Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial.

Background: Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients. Methods: Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed. Results: We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% vs. 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% vs. 66%, P=0.586), and overall response rate (69% vs. 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%). Conclusions: Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients. Trial Registration: ClinicalTrials.gov identifier: NCT04873284.

Cost-effectiveness analysis of dinutuximab ß for the treatment of high-risk neuroblastoma in China.

BACKGROUND: Dinutuximab ß can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab ß is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab ß in children with high-risk NB is of high importance. METHODS: The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab ß (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. RESULTS: Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab ß was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. CONCLUSION: Results found that dinutuximab ß is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.

Neutrophil to lymphocyte rate and serum prealbumin maybe predictors for abnormal high blood pressure caused by adrenocorticotropic hormone therapy in children with epileptic spasms: two cases report.

Epileptic spasms are a catastrophic form of epilepsy. When epileptic spasms occur under 2-year-old, they may be also called "infantile spasms". Adrenocorticotropic hormone (ACTH) is recommended as first line intervention for the treatment of epileptic spasms without tuberous sclerosis complex. The chief risks of ACTH therapy are immunosuppression and hypertension. We reported rare cases of abnormal high blood pressure in two male epileptic spasms patients during ACTH therapy. Both patients' blood pressure reached a high blood pressure stage 2 on the 9th day and 10th day of ACTH treatment, respectively. The blood pressure returned to normal range after the drug dosage was reduced or stopped. The lower level of neutrophil%, neutrophil count, and a higher level of lymphocyte%, lymphocyte count and prealbumin than normal range were observed in both patients before ACTH therapy. The neutrophil to lymphocyte rate might be a predictor for high blood pressure among patients treated with ACTH. The rates of both patients were under 0.50 (0.42 for Case 1 and 0.17 for Case 2). We reported the documented cases in two Chinese pediatric patients who suffered from epileptic spasms treated with ACTH resulted in abnormal high blood pressure, which could be predicted by using neutrophil to lymphocyte rate. We also mentioned serum prealbumin might be another predictor. More clinical data is required to elucidate the relationship between serum prealbumin level and blood pressure.

Grape seed proanthocyanidin extract reverses multidrug resistance in HL-60/ADR cells via inhibition of the PI3K/Akt signaling pathway.

BACKGROUND AND PURPOSE: Multidrug resistance (MDR) is a great challenge and obstacle in cancer treatment. It is a common problem in the treatment of acute myeloid leukemia (AML). Whether grape seed proanthocyanidin extract (GSPE) could reverse MDR in patients with AML is still unknown. The aim of this study was to investigate the MDR reverse ability of GSPE and its possible mechanism in vitro. MATERIALS AND METHODS: Human leukemia cell line HL-60 cells and HL-ADR cells were used. MTT assay were employed to identify the cytotoxic effects of different chemotherapeutic drugs and reverse ability of GSPE. Flow cytometry assays were used to verify the cell apoptosis induced by GSPE. MDR-related genes expression was tested by real-time polymerase chain reaction (Q-PCR). MDR-related protein expression was assessed by Western blotting assays. The genes and their related protein expression of multidrug resistance-associated protein 1 (MRP1), multidrug resistance protein 1 (MDR1) and lung resistance-related protein (LRP) were tested in this study. KEY RESULTS: We found that HL-60/ADR cells were resistant to a variety of chemotherapeutic drugs, including cytarabine (Ara-C), adriamycin (ADR), vincristine (VCR), daunorubicin (DNR), mitoxantrone (MTZ), pirarubicin (THP), homoharringtonine (HHT) and etoposide (VP16). Co-treatment with GSPE could significant lower the IC50 of Ara-C and ADR in HL-60/ADR cells (P < 0.01). MDR related mRNA and their protein expression of MRP1 and MDR1 were significant highly expressed in HL-60/ADR cells than HL-60 cells (P < 0.01). But only protein expression of LRP was higher in HL-60/ADR cells than HL-60 cells (P < 0.05). GSPE could induce a higher intracellular level of ADR in HL-60/ADR cells. It could also inhibit Akt phosphorylation resulted in the down regulation of MRP1, MDR1 and LRP and induce cell apoptosis. 25.0 µg/mL GSPE significant inhibited the Akt phosphorylation (P < 0.05). CONCLUSION AND IMPLICATIONS: GSPE-reversed MDR of HL-60/ADR cells might be associated with the inhibition of the PI3K/Akt signaling pathway, which resulted in the down-regulation the expression of MRP1, MDR1 and LRP. These results provide that GSPE may serve as a combination therapy in AML chemotherapy for future study.

Protocol for a systematic evaluation of pediatric pharmacy development and pediatric pharmacy experts' research area in China.

BACKGROUND: The pediatric pharmacy research status of children's hospitals in China is still unknown. Our previous findings suggest the regional differences in academic level in tertiary (grade III level A) children's hospitals in China. METHODS: This systemic evaluation described in this protocol will be conducted to follow the Cochrane Handbook. We will perform a systemic literature search of relevant databases including Chinese databases (CNKI, Wanfang Data, VIP Paper Check System) and English databases (Medline, EMbase, Cochrane Library) from inception to December 31, 2018. The search strategy will be enacted according to the guidance offered from the Cochrane Handbook. Two rounds of searches will be conducted to prevent the omission of relevant literature. A pre-set grading standard will be used to give calculation weight (W) to evaluate the quality of each article. Data synthesis will be performed using STATA software (version 13.1, Statacorp, College Station, Texas). Pediatric pharmacy development index (PPDI) of each hospital will be used to evaluate the pediatric pharmacy development in each tertiary children's hospitals. The cumulative calculation weight (∑W) and annual calculation weight (∑yearW) will be used to evaluate the academic level of pharmaceutical departments in different tertiary children's hospitals. Subgroup analysis will be performed to compare the number of different types of articles published between different hospitals base on different research areas such as policy research, basic research, and clinical research. RESULTS: In this article, we will evaluate pediatric pharmacy development and the research area of pediatric pharmacy experts in China. Based on the results from this research, we will analyze the professional backgrounds of pediatric pharmacy experts from 23 tertiary children's hospitals in China. According to the contents and research directions of literature published by the pediatric pharmacy experts in these 23 hospitals, we will determine the professional field of pediatric pharmacy experts and establish an expert database. In the process of formulating the related national or local policies in the future, the expert database will be selected accurately to reach the expert consensus. CONCLUSION: Our study will provide a comprehensive picture of pediatric pharmacy development in China. The pediatrics pharmacy expert's database constructed by this study will be used to build consensus on pediatric pharmacology in the future.

Warfarin and the Risk of Death, Stroke, and Major Bleeding in Patients With Atrial Fibrillation Receiving Hemodialysis: A Systematic Review and Meta-Analysis.

Background: Up to date, the efficacy and safety of warfarin treatment in atrial fibrillation patients receiving hemodialysis remain controversial. So we performed this meta-analysis to try to offer recommendations regarding warfarin management in this population. Methods: We searched Pubmed, Embase, and Cochrane library and reviewed relevant reference lists from 1980 to March 2018. Studies were included if they described the risks of mortality, stroke, and bleeding events with or without warfarin in atrial fibrillation patients receiving hemodialysis. Results: Overall, the use of warfarin was not associated with mortality (OR = 0.95, 95%CI = 0.89-1.02), stroke (OR = 1.06, 95% CI = 0.87-1.30) and ischemic stroke (OR = 0.85, 95% CI = 0.68-1.05), but its use could increase the risks of hemorrhagic stroke (OR = 1.34, 95% CI = 1.13-1.59) and major bleeding (OR = 1.24, 95% CI = 1.14, 1.35). In subgroup analyses, when analyses were mainly restricted to atrial fibrillation patients who were undergoing hemodialysis and taking other anticoagulation agents, warfarin therapy didn't reduce the risks for mortality (OR = 0.98, 95% CI = 0.68-1.42) and ischemic stroke (OR = 1.03, 95% CI = 0.89-1.19), but significantly increased the risks of stroke (OR:1.14, 95% CI = 1.01-1.29) and bleeding events such as hemorrhagic stroke (OR = 1.42, 95% CI = 1.14-1.77) and major bleeding (OR = 1.24, 95% CI = 1.14-1.35). While in patients who didn't take other anticoagulation agents or aspirin, warfarin use was not associated with all-cause mortality (OR = 0.90, 95% CI = 0.78-1.04), or any stroke (OR = 1.00, 95% CI = 0.71-1.40). Its use was associated with significantly decreased risk of ischemic stroke (OR = 0.71, 95% CI = 0.60-0.85), but not associated with hemorrhagic stroke (OR = 1.45, 95% CI = 0.83-2.55). Besides, another subgroup analysis showed that warfarin therapy didn't exert a protective role in patients with normal serum lipid levels (OR = 1.04, 95% CI = 0.85-1.26), but seemed to decrease the risk of ischemic stroke in patients with hyperlipidemia (OR = 0.38, 95% CI = 0.11-1.29). Conclusion: Our results suggested that it was necessary to prescribe warfarin for the prevention of ischemic events in hemodialysis patients with atrial fibrillation, but if these patients were already prescribed with other anticoagulants for the treatment of other co-existing diseases, then warfarin was not recommended.

α4ß7 integrin inhibitors: a patent review.

INTRODUCTION: The α4ß7 integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α4ß7 integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α4ß7 integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α4ß7 integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α4-subunit blocking both α4ß1 and α4ß7 integrin. Vedolizumab selectively targets the α4ß7 integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the ß7-subunit and AMG-181 specifically against the α4ß7 integrin are the most promising anti-α4ß7 integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α4ß7 integrin inhibitors.

Clinical adverse effects of sodium-glucose cotransporter 2 inhibitors: Protocol for a systematic review and meta-analysis.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antidiabetic drugs, which mainly increase urinary glucose excretion through reducing renal glucose reabsorption. There is still a concern about the overall safety profile of SGLT2 inhibitors. In this systematic review and meta-analysis, we will assess the clinical adverse effects of SGLT2 inhibitors in type 2 diabetes mellitus. METHODS: This systemic review and meta-analysis described in this protocol will be conducted to follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We will search Medline, EMbase, the Cochrane library and the ClinicalTrials.gov Website from 1946 to June 2018. Studies will be screened by title, abstract, and full text independently in duplicate. Double-blinded, placebo-controlled, and randomized controlled trials reporting safety data of SGLT2 inhibitors will be eligible for inclusion. Outcomes will include adverse events (AEs) varying degrees and AEs occurring in ≥3% patients or AEs aroused concerns by the Food and Drug Administration (FDA). The assessment of risk bias and data synthesis will be performed using STATA software (version12, Statacorp, College Station, TX). Outcomes will be reported by risk ratios for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes and their 95% confidence intervals. Subgroup, sensitivity, regression analyses will be performed to evaluate intertrial heterogeneity and bias of the results. I statistic will be used to evaluate heterogeneity among studies. RESULTS: This systemic review and meta-analysis will evaluate AEs occurring in ≥3% patients or AEs aroused concerns by the FDA of SGLT2i as compared to placebo. CONCLUSION: Our study will provide a comprehensive picture of AEs of SGLT2 inhibitors.

Clinical adverse effects of natalizumab: Protocol for a meta-analysis of randomized double-blind placebo-controlled clinical trails.

BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, which binds in both α4ß1 integrins and α4ß7 integrins, is approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). An uncommon but serious adverse event from NAT treatment is known as progressive multifocal leukoencephalopathy (PML). However, clinical comprehensive safety evidence of NAT is limited. METHODS: We will search Medline, Embase, Cochrane library, and ClinicalTrials.gov website from inception to May 9, 2018. Double-blind, randomized placebo-controlled trials reporting safety data of NAT will be eligible for inclusion. Outcome variables will include adverse events (AEs) varying degrees and AEs occurring in ≥ 5% patients with NAT or placebo. STATA software (version 12, Statacorp, College Station, TX) will be utilized to assess risk of bias and synthesize data. Outcomes will be reported by weight mean difference (WMD), risk ratios (RRs), and their 95% confidence intervals (95% CIs). I statistic will be used to evaluate heterogeneity among studies. RESULTS: This systemic review and meta-analysis will evaluate serious AEs and AEs of NAT as compared to placebo. CONCLUSION: Our study will provide a comprehensive picture of AEs of NAT.

A Review on Clinical Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Natalizumab: A Humanized Anti-α4 Integrin Monoclonal Antibody.

BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4ß1 and α4ß7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT. METHODS: We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017). RESULTS: Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS. CONCLUSION: As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.

The pharmacokinetic profiles of dexamethasone and methylprednisolone concentration in perilymph and plasma following systemic and local administration.

CONCLUSION: Both methylprednisolone (MTH) and dexamethasone (DEX) could successfully and effectively penetrate the round window membrane (RWM) into perilymph. RWM topical application and otocyst infusion with MTH and DEX result in high perilymph drug concentrations and low plasma levels. An intratympanic administration schedule for DEX or MTH could be carried out twice daily. OBJECTIVE: To explore the pharmacokinetics of DEX and MTH in the inner ear fluids and plasma following systemic and local administration. MATERIALS AND METHODS: Three routes of administration of steroids were used in guinea pigs: intracardial injection, otocyst infusion and RWM topical application by granule gelfoam soaked with steroids. Samples of blood or perilymph of the scala tympani were collected at 1-6 h after administration. High-performance liquid chromatography was used to assay concentrations of steroids. RESULTS: Both the topical application and infusion administration resulted in a significantly higher concentration of steroids in perilymph than intracardial injection. The level of steroids in the perilymph reached a peak at 1-2 h after dosing, and this was maintained at a relatively high level for several hours. The intracardial injection with steroids yielded very low perilymph levels at all sampling times after administration.