Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.

BACKGROUND: There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet®; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta®; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations. DESIGN: Systematic review and cost-effectiveness analysis. SETTING: Secondary care. PARTICIPANTS: Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery. INTERVENTIONS: Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl). MAIN OUTCOME MEASURES: Risk of platelet transfusion and rescue therapy or risk of rescue therapy only. REVIEW METHODS: Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019. ECONOMIC EVALUATION: Model-based cost-effectiveness analysis. RESULTS: From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective. LIMITATIONS: Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag. CONCLUSIONS: Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost. FUTURE WORK: A head-to-head trial is warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019125311. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.

Thrombocytopenia, which is a reduction in platelet numbers in the blood, is a common complication of chronic liver disease. It increases the risk of bleeding during procedures including liver biopsy and transplantation. It can delay or prevent procedures, leading to illness and death. Established treatment largely involves platelet transfusion before the procedure or as rescue therapy for bleeding. This report aims to systematically review the clinical effectiveness and estimate the cost-effectiveness of the first two recently licensed treatments, thrombopoietin receptor agonists avatrombopag (Doptelet^®; Dova Pharmaceuticals, Durham, NC, USA) (60 mg if platelet count is < 40,000/µl and 40 mg if platelet count is 40,000­< 50,000/µl) and lusutrombopag (Mulpleta^®; Shionogi Inc., London, UK) (3 mg if platelet count is < 50,000/µl), compared with established treatment. From a comprehensive search, six studies were included. Clinical effectiveness analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy. Only avatrombopag seemed superior to no thrombopoietin receptor agonist in reducing rescue therapy alone. Cost-effectiveness analysis found that lusutrombopag and avatrombopag were more expensive than no thrombopoietin receptor agonist over a lifetime, as the savings from avoiding platelet transfusions were exceeded by the drug cost, and without long-term health benefits. The probabilistic sensitivity analysis, which examined the effect of uncertainty, showed that no thrombopoietin receptor agonist had 100% probability of being cost-effective. Uncertainty about the price of avatrombopag and the content and costs of platelet transfusions and the potential under-reporting of use to estimate platelet transfusion-specific mortality had the greatest impact on results. If the price of avatrombopag was (confidential information has been removed) below the price of lusutrombopag, avatrombopag would become cost saving in the 40,000­< 50,000/µl subgroup. However, although in some scenarios avatrombopag costs could decrease in the 40,000­< 50,000/µl subgroup to around 10% more than the cost of no thrombopoietin receptor agonist, there would be negligible health benefits and the incremental cost-effectiveness ratios would remain very high, meaning that lusutrombopag and avatrombopag would still not be considered cost-effective.

A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer.

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACRSee related commentary by Jordan, p. 3480.

Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor.

SCOPE: Aberrant vascular smooth muscle cell (VSMC) proliferation is involved in atherosclerotic plaque formation and restenosis. Mediterranean spices have been reported to confer cardioprotection, but their direct influence on VSMCs has largely not been investigated. This study aims at examining rosmarinic acid (RA) and 11 related constituents for inhibition of VSMC proliferation in vitro, and at characterizing the most promising compound for their mode of action and influence on neointima formation in vivo. METHODS AND RESULTS: RA, rosmarinic acid methyl ester (RAME), and caffeic acid methyl ester inhibit VSMC proliferation in a resazurin conversion assay with IC50 s of 5.79, 3.12, and 6.78 µm, respectively. RAME significantly reduced neointima formation in vivo in a mouse femoral artery cuff model. Accordingly, RAME leads to an accumulation of VSMCs in the G0 /G1 cell-cycle phase, as indicated by blunted retinoblastoma protein phosphorylation upon mitogen stimulation and inhibition of cyclin-dependent kinase 2 in vitro. CONCLUSION: RAME represses PDGF-induced VSMC proliferation in vitro and reduces neointima formation in vivo. These results recommend RAME as an interesting compound with VSMC-inhibiting potential. Future metabolism and pharmacokinetics studies might help to further evaluate the potential relevance of RAME and other spice-derived polyphenolics for vasoprotection.

UV-selective face cream (Acne RA-1,2) in acne patients: clinical study of its effects on epidermal barrier function, sebum production, tolerability and therapy adherence.

BACKGROUND: General skin care recommendations such as the use of moisturizers and products with adequate photoprotection are important components of management for acne patients to complement the medical regimen. This study aimed to evaluate the real-life clinical effects of a novel UV-selective face cream (Acne RA-1,2, Meda Pharma, Solna, Sweden) on acne, epidermal barrier function, sebum production, adherence and tolerability when used together with pharmacological acne treatment. METHODS: Forty patients receiving pharmacological acne treatment applied Acne RA-1,2 once-daily for three months. Investigator's Global Assessment of acne, trans-epidermal water loss, sebum production and tolerability were assessed at one and three months. RESULTS: After 3 months, there was a 38% significant clinical improvement in mean Investigator Global Assessment score (3.4 to 2.1), a 29% significant reduction in trans-epidermal water loss (13.2 to 9.4 g/h/m2), and a 17% significant decrease in sebum production vs. baseline (234.6 to 195.6 µg/cm2; all P<0.01). One hundred percent of patients reported complete adherence to pharmacological therapy over the summer of the study vs. 52.5% in the previous summer. About 87.5% of patients considered their acne improved over the summer of the study, vs. 55.0% in the previous summer. Pruritus, erythema, dryness and total tolerability symptom scores were significantly reduced after 3 months vs. baseline (P<0.05). CONCLUSIONS: Acne RA-1,2 is a useful daily adjunct to pharmacological therapy as it helps to mitigate the irritation these therapies cause, increasing adherence to therapy, and leading to a clinical improvement in acne and epidermal barrier function and a decrease in sebum production.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

A randomized, placebo-controlled trial of beloranib for the treatment of hypothalamic injury-associated obesity.

AIMS: Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4. RESULTS: Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2 and weight of 126 (22) kg. Compared with placebo (N = 4), beloranib 1.8 mg (N = 8) resulted in a mean (95% CI) difference in weight of -3.2 (-5.4, -0.9) kg after 4 weeks. Weight loss continued through the 8 weeks in patients randomized to beloranib (mean -6.2 [-8.2, -4.1] kg). Beloranib treatment was associated with improvements in high-sensitivity CRP. Adverse events were mild to moderate. No patients who received beloranib discontinued treatment. CONCLUSION: Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.

Acne RA-1,2, a novel UV-selective face cream for patients with acne: Efficacy and tolerability results of a randomized, placebo-controlled clinical study.

BACKGROUND: General skincare measures such as the use of moisturisers and products containing adequate photoprotection are important components of acne patients' management to complement the pharmacological regimen. Acne RA-1,2 is a novel dermato-cosmetic product which contains selective photofilters and active ingredients against the multifactorial pathophysiology of acne. OBJECTIVES: To evaluate the tolerability of Acne RA-1,2 and its effect on the clinical signs of acne. METHODS: This double-blind, placebo-controlled study randomized 40 adult patients with 10-25 comedones per half face to once-daily application of Acne RA-1,2 or placebo for 8 weeks. Evaluations after 4 and 8 weeks included the number of comedones, transepidermal water loss (TEWL), sebum production, and tolerability. RESULTS: In the Acne RA-1,2 group, there was a significant 35% decrease in the mean number of comedones from 26 at baseline to 17 at Week 8 (P<.001), a 7% significant reduction in TEWL (9.32 to 8.66 g/h/m2 ; P<.001), and a 24% significant reduction in sebum production (154.8 to 117.6 µg/cm2 ; P<.001). The reductions in TEWL and sebum production were significantly greater than those in the placebo group at Weeks 4 and 8 (P<0.05). There were no adverse events. CONCLUSIONS: Acne RA-1,2 was well tolerated and effective at reducing comedones and sebum production and improving epidermal barrier function. These results suggest that Acne RA-1,2 is useful against acne-prone facial skin, particularly as it targets sebum production, which topical pharmacological acne therapies do not address.

Lusutrombopag: First Global Approval.

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.

Hydrophobicity and antioxidant activity acting together for the beneficial health properties of nordihydroguaiaretic acid.

Nordihydroguaiaretic acid (NDGA) and rosmarinic acid (RA), phenolic compounds found in various plants and functional foods, have known antioxidant and anti-inflammatory properties. In the present study, we comparatively investigated the importance of hydrophobicity and oxidisability of NDGA and RA, regarding their antioxidant and pharmacological activities. Using a panel of cell-free antioxidant protocols, including electrochemical measurements, we demonstrated that the anti-radical capacities of RA and NDGA were similar. However, the relative capacity of NDGA as an inhibitor of NADPH oxidase (ex vivo assays) was significantly higher compared to RA. The inhibitory effect on NADPH oxidase was not related to simple scavengers of superoxide anions, as confirmed by oxygen consumption by the activated neutrophils. The higher hydrophobicity of NDGA was also a determinant for the higher efficacy of NDGA regarding the inhibition of the release of hypochlorous acid by PMA-activated neutrophil and cytokine (TNF-α and IL-10) production by Staphylococcus aureus-stimulated peripheral blood mononuclear cells. In conclusion, although there have been extensive studies about the pharmacological properties of NDGA, our study showed, for the first time, the importance not only of its antioxidant activity, but also its hydrophobicity as a crucial factor for pharmacological action.

Antinociceptive and anti-inflammatory effects of rosmarinic acid isolated from Thunbergia laurifolia Lindl.

Rosmarinic acid (RA) was isolated from an ethanolic extract of Thunbergia laurifolia leaves. The antinociceptive activity of RA was assessed in mice using hot-plate, acetic acid-induced writhing, and formalin tests. The anti-inflammatory effects of RA were determined in two mouse models of carrageenan-induced paw edema and cotton pellet-induced granuloma formation. Orally administered RA (50, 100, and 150 mg/kg) showed significant (p<0.001) antinociceptive activity in the hot-plate test and this effect was reversed by naloxone. RA at doses of 50 and 100mg/kg significantly reduced acetic acid-induced writhing by 52% (p<0.01) and 85% (p<0.001), respectively, and RA at 100mg/kg also caused significant inhibition of formalin-induced pain in the early and late phases (p<0.01 and p<0.001, respectively). RA at 100mg/kg significantly suppressed carrageenan-induced paw edema at 3, 4, 5 and 6h after carrageenan injection (p<0.01, p<0.05 p<0.01, and p<0.05, respectively) and showed significant activity against PGE2-induced paw edema. RA at 100mg/kg also inhibited cotton pellet-induced granuloma formation in mice. Taken together, these results demonstrate that RA possesses both central and peripheral antinociceptive activities and has anti-inflammatory effects against acute and chronic inflammation. While further evaluation regarding the safety profile of RA is needed, these data may provide a basis for the rational use of RA and T. laurifolia for treatment of pain and inflammatory disorders.

Molecular mechanism depressing PMA-induced invasive behaviors in human lung adenocarcinoma cells by cis- and trans-cinnamic acid.

Dietary polyphenols have been reported as an effective phytochemical for health protection and cinnamic acid (CA) is one of the polyphenols that has been demonstrated having chemopreventive potential. It was known that the early and distal metastasis might lead to the high mortality of patients with lung adenocarcinoma. We previously compared and verified the inhibitory effect of cis-CA and trans-CA on phorbol-12-myristate-13-acetate (PMA)-induced invasion of human lung adenocarcinoma A549 cells. The aim of this study was to explore the underlying molecular mechanism. By gelatin zymography and semi-quantitative RT-PCR, the activities and mRNA of MMP-9/MMP-2 exerted a significantly (p<.05) dose-dependent reduction by treating with cis-CA and trans-CA. Western blots further showed that the cis-CA- and trans-CA-inhibited MMPs might partly through modulating TIMP-1 and the PAI-2-regulated uPA activity. In molecular level, the AP-1 and NF-κB as well as the downstream of the MAPK pathway might be involved in cis-CA- and trans-CA-inhibited MMPs expression. This study disclosed the molecular mechanism underlying the anti-invasive activity of cis-CA and trans-CA and concluded the cis- and trans-form of CA should be a safe and potential agent to prevent lung tumor cells from metastasizing.

Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters.

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.

Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model.

Although cisplatin attacks various tumors with remarkable efficacy, its clinical usage has been limited by its side effects, particularly nephrotoxicity. Salubrinal, a selective eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation inhibitor, has been found to protect cells from endoplasmic reticulum (ER)-stress-induced cytotoxicity. In this study, we hypothesized that salubrinal would protect against cisplatin-induced nephrotoxicity in a mouse model. Cisplatin treatment significantly increased serum blood urea nitrogen and creatinine levels, renal kidney injury marker (kim-1) mRNA expression, renal cell apoptosis, and renal histopathological changes in mice. Unexpectedly, administration of salubrinal significantly enhanced the cisplatin-induced nephrotoxicity in mice. Salubrinal by itself did not induce alterations in the function or histomorphology of mouse kidneys. Salubrinal significantly enhanced the phosphorylation of eIF2α, the protein expression of activating transcription factor 4 and CCAAT/enhancer binding protein homologous protein, and the cleavage of caspases 12, 9, and 3 in the kidneys of cisplatin-treated mice. Moreover, salubrinal enhanced the cisplatin-induced oxidative stress in the kidneys. The antioxidant N-acetylcysteine significantly reversed the increased renal lipid peroxidation, activated renal caspase cascade, and increased blood BUN and creatinine in cisplatin-alone- or cisplatin plus salubrinal-treated mice. These findings suggest that salubrinal aggravates cisplatin-induced nephrotoxicity through the enhancement of oxidative stress and ER stress-related cell apoptosis.

Anti-nociceptive effects of Carpolobia lutea G. Don (Polygalaceae) leaf fractions in animal models.

Leaves from Carpolobia lutea (Polygalaceae) were screened to establish the antiulcer ethnomedicinal claim and to quantitatively isolate, elucidate the active compounds by semi-preparative HPLC. The anti-nociceptive effects of Carpolobia lutea (CL) G. Don (Polygalaceae) organic leaf extracts were tested in experimental models in mice. The anti-nociceptive mechanism was determined using tail-flick test, acetic acid-induced abdominal constrictions, formalin-induced hind paw licking and the hot plate test. The fractions (ethanol, ethyl acetate, chloroform, n-hexane) and crude ethyl acetate extract of CL (770 mg/kg, i.p.) produced significant inhibitions of both phases of the formalin-induced pain in mice, a reduction in acetic acid-induced writhing as well as and an elevation of the pain threshold in the hot plate test in mice. The inhibitions were greater to those produced by indomethacin (5 mg/kg, i.p.). Ethyl acetate fraction revealed cinnamic and coumaric acids derivatives, which are described for the first time in literature. These cinnamalglucosides polyphenols characterised from CL may in part account for the pharmacological activities. These findings confirm its ethnomedical use in anti-inflammatory pain and in pains from gastric ulcer-associated symptoms.

A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer.

We conducted a phase I trial of the antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate (CKD-732). Our aims were to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profiles as well as identify the biologically active dose (BAD) from ex vivo pharmacodynamics (PD) and biomarkers of CKD-732. Using a dose escalation schedule, 19 patients with refractory solid tumors were enrolled at dose levels of CKD-732 ranging from 1 to 15 mg/m(2) given twice weekly for 2 weeks followed by a 1-week rest. No treatment-related deaths occurred in this study. Confusion and insomnia were dose-limiting toxicities (DLTs), and MTD was 15 mg/m(2). The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m(2) according to ex vivo PD. A decrement in soluble vascular endothelial growth factor receptor-3 (sVEGF-3) level was correlated with a reduction in tumor size (r = 0.54, P = 0.045). The results from this study showed an MTD of 15 mg/m(2) and a BAD of 5 mg/m(2).

Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21(WAF1) expression.

Pathological angiogenesis is the most common cause of blindness at all ages including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Despite advances in therapy, retinopathy of prematurity remains the most sight-threatening vaso-proliferative retinopathy in children. Herein, we demonstrated that rosmarinic acid has an anti-angiogenic activity to retinal neovascularization in a mouse model of retinopathy of prematurity, which is related to cell cycle arrest with increase of p21(WAF1). Rosmarinic acid significantly inhibited the proliferation of retinal endothelial cells in a dose-dependent manner, and inhibited in vitro angiogenesis of tube formation. Interestingly, the anti-proliferative activity of rosmarinic acid on retinal endothelial cells was related to G2/M phase cell cycle arrest in a dose-dependent manner. With treatment of rosmarinic acid, retinal endothelial cells in G2/M phase increased whereas those in G0/G1 and S phases decreased, which was accompanied by increase of p21(WAF1) expression in a dose-dependent manner. Moreover, rosmarinic acid effectively suppressed retinal neovascularization in a mouse model of retinopathy of prematurity, and showed no retinal toxicity. These data suggest rosmarinic acid could be a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.