mean group difference in the vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36) and urinary F2-isoprostane concentration (an oxidative stress biomarker), Eastern Cooperative Oncology Group scores, adverse events, and biochemical and hematologic parameters. Analysis was performed by intention-to-treat (ITT). Primary and secondary outcomes were assessed by two-way repeated-measures analysis of variance (mixed ANOVA). Results The Nuvastatic™ group exhibited an overall decreased fatigue score compared with the placebo group. Compared with the placebo group, the Nuvastatic™ group significantly reduced BFI-fatigue (BFI fatigue score, F (1.4, 147) = 16.554, p  < 0.001, partial η 2  = 0.333). The Nuvastatic™ group significantly reduced VAS-F fatigue ( F (2, 210) = 9.534, p  < 0.001, partial η 2  = 0.083), improved quality of life (QoL) ( F (1.2, 127.48) = 34.07, p  < 0.001, partial η 2  = 0.243), and lowered urinary F2-IsoP concentrations (mean difference (95% CI) = 55.57 (24.84, 86.30)), t (55) = 3.624, p  < 0.001, Cohen’s d (95% CI) = 0.48 (0.20, 0.75)). Reported adverse events were vomiting (0.9%), fever (5.4%), and headache (2.7%). Conclusion Nuvastatic™ is potentially an effective adjuvant for CRF management in solid tumor patients and worthy of further investigation in larger trials. Trial registration ClinicalTrial.gov ID: NCT04546607. Study registration date (first submitted): 11–05-2020.

We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis ( M. officinalis ) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer’s disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients ( n  = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference ( P  = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms. Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

Purpose Wild blueberries (WB) ( Vaccinium angustifolium ) are rich sources of polyphenols, such as flavonols, phenolic acids and anthocyanins (ACNs), reported to decrease the risk of cardiovascular and degenerative diseases. This study investigated the effect of regular consumption of a WB or a placebo (PL) drink on markers of oxidative stress, inflammation and endothelial function in subjects with risk factors for cardiovascular disease. Methods Eighteen male volunteers (ages 47.8 ± 9.7 years; body mass index 24.8 ± 2.6 kg/m 2 ) received according to a cross-over design, a WB (25 g freeze-dried powder, providing 375 mg of ACNs) or a PL drink for 6 weeks, spaced by a 6-week wash-out. Endogenous and oxidatively induced DNA damage in blood mononuclear cells, serum interleukin levels, reactive hyperemia index, nitric oxide, soluble vascular adhesion molecule concentration and other variables were analyzed. Results Wild blueberry drink intake significantly reduced the levels of endogenously oxidized DNA bases (from 12.5 ± 5.6 % to 9.6 ± 3.5 %, p  ≤ 0.01) and the levels of H 2 O 2 -induced DNA damage (from 45.8 ± 7.9 % to 37.2 ± 9.1 %, p  ≤ 0.01), while no effect was found after the PL drink. No significant differences were detected for markers of endothelial function and the other variables under study. Conclusions In conclusion, the consumption of the WB drink for 6 weeks significantly reduced the levels of oxidized DNA bases and increased the resistance to oxidatively induced DNA damage. Future studies should address in greater detail the role of WB in endothelial function. This study was registered at www.isrctn.org as ISRCTN47732406.

Microtubule affinity regulating kinase (MARK4) is a potential drug target for different types of cancer as it controls the early step of cell division. In this study, we have screened a series of natural compounds and finally identified rosmarinic acid (RA) as a potential inhibitor of MARK4. Molecular docking and 500 ns all-atom simulation studies suggested that RA binds to the active site pocket of MARK4, forming enough number of non-covalent interactions with critical residues and MARK4-RA complex is stable throughout the simulation trajectory. RA shows an excellent binding affinity to the MARK4 with a binding constant ( K ) of 10 7  M −1 . Furthermore, RA significantly inhibits MARK4 activity (IC 50  = 6.204 µM). The evaluation of enthalpy change (∆ H ) and entropy change (∆ S ) suggested that the MARK4-RA complex formation is driven by hydrogen bonding and thus complexation process is seemingly specific. The consequence of MARK4 inhibition by RA was further evaluated by cell-based tau-phosphorylation studies, which suggested that RA inhibited the phosphorylation of tau. The treatment of cancer cells with RA significantly controls cell growth and subsequently induces apoptosis. Our study provides a rationale for the therapeutic evaluation of RA and RA-based inhibitors in MARK4 associated cancers and other diseases.

Parasitic infections like leishmaniasis and trypanosomiasis remain as a worldwide concern to public health. Improvement of the currently available drug discovery pipelines for those diseases is therefore mandatory. We have recently reported on the antileishmanial and antitrypanosomal activity of a set of cinnamate esters where we identified several compounds with interesting activity against L. donovani and T. brucei rhodesiense. For a better understanding of such compounds’ anti-infective activity, analyses of the underlying structure-activity relationships, especially from a quantitative point of view, would be a prerequisite for rational further development of such compounds. Thus, quantitative structure-activity relationships (QSAR) modeling for the mentioned set of compounds and their antileishmanial and antitrypanosomal activity was performed using a genetic algorithm as main variable selection tool and multiple linear regression as statistical analysis. Changes in the composition of the training/test sets were evaluated (two randomly selected and one by Kennard-Stone algorithm). The effect of the size of the models (number of descriptors) was also investigated. The quality of all resulting models was assessed by a variety of validation parameters. The models were ranked by newly introduced scoring functions accounting for the fulfillment of each of the validation criteria evaluated. The test sets were effectively within the applicability domain of the best models, which demonstrated high robustness. Detailed analysis of the molecular descriptors involved in those models revealed strong dependence of activity on the number and type of polar atoms, which affect the hydrophobic/hydrophilic properties causing a prominent influence on the investigated biological activities.

Lusutrombopag (Mulpleta ® ) is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist being developed by Shionogi for chronic liver disease (CLD) patients with thrombocytopenia prior to elective invasive surgery. Lusutrombopag acts selectively on the human TPO receptor and activates signal transduction pathways that promote the proliferation and differentiation of bone marrow cells into megakaryocytes, thereby increasing platelet levels. In September 2015, lusutrombopag received its first global approval in Japan for the improvement of CLD-associated thrombocytopenia in patients scheduled to undergo elective invasive procedures. This article summarizes the milestones in the development of lusutrombopag leading to this first approval.

Polyphenolic acids are the widely occurring natural products in almost each herbal plant, among which rosmarinic acid (RA, C18H16O8) is well-known, and is present in over 160 species belonging to many families, especially the Lamiaceae. Aside from this herbal ingredient, dozens of its natural derivatives have also been isolated and characterized from many natural plants. In recent years, with the increasing focus on the natural products as alternative treatments, a large number of pharmacological studies have been carried out to demonstrate the various biological activities of RA such as anti-inflammation, anti-oxidation, anti-diabetes, anti-virus, anti-tumor, neuroprotection, hepatoprotection, etc. In addition, investigations concerning its biosynthesis, extraction, analysis, clinical applications, and pharmacokinetics have also been performed. Although many achievements have been made in various research aspects, there still exist some problems or issues to be answered, especially its toxicity and bioavailability. Thus, we hope that in the case of natural products, the present review can not only provide a comprehensive understanding on RA covering its miscellaneous research fields, but also highlight some of the present issues and future perspectives worth investigating later, in order to help us utilize this polyphenolic acid more efficiently, widely, and safely.