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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.

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.

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.

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.

Recent in vitro and animal studies have reported estrogen-like activity of chemicals used in sunscreen preparations. We investigated whether the three sunscreens benzophenone-3 (BP-3), octyl-methoxycinnamate (OMC), and 3-(4-methylbenzylidene) camphor (4-MBC) were absorbed and influenced endogenous reproductive hormone levels in humans after topical application. In this 2-wk single-blinded study 32 healthy volunteers, 15 young males and 17 postmenopausal females, were assigned to daily whole-body topical application of 2 mg per cm2 of basic cream formulation without (week 1) and with (week 2) the three sunscreens at 10% (wt/wt) of each. Maximum plasma concentrations were 200 ng per mL BP-3, 20 ng per mL 4-MBC, and 10 ng per mL OMC for females and 300 ng per mL BP-3, 20 ng per mL 4-MBC, and 20 ng per mL OMC for men. All three sunscreens were detectable in urine. The reproductive hormones FSH, LH were unchanged but minor differences in testosterone levels were observed between the 2 wk. A minor difference in serum estradiol and inhibin B levels were observed in men only. These differences in hormone levels were not related to sunscreen exposure.

Despite the prevalence of internal hemorrhoid disease (HD), there are few pharmacologic options. Iferanserin, a selective serotonin receptor antagonist, is being studied for use in the treatment of HD. This Phase IIb study evaluated the efficacy and tolerability of 10-mg twice-daily iferanserin intra-anal ointment for the cessation of bleeding and other symptoms associated with internal HD. This randomized, double-blind, placebo-controlled study was conducted at 5 sites in Germany. Outpatients with Goligher grade I, II, and/or III hemorrhoids and bleeding were randomly assigned to receive iferanserin ointment 10 mg or inactive vehicle (placebo) BID for 14 days. During treatment, patients rated the severity of HD symptoms daily on a 10-point scale using a diary form. At enrollment and study end, physicians recorded the frequency and intensity of HD symptoms, adverse events, and results from blood and urine analyses on clinical-report forms. Of the 121 patients enrolled in the study, 118 were evaluable for tolerability and 111 for efficacy. The mean age of the tolerability population was 52.7 years, 78.9% were male, and all were white. The 2 groups had similar HD symptoms at baseline, but overall, patients in the placebo group had numerically higher grades of HD than did patients in the iferanserin group. Compared with placebo, iferanserin was associated with significantly lower patient-reported severity ratings of daily bleeding and itching, beginning at day 1 for bleeding and at day 2 for itching (P < 0.05), but not with reduced ratings for severity of other HD symptoms, including pain, tenderness, difficulty with defecation, fullness, throbbing, and gas. In the physician assessments, iferanserin was associated with significantly reduced bleeding frequency by day 14 compared with placebo (P < 0.05). Adverse events were mild and infrequent, with no significant differences in prevalences between the 2 treatment groups and no clinically significant changes in laboratory values in any patient. Compared with placebo, intra-anal iferanserin was associated with significantly reduced patient-reported severity of bleeding and itching and physician-assessed bleeding frequency in these patients presenting with grade I, II, and/or III internal hemorrhoids and bleeding at 5 sites in Germany. ClinicalTrials.gov identifier: 01483833.

Stimulation of the penetration of topically applied substances into the skin is a topic of intensive dermatological and pharmacological research. Next to intercellular penetration, i.e. a penetration inside the lipid layers around the corneocytes, follicular penetration also represents an efficient penetration pathway. The hair follicles act as a long-term reservoir for topically applied substances. They are surrounded by or contain several important target structures, such as blood capillaries, stem cells and dendritic cells. Therefore, the hair follicles have to be well protected from hazardous substances coming into contact with the skin. The traditional method of decontamination of the skin involves an intensive washing procedure. However, this process represents a massage, which pushes the hazardous substances even deeper into the hair follicles. In the present study, the application of absorbing materials for decontamination of the skin was investigated after the application of a model substance utilizing the tape-stripping procedure. It was found that absorbing materials are better suited than the washing process for decontamination of the skin.

Current therapeutics for hepatitis B virus (HBV) patients such as nucleoside analogs (NAs) are effective; however, new antiviral drugs against HBV are still desired. Since the interaction between the epsilon (ε) sequence of HBV pregenomic RNA and viral polymerase (Pol) is a key step in the HBV replication cycle, we aimed to identify small compounds for its inhibition, and established a pull-down assay system for the detection of ε-RNA-binding-Pol. Screening showed that 5 out of 3,965 compounds inhibited ε-Pol binding, and we identified rosmarinic acid, which exhibited specificity, as a potential antiviral agent. In order to examine the anti-HBV effects of rosmarinic acid, HBV-infected primary human hepatocytes from a humanized mouse liver were treated with rosmarinic acid. The rosmarinic acid treatment decreased HBV components including the amounts of extracellular HBV DNA with negligible cytotoxicity. We also investigated the combined effects of rosmarinic acid and the NA, lamivudine. rosmarinic acid slightly enhanced the anti-HBV activity of lamivudine, suggesting that the HBV replication step targeted by rosmarinic acid is distinct from that of NA. We analyzed an additional 25 rosmarinic acid derivatives, and found that 5 also inhibited ε-Pol. Structural comparisons between these derivatives implied that the \"two phenolic hydroxyl groups at both ends\" and the \"caffeic acid-like structure\" of rosmarinic acid are critical for the inhibition of ε-Pol binding. Collectively, our results demonstrate that rosmarinic acid inhibits HBV replication in HBV-infected cells by specifically targeting ε-Pol binding.

Background The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations. Methods Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models. Results In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance. Conclusions These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.