Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.

BACKGROUND: Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis. METHODS: In a phase 2b, double-blind, vehicle-controlled study, adults with plaque psoriasis were randomized to tapinarof cream 0.5% or 1% once or twice daily or vehicle once or twice daily for 12 weeks with 4-week follow-up. Efficacy outcomes included Physician Global Assessment (PGA) scores, change in PGA and total target lesion grading scores, and proportion of patients achieving ≥50%, ≥75%, and ≥90% reductions in the Psoriasis Area and Severity Index scores from baseline (PASI50, PASI75, and PASI90). RESULTS: At week 12, improvements were observed in all tapinarof groups vs vehicle in PGA response, change in PGA and total target lesion grading scores, PASI50 (71%-92% vs 10%-32%), PASI75 (46%-65% vs 5%-16%), and PASI90 (18%-40% vs 0%); all differences were statistically significant with tapinarof 1% once daily. Tapinarof responses were apparent from week 2, with significant efficacy at week 8 maintained through week 16. Most adverse events were mild or moderate. LIMITATIONS: The analyses reported require confirmation in larger prospective studies. CONCLUSIONS: Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.

BACKGROUND: Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment. METHODS: A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores. RESULTS: Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate. LIMITATIONS: Larger prospective studies are required to confirm the reported analyses. CONCLUSIONS: Tapinarof is a potential important advance in topical medicine development for AD.

Bevacizumab plus fosbretabulin in recurrent ovarian cancer: Overall survival and exploratory analyses of a randomized phase II NRG oncology/gynecologic oncology group study.

OBJECTIVE: To explore the relationship between tumor size and response to combined anti-vascular targeted therapy using the anti-angiogenesis inhibitor, bevacizumab, and the tubulin-binding vascular disrupting agent, fosbretabulin. METHODS: An exploratory, post-hoc analysis of the randomized phase II trial, Gynecologic Oncology Group-0186I, was performed. One hundred and seven patients with recurrent ovarian carcinoma, treated with up to 3 prior regimens, were randomized to bevacizumab 15 mg/kg body weight with or without intravenous fosbretabulin 60 mg/m2 body surface area every 21 days until progression or unacceptable toxicity. The primary analysis favored the combination (HR 0.69; 95% CI, 0.47-1.00; p = .049) [Monk BJ, et al. J Clin Oncol 2016;34:2279-86]. The Cox proportional hazards model was used to estimate the treatment effect in various subpopulations. RESULTS: With extended follow-up, the median PFS for bevacizumab plus fosbretabulin was 7.6  months as compared to 4.8  months with bevacizumab alone (HR 0.74; 90% CI, 0.54-1.02). Overall survival was similar in the experimental and control arms (25.2 vs 24.4 mos, respectively, HR 0.85; 90% CI, 0.59-1.22; p = .461). Eighty-one patients had measurable disease and median tumor size was 5.7  cm. In the ≤5.7  cm subgroup, the HR for progression or death was 0.77 (90% CI 0.45-1.31). Patients with tumors >5.7  cm (n = 40) had a HR for progression or death of 0.55; 90% CI, 0.32-0.96; p = .075). CONCLUSIONS: Although no significant survival benefit was observed, the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study.

Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial.

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Topical Agents Currently in Phase II or Phase III Trials for Atopic Dermatitis.

Mild to moderate atopic dermatitis (AD) occurs frequently in children and adults and is usually managed through the use of pharmacologic treatments, such as topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs), and good skin care practices. As chronic TCS or TCI can lead to the development of adverse effects, there is a need for safe, alternative treatments for patients with resistant AD. A systemic literature review was performed to examine the safety and efficacy of topical agents currently in phase II and phase III clinical trials for AD. Our team searched the databases, PubMed, Google Scholar, and ClinicalTrials.gov, on March 2020 for studies pertaining to the use of topical agents in AD. Key words included each drug (tapinarof, crisaborole, ARQ-151 cream, ruxolitinib) or "topical agents"; combined with "atopic dermatitis"; Articles published within the last 5 years were included as references. References within retrieved articles were also reviewed to identify potentially missed studies. A total of 24 articles were included in this review. Tapinarof, crisaborole, and ruxolitinib lead to statistically significant improvements in multiple disease severity scores. ARQ-151 cream achieved statistical significance in secondary endpoints, including vIGA-AD and EASI-75, but not in the primary endpoint of the study. All topical agents were well-tolerated by study participants. The findings demonstrate that tapinarof, crisaborole, ARQ-151 cream, and ruxolitinib are safe, effective treatment options for patients with mild to moderate AD. J Drugs Dermatol. 2020;19(10):956-959. doi: 10.36849/JDD.2020.5214.

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.

Postoperative resveratrol administration improves prognosis of rat orthotopic glioblastomas.

BACKGROUND: Although our previous study revealed lumbar punctured resveratrol could remarkably prolong the survival of rats bearing orthotopic glioblastomas, it also suggested the administration did not completely suppress rapid tumour growth. These evidences led us to consider that the prognosis of tumour-bearing rats may be further improved if this treatment is used in combination with neurosurgery. Therefore, we investigated the effectiveness of the combined treatment on rat orthotopic glioblastomas. METHODS: Rat RG2 glioblastoma cells were inoculated into the brains of 36 rats. The rats were subjected to partial tumour removal after they showed symptoms of intracranial hypertension. There were 28 rats that survived the surgery, and these animals were randomly and equally divided into the control group without postoperative treatment and the LP group treated with 100 µl of 300 µM resveratrol via the LP route. Resveratrol was administered 24 h after tumour resection in 3-day intervals, and the animals received 7 treatments. The intracranial tumour sizes, average life span, cell apoptosis and STAT3 signalling were evaluated by multiple experimental approaches in the tumour tissues harvested from both groups. RESULTS: The results showed that 5 of the 14 (35.7%) rats in the LP group remained alive over 60 days without any sign of recurrence. The remaining nine animals had a longer mean postoperative survival time (11.0 ± 2.9 days) than that of the (7.3 + 1.3 days; p < 0.05) control group. The resveratrol-treated tumour tissues showed less Ki67 labelling, widely distributed apoptotic regions, upregulated PIAS3 expression and reduced p-STAT3 nuclear translocation. CONCLUSIONS: This study demonstrates that postoperative resveratrol administration efficiently improves the prognosis of rat advanced orthotopic glioblastoma via inhibition of growth, induction of apoptosis and inactivation of STAT3 signalling. Therefore, this therapeutic approach could be of potential practical value in the management of glioblastomas.

Efficacy and safety of resveratrol, an oral hemoglobin F-augmenting agent, in patients with beta-thalassemia intermedia.

Recently, resveratrol showed induction of γ-globin mRNA synthesis in human erythroid precursors and reducing oxidative stress in red cells of thalassemia patients in many in vitro studies. We aimed to investigate the efficacy and safety of resveratrol, for the first time, in non-transfusion-dependent beta-thalassemia intermedia (B-TI) in Southern Iran. In this double-blind randomized clinical trial, 54 patients with B-TI were investigated during 6 months between October 2016 and March 2017. Patients were randomly allocated into three groups by simple randomization method. Group 1 (hydroxyurea (HU) and placebo, 18 patients), group 2 (resveratrol/piperine and placebo, 16 patients), and group 3(HU and resveratrol/piperine, 20 patients). Primary end point was considered as change in hemoglobin (Hb) levels and need for blood transfusion. Drug safety was considered as a secondary end point. Mean age of the patients was 28.2 ± 5.6 (18-42) years. Response rate was not significantly different among the three groups (P > 0.05). Higher percentages of adverse events were detected in groups 2 (31.3%) and 3 (25%) compared to group 1 (5.6%). However, the difference was not statistically significant (P > 0.05). All reported adverse events were gastrointestinal symptoms. Resveratrol showed a similar efficacy with HU in the small population of non-transfusion B-TI patients during a 6-month follow-up. Complications, mostly gastrointestinal, were observed more frequently in resveratrol groups compared to the HU group. Although it was not statistically significant, more attention should be given to safety and efficacy of resveratrol as an oral HbF-augmenting agent.

Gut microbiota analysis of juvenile genetically improved farmed tilapia (Oreochromis niloticus) by dietary supplementation of different resveratrol concentrations.

The genetically improved farmed tilapia (GIFT, Oreochromis niloticus) is cultured widely for production of freshwater fish in China, while streptococcosis, likely related to pathogenic infections, occurs frequently in juvenile, mother, and operated GIFT. The gut microbiota plays an important role in nutrient digestibility in animals, and resveratrol (RES) has been used in feed for different freshwater fish species. Therefore, understanding changes in the tilapia gut microbiota across different concentrations of dietary RES supplementation is extremely important. The gut microbiota population in tilapia at 45 d after supplementation with different concentrations (0, 0.025, 0.05, 0.1 g/kg) of dietary RES was assessed by 16S rDNA gene sequencing. A total of 5445 operational taxonomic units were identified from all samples, and 14 phyla and 81 families were identified from all fecal samples. The bacteria of the phylum Firmicutes were significantly enriched in the 0.025 g/kg RES group when compared with the controls. Proteobacteria, Firmicutes and Cyanobacteria were the most dominant three phyla in all samples. With the increasing concentrations, the proportion of beneficial microbial taxa (Acetobacteraceae and Methylobacteriaceae) increased, whereas the proportion of harmful microbial taxa decreased, eg. Streptococcaceae except for 0.1 g/kg RES groups. RES did not affect the richness and diversity in tilapia gut microbiota. These findings provide information on the diversity and differences in GIFT gut microbiota database, and may contribute to developing strategies for management of diseases and long-term sustainability of O. niloticus culture.

Antioxidant activities of novel resveratrol analogs in breast cancer.

The objective of the present study was to characterize the role of novel resveratrol (Res) analogs: 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1, 2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) as potent antioxidants against breast cancer. Non-neoplastic breast epithelial cell lines MCF-10A and MCF-10F were treated with 17ß-estradiol (E2), Res, HPIMBD, and TIMBD for up to 72 h. mRNA and protein levels of antioxidant genes, superoxide dismutase 3 (SOD3) and N-quinoneoxidoreductase-1 (NQO1) and transcription factors, nuclear factor erythroid 2-related factor (Nrf) 1, 2 and 3 were quantified after the above treatments. Generation of reactive oxygen species (ROS) was measured by CM-H2-DCFDA and oxidative-DNA damage was determined by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG). HPIMBD and TIMBD scavenged cellular ROS production, attenuated oxidative DNA damage, increased mRNA and protein expression levels of SOD3 and NQO1 and activated Nrf signaling pathway. Our studies demonstrate that HPIMBD and TIMBD have the potential as novel antioxidants to prevent development of breast cancer.

A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Men with biochemical recurrence of prostate cancer following local therapies often use natural supplements in an attempt to delay metastases and/or avoid the need for more aggressive treatments with undesirable side-effects. While there is a growing body of research into phytotherapeutic agents in this cohort, with some promising results, as yet no definitive recommendations can be made. This pilot study was undertaken to assess the feasibility of a fully-powered study to examine the effects of this phytotherapeutic intervention (containing turmeric, resveratrol, green tea and broccoli sprouts) on PSA doubling time in men with biochemical recurrence with a moderate PSA rise rate. METHODS: A double blind, randomized, placebo-controlled parallel trial was conducted with 22 men with biochemically recurrent prostate cancer and a moderate rise rate (PSA doubling time of 4-15 months and no evidence of metastases from conventional imaging methods). Patients were randomized to either the active treatment arm or placebo for 12 weeks. The primary endpoints were feasibility of study recruitment and procedures, and measurement of proposed secondary endpoints (prostate symptoms, quality of life, anxiety, and depression as measured on the EORTC QLQ-C30 and PR-25, the IPSS and HADS). Data were collected to estimate PSA-log slopes and PSA-doubling times, using a mixed model, for both the pre-intervention and post-intervention periods. RESULTS: Adherence to study protocol was excellent, and the phytotherapeutic intervention was well-tolerated, with similar numbers of mild-to-moderate adverse events in the active and placebo arms. Both the intervention and data collection methods were acceptable to participants. No statistical difference between groups on clinical outcomes was expected in this pilot study. There was between-subject variation in the PSA post treatment, but on average the active treatment group experienced a non-significant increase in the log-slope of PSA (pre-treatment doubling time = 10.2 months, post-treatment doubling time = 5.5 months), and the placebo group experienced no change in the log-slope of PSA (pre-treatment doubling time = 10.8 months, post-treatment doubling time = 10.9 months). CONCLUSION: The findings suggest that a fully powered study of this combination is feasible in men with biochemically recurrent prostate cancer and a moderate PSA rise rate. Prostate 77:765-775, 2017. © 2017 Wiley Periodicals, Inc.

Stimulation of Eryptosis, the Suicidal Erythrocyte Death by Piceatannol.

BACKGROUND/AIMS: Piceatannol, an analog and metabolite of resveratrol, is effective against various disorders including malignancy. It is in part effective by triggering suicidal death or apoptosis of tumor cells. Cellular mechanisms mediating the proapoptotic effect of Piceatannol include mitochondrial depolarization and cytochrome c release. Erythrocytes lack mitochondria but may nevertheless enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide formation. The present study explored, whether Piceatannol induces eryptosis and, if so, to shed some light on the cellular mechanisms involved. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) formation from 2',7'-dichlorodihydrofluorescein (DCF) diacetate-dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemoglobin concentration in the supernatant was taken as measure of hemolysis. RESULTS: A 48 hours exposure of human erythrocytes to Piceatannol (10 - 20 µM) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased DCFDA-fluorescence, significantly increased ceramide abundance, but did not significantly increase Fluo3-fluorescence. Removal of extracellular Ca2+ slightly blunted but did not abolish the effect of Piceatannol on annexin-V-binding and forward scatter. Piceatannol (20 µM) significantly augmented the increase of annexin-V-binding, but significantly blunted the decrease of forward scatter following treatment with the Ca2+ ionophore ionomycin. CONCLUSIONS: Piceatannol triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part downstream of Ca2+ and involving oxidative stress and ceramide formation.

Diagnostic accuracy of (18)F amyloid PET tracers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.

Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer's disease (AD). PET using (18)F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway.

Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis.

BACKGROUND: Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model. METHODS: CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study. RESULTS: Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance. CONCLUSIONS: Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.

Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial.

The polyphenol resveratrol is considered to exert many beneficial actions, such as antioxidant, anti-inflammatory, insulin-sensitizer and anticancer effects. Its benefits in patients with type 2 diabetes mellitus (T2DM) are controversial. Our aims were to determine whether resveratrol supplementation at two different dosages (500 and 40mg/day) for 6 months i) reduced the concentrations of C-reactive-protein (CRP) and ii) ameliorated the metabolic pattern of T2DM patients. In the present double-blind, randomized, placebo-controlled trial, 192 T2DM patients were randomized to receive resveratrol 500mg/day (Resv500arm), resveratrol 40mg/day (Resv40arm) or placebo for 6-months. At baseline and at the trial end, CRP values, anthropometric, metabolic and liver parameters were determined. No serious adverse event occurred. A dose-dependent, though not significant, CRP decrease of 5.6% (Resv40arm) and 15.9% (Resv500arm) was observed vs placebo. We failed to detect significant differences in weight, BMI, waist circumference, and values of arterial blood pressure, fasting glucose, glycated hemoglobin, insulin, C-peptide, free fatty acids, liver transaminases, uric acid, adiponectin, interleukin-6, in both the Resv500 and Resv40 arms vs placebo. Total cholesterol and triglycerides slightly increased in the Resv500arm. Subgroup analyses revealed that lower diabetes duration (in both Resv500 and Resv40arms), and, in the Resv500arm, younger age, aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo. The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations, nor improve the metabolic pattern of T2DM patients.

Dose-related effects of chronic resveratrol administration on neurogenesis, angiogenesis, and corticosterone secretion are associated with improved spatial memory retention following global cerebral ischemia.

OBJECTIVES: The polyphenol resveratrol has shown regulatory effects on hippocampal neurogenesis, which according to the neurovascular niche hypothesis, is likely to involve stimulation of angiogenesis. In rodents, global cerebral ischemia leads to selective CA1 neuronal damage, spatial memory impairments, lasting changes in corticosterone (CORT) secretion, and increased neurogenesis. This study examined dose-related effects of 21-day RSV treatment on markers associated with neurogenesis (DCX, PSA-NCAM) and angiogenesis (CD31) in the hippocampus at short (7-day) and long-term (85-day) intervals following global ischemia. In parallel, post-ischemic and stress-induced CORT levels and spatial memory in the Morris water maze were determined. METHODS: Five groups of male Wistar rats were included: sham/saline, ischemia/saline, ischemia/1 mg/kg RSV, ischemia/10 mg/kg RSV, and sham/10 mg/kg RSV. Changes in expression of plasticity markers were paralleled by assessment of basal- and stress-induced CORT secretions, and spatial memory performance. RESULTS: Our findings revealed a significant attenuation of ischemia-induced DCX/PSA-NCAM expression in RSV-treated rats, whereas RSV treatment increased angiogenesis in the injured CA1 region. RSV attenuated CORT levels 3 days post-ischemia and a trend toward attenuating CORT secretion in response to 15 minutes restraint stress. Increased swimming latencies in the target quadrant during the MWM probe trial in RSV-treated ischemic rats support beneficial effects of RSV on spatial memory retention. DISCUSSION: Our findings uncover time- and dose-related effects of RSV and global ischemia on the regulation of hippocampal plasticity. Changes in neuro- and angiogenesis are consistent with RSV neuroprotective effects, but appear independent of RSV regulatory effects on corticosterone secretion.

Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Progressive microvascular dysfunction in type 2 diabetes mellitus (T2DM) may impair the ability of cerebral vessels to supply blood to brain regions during local metabolic demand, thereby increasing risks of dementia. Having previously demonstrated that resveratrol can enhance vasodilator function in the systemic circulation, we hypothesised that resveratrol could similarly benefit the cerebral circulation. We aimed to determine the most efficacious dose of resveratrol to improve cerebral vasodilator responsiveness (CVR) in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled, balanced crossover intervention, 36 dementia-free, non-insulin dependent T2DM older adults (49-78 years old) consumed single doses of synthetic trans-resveratrol (0, 75, 150, and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to assess CVR to a hypercapnic stimulus, both before and 45 min after treatment. CVR, measured bilaterally in the middle cerebral arteries (MCA) and posterior cerebral arteries (PCA), was expressed as the percentage change in mean blood flow velocity from baseline to the peak velocity attained during hypercapnia. Resveratrol consumption increased CVR in the MCA; mean within-individual changes for each dose from placebo were 13.8 ± 3.5% for 75 mg (P = 0.001), 8.9 ± 3.5% for 150 mg (P = 0.016), and 13.7 ± 3.3% for 300 mg (P < 0.001); only the 75 mg dose was efficacious in the PCA (13.2 ± 4.5%, P = 0.016). CONCLUSIONS: Our results provide the first clinical evidence of an acute enhancement of vasodilator responsiveness in cerebral vessels following consumption of resveratrol in this population who are known to have endothelial dysfunction and sub-clinical cognitive impairment. Importantly, maximum improvement was observed with the lowest dose used. CLINICAL TRIAL REGISTRATION: ACTRN12614000891628 (www.anzctr.org.au).

Use of a dose-response model to guide future clinical trial of benvitimod cream to treat mild and moderate psoriasis.

OBJECTIVE: To investigate the time-dose-response relationship of benvitimod cream after topical administration in patients with mild and moderate psoriasis vulgaris for dosage regimen exploring. METHODS: 36 patients with mild and moderate psoriasis vulgaris were randomly assigned to receive 0.5%, 1.0%, 1.5%, and 0% (placebo) benvitimod cream of 30 g/1.7 m2 twice daily for 6 weeks. The primary efficacy outcome was the proportion of patients achieving more than 75% change of the psoriasis area and severity index (PASI 75) from baseline. A longitudinal Emax model was established using the NONMEM method, and then applied to try to find an appropriate dose for following trials. RESULTS: In the final time-dose-response model, the primary outcome at week 6 of PASI 75 of the 0.5%, 1.0%, and 1.5% benvitimod cream was 31%, 63%, and 75%, respectively, demonstrating that the 1.0% benvitimod cream was an appropriate dose for the next trial. The time parameters of ET50 and ET90 were 15 and 69 days for 1.0% benvitimod cream, indicating that the maximum efficacy of PASI change rate was obtained at approximately week 10. The accuracy of PASI change rate by extrapolation prediction was limited at week 10, so the treatment period should be longer in future trials. CONCLUSIONS: The established dose-response model could well describe the relationship between PASI change rate and doses of benvitimod cream in patients with mild and moderate psoriasis vulgaris. This modeling approach may help choose 1.0% benvitimod cream twice daily as a dosage regimen in following clinical trials.

Efficacy and Tolerability of a Skin Brightening/Anti-Aging Cosmeceutical Containing Retinol 0.5%, Niacinamide, Hexylresorcinol, and Resveratrol.

Consumers are increasingly interested in over-the-counter skin care products that can improve the appearance of photodamaged and aging skin. This 10-week, open-label, single- center study enrolled 25 subjects with mild to moderate hyperpigmentation and other clinical stigmata of cutaneous aging including fine lines, sallowness, lack of clarity, and wrinkling. Their mean age was 53.4±7.7 years. The test product contained retinol 0.5% in combination with niacinamide 4.4%, resveratrol 1%, and hexylresorcinol 1.1% in a moisturizing base. Subjects were provided a skin care regimen including a cleanser, hydrating serum, moisturizer, and an SPF 30 sunscreen for daily use. The test product was applied only at night.

The use of this skin brightening/anti-aging cosmeceutical was found to provide statistically significant improvements in all efficacy endpoints by study end. Fine lines, radiance, and smoothness were significantly improved as early as week 2 (P<.001). By week 4, hyperpigmentation, overall skin clarity, evenness of skin tone, and wrinkles showed statistically significant improvement compared to baseline. Mild retinoid dermatitis including flaking and redness occurred early in the study as reflected by tolerability scores. By week 10, subjects reported no stinging, itching, dryness, or tingling.

The results of this open-label clinical study suggest that a topical cream containing retinol 0.5% in combination with niacinamide, resveratrol, and hexylresorcinol is efficacious and tolerable for skin brightening/anti-aging when used with a complementary skin care regimen including SPF 30 sun protection.

J Drugs Dermatol. 2016;15(7):863-868.