Efficacy and safety of Chinese patent medicines combined with antidepressants for treatment of depression in adults: A multiple-treatment meta-analysis.

BACKGROUND: Combinations of Chinese patent medicines (CPM) with antidepressants (including selective serotonin reuptake inhibitors (SSRI), selective serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), and noradrenergic and specific serotonergic antidepressants (NaSSA)) are frequently utilized for treating depression in adults. However, the efficacy and safety of these combination treatments remain to be established. METHODS: Systematic search was conducted in seven electronic databases, regulatory websites and international registers of trials from 1994 to 2023 that included adult patients with depressive disorders who received CPM combined with antidepressants. The Multiple-Treatment Meta-Analysis (MTMA) was conducted using a random effects model with Stata/MP17 and R4.3.5 software. Primary outcomes were total efficacy rate, Hamilton Depression Scale (HAMD) score, and Treatment Emergency Symptom Scale (TESS) score. Secondary outcomes included brain-derived neurotrophic factor (BDNF) levels. RESULTS: A total of 146 randomized controlled trials (13,754 participants: 6929 in intervention and 6825 in control groups) were included. For total effective rate, Multiple-Treatment Meta-Analysis results showed that the overall effect of combined intervention was better compared with antidepressants alone, where Jieyuanshenkeli (JYASKL) presented the optimal option for improving total efficacy (OR = 5.39, 95% CI [2.60, 11.18], SUCRA = 84.50%). In reduding the HAMD, Shuganjieyujiaonang (SGJYJN) was most likely to reduce the HAMD score (SMD = -2.20, 95% CI [-3.06, -1.33], SUCRA = 86.10%), Jieyuanshenkeli (JYASKL),Tianewangbuxindan (TWBXD), Shuyukeli (SYKL), Anshenbuxinwan (ASBXW) combination intervention did not appear to be statistically superior to antidepressants alone. In theTreatment Emergency Symptom Scale (TESS), Wulinjiaonang induced the most significant reduction in TESS score (SMD = -1.98, 95% CI [-3.59, -0.36], SUCRA = 90.40%). Tianmengjiaonang (TMJN) + Antidepressants(AD) (SUCRA = 88.30%) displayed the highest scores in increasing the levels of BDNF, although not statistically significant compared to Antidepressants(AD) alone (SMD = 1.23, 95% CI [0.90, 1.55]). CONCLUSION: Combinations of CPM and antidepressants showed superior efficacy over antidepressants alone. The optimal combinations were determined as Shuganjieyu Jiaonang (SGJYJN)/SSRIs and Jieyuanshenkeli (JYASKL)/SSRIs. In terms of safety, results showed that combination therapy did not show better TESS efficacy than antidepressants alone.Although some of the combination interventions were not superior than antidepressants alone in reducing HAMD scores,our findings provide a potentially significant alternative option for clinical complementary therapy. However, these results require further validation through larger sample sizes, multicenter randomized controlled trials, and real-world data.

A numerical investigation of the behavior of a tunnel with adaptive anti-dislocation measures subjected to the action of fault dislocation.

In the context of long-distance cross-basin water transfer projects, the water conveyance tunnel serves as a pivotal component in mitigating regional disparities between economic development and water resources allocation. However, in high seismic-intensity areas of southwest China, geological complexities and densely distributed active faults present formidable challenges. Consequently, the construction of water conveyance tunnels necessitates traversing one or more active fault zones. This study examines the impact of an adaptive tunnel structure in the presence of fault dislocation, focusing on the Xianglushan Tunnel, a constituent of the Central Yunnan Water Diversion Project. Taking the Longpan-Qiaohou Fault F10-1 as a case study, we assess the influence of active faults on the anti-dislocation adaptive structure of the Xianglushan Tunnel, considering factors such as displacement, relative deformation, maximum principal stresses, and longitudinal equivalent internal force in critical tunnel sections. Numerical calculations validate the efficacy of this adaptive structure in reducing induced internal forces and deformations of the tunnel lining. The results show that, under the influence of strike-slip dominated fault movement, one side of the tunnel exhibits tensile stress, with a magnitude of approximately 5 MPa. The maximum normal and tangential deformation of the hinge joint is concentrated in the central section of the fault zone. The incorporation of an articulated adaptive design significantly enhances the stress state of lining under dislocation condition. These research results directly inform the engineering design and construction of water conveyance tunnels traversing active fault regions, providing valuable guidance for related tunnel construction endeavors.

Cognitive-Based Interventions for Improving Psychological Health and Well-Being for Parents of Children with Developmental Disabilities: A Systematic Review and Meta-analysis.

This review aims to systematically summarize existing evidence to determine the effectiveness of cognitive-based interventions (CBIs) on psychological health and well-being among parents of children with developmental disabilities (DD). Six databases were searched to identify eligible randomized controlled trials (RCTs) from their inception to April 2023. The revised Cochrane Risk of Bias tool for RCTs was applied to assess the risk of bias and the certainty of evidence was evaluated using the Grading of Recommendation, Assessment, Development and Evaluation. Meta-analyses were conducted using a random-effects model. Twenty-five RCTs involving 1915 participants were identified. The results indicated that CBIs reduced parental stress levels (Hedges' g = - 0.69), depressive symptoms (g = - 0.95), anxiety levels (g = - 0.78), and parental distress (g = - 0.29), and improved parental well-being (g = 0.62) and parent‒child relationships (g = 0.43) postintervention compared with the active/inactive control groups. Subgroup analysis of the effectiveness of interventions using mindfulness-based interventions and cognitive behavioural therapy showed positive effects. The favourable intervention duration and participant targets were also identified in this review. Furthermore, the effects of CBIs were impacted by the different types of DD among the children. This review highlighted the positive effects of CBIs on parental stress levels, depressive symptoms, anxiety levels, parental distress levels, parental well-being levels, and parent‒child relationships. Future well-designed RCTs are needed to further investigate the effects of MBIs and CBT interventions on children with DD and their parents, as well as the factors and mechanisms of action affecting the efficacy of these interventions.

Cost-effectiveness of sacituzumab govitecan versus chemotherapy in patients with relapsed or refractory metastatic triple-negative breast cancer.

BACKGROUND: The effectiveness of sacituzumab govitecan for metastatic triple-negative breast cancer (TNBC) has been reported in recent research, however, the value of the effectiveness and cost of sacituzumab govitecan is still unclear. METHODS: A microsimulation model was developed using data from the ASCENT trial to assess the cost-effectiveness of sacituzumab govitecan for patients with relapsed or refractory metastatic TNBC over a lifetime. Model inputs, including clinical data, patient characteristics, and direct medical costs, were based on the ASCENT trial, public databases, and published literature. The primary outcomes of the model were the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). Univariate and probabilistic sensitivity analysis (PSA) and multiple scenario analyses were performed to address the uncertainty of the model. RESULTS: Our results revealed that sacituzumab govitecan versus chemotherapy costs $293,037 and yielded an additional 0.2340 of QALYs in the whole population with metastatic TNBC, leading to an ICER of $1,252,295 gained. And in the population with metastatic TNBC without brain metastasis, the sacituzumab govitecan versus chemotherapy costs $309,949 and obtained an extra 0.2633 of QALYs, which resulted in an ICER of $1,177,171/QALYs. Univariate analyses indicated that the model outcomes were most sensitive to the drug cost of sacituzumab govitecan, the utility of progression-free disease, and the utility of progressed disease. CONCLUSION: From the US payer perspective, sacituzumab govitecan is unlikely to be a cost-effective option for patients with relapsed or refractory metastatic TNBC compared with chemotherapy. Based on the value standpoint, a price decrease of sacituzumab govitecan is expected to increase the cost-effectiveness of sacituzumab govitecan in patients with metastatic TNBC.

Comparative efficacy of various CHIs combined with western medicine for non-small cell lung cancer: A bayesian network meta-analysis of randomized controlled trials.

Background: Given the limitations of Western medicine (WM) for the treatment of non-small cell lung cancer (NSCLC) and the wide exploration of Chinese herbal injections (CHIs), systematically evaluate the efficacy of Various CHIs Combined with WM for Non-small Cell Lung Cancer. In this study, we performed a network meta-analysis to evaluate the comparative efficacy of 16 CHIs combined with WM regimens for the treatment of NSCLC. Methods: Literature databases were searched from their inception to November 2021, and all randomized control trials (RCTs) involving NSCLC patients treated with a combination of Chinese and WM were retrieved. Outcomes, including disease control rate, survival quality score, incidence of gastrointestinal adverse reactions, incidence of leukopenia, and incidence of thrombocytopenia, were analyzed using RevMan (5.3), Stata17, and R software. Surface under the cumulative ranking curve (SUCRA) probability values were calculated to rank the treatments examined, and clustering analysis was used to compare the effects of CHIs on different outcomes. Results: A total of 389 studies involving 31,263 patients and 16 CHIs were included. The 16 CHIs were: Aidi injection (ADI), Huachansu injection (HCSI), oil of Ophiopogon injection (OOMI), disodium cantharidinate and vitamin B6 injection (DCI), Shenfu injection (SFI), Shenmai injection (SMI), Shenqi Fuzheng injection (SQFZI), Chansu injection (CSI), Delisheng injection (DLSI), Fufang Kushen injection (FFKSI), Huangqi injection (HQI), Kangai injection (KAI), Kanglaite injection (KLTI), Shengmai injection (SI), Xiangguduotang injection (XGDTI), and Xiaoaiping injection (XAPI). The results of the network meta-analysis showed that, with WM treatment as a co-intervention, CSI was most likely to improve the disease control rate (SUCRA = 80.90%), HQI had the highest probability of being the best option for improving the survival quality score (SUCRA = 82.60%), DCI had the highest probability of reducing the incidence of gastrointestinal adverse reactions (SUCRA = 85.50%), HCSI + WM had the highest probability of reducing the incidence of thrombocytopenia (SUCRA = 91.30%), while SMI had the highest probability of reducing the incidence of leukopenia (SUCRA = 79.10%). Conclusion: CHIs combined with WM is proved to be more effective than WM alone, which may be beneficial to NSCLC patients. SMI + WM and DCI + WM are most likely the optimal CHI to improve disease control rates, survival quality score, and reduce adverse effects. This study has limitations; therefore, higher quality RCTs and real-world evidence are required to support our conclusions.

Cost-Effectiveness of Nivolumab Plus Cabozantinib Versus Sunitinib as a First-Line Treatment for Advanced Renal Cell Carcinoma in the United States.

Background: In a recent randomized, phase 3 trial (CheckMate 9ER), nivolumab combined with cabozantinib significantly improved patient outcomes compared with sunitinib. However, the cost-effectiveness of these novel agents for untreated advanced renal cell carcinoma (aRCC) remains unknown. Materials and Methods: We constructed a microsimulation decision-analytic model to measure the healthcare costs and outcomes of nivolumab plus cabozantinib compared with those of sunitinib for patients with aRCC. The transition probability of patients was calculated from CheckMate 9ER using parametric survival modeling. Lifetime direct medical costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated for nivolumab-plus-cabozantinib treatment compared with sunitinib from a US payer perspective. We conducted one-way and probabilistic sensitivity analyses and a series of scenario analyses to evaluate model uncertainty. Results: Nivolumab plus cabozantinib was associated with an improvement of 0.59 LYs and 0.56 QALYs compared with sunitinib. However, incorporating nivolumab plus cabozantinib into first-line treatment was associated with significantly higher lifetime costs ($483,352.70 vs. $198,320.10), causing the incremental cost-effectiveness ratio for nivolumab plus cabozantinib to be $508,987/QALY. The patients' age of treatment, first-line utility, and cost of nivolumab had the greatest influence on the model. The outcomes were robust when tested in sensitivity and scenario analyses. Conclusion: For aRCC, substituting nivolumab plus cabozantinib in the first-line setting is unlikely to be cost-effective under the current willingness-to-pay threshold ($150,000/QALY). Significant price decreases for nivolumab used in first-line therapy would be needed to drop ICERs to a more diffusely acceptable value.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy as first-line therapy for extensive-stage small-cell lung cancer.

BACKGROUND: The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). Taken into account the clinical benefits of pembrolizumab and its high cost, this study aimed to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the US payer perspective. METHODS: A Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examine the robustness of our model. RESULTS: Adding pembrolizumab to standard first-line EP resulted in the better effectiveness than EP chemotherapy alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio (ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerted no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide range of willingness to pay were modest. CONCLUSION: From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compared with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary to improve its cost-effectiveness.

Cost-Effectiveness of Frontline Treatment for Advanced Renal Cell Carcinoma in the Era of Immunotherapies.

Background: Recent randomized controlled trials have demonstrated that immune checkpoint inhibitors (ICIs) improve patient outcomes, but whether these novel agents are cost-effective for untreated advanced renal cell carcinoma (aRCC) remains unclear. Materials and Methods: A microsimulation model was created to project the healthcare costs and outcomes of six strategies (lenvatinib-plus-pembrolizumab, nivolumab-plus-cabozantinib, nivolumab-plus-ipilimumab, pembrolizumab-plus-axitinib, avelumab-plus-axitinib, and sunitinib monotherapy) for patients with aRCC. Transition probability of patients was estimated from CLEAR, CheckMate 9ER, CheckMate 214, KEYNOTE-426, JAVELIN Renal 101, and other data sets by using parametric survival modeling. Lifetime direct medical costs, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated from a United States payer perspective. One-way and probabilistic sensitivity analyses were performed, along with multiple scenario analyses, to evaluate model uncertainty. Results: Of the six competing strategies, nivolumab-plus-cabozantinib yielded the most significant health outcomes, and the sunitinib strategy was the least expensive option. The cost-effective frontier consisted of the nivolumab-plus-cabozantinib, pembrolizumab-plus-axitinib, and sunitinib strategies, which displayed the ordered ICERs of $81282/QALY for pembrolizumab-plus-axitinib vs sunitinib and $453391/QALY for nivolumab-plus-cabozantinib vs pembrolizumab-plus-axitinib. The rest of the strategies, such as lenvatinib-plus-pembrolizumab, nivolumab-plus-ipilimumab, and avelumab-plus-axitinib, were dominated. The cost of sunitinib drove the model most influentially. Conclusions: For aRCC, the pembrolizumab-plus-axitinib strategy is likely to be the most cost-effective alternative at the willingness-to-pay threshold of $100,000.

First-line Daratumumab in Addition to Chemotherapy for Newly Diagnosed Multiple Myeloma Patients Who are Transplant Ineligible: A Cost-Effectiveness Analysis.

PURPOSE: Daratumumab is a standard-of-care treatment for newly diagnosed multiple myeloma (NDMM). According to the ALCYONE trial, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) provides significantly longer overall survival and progression-free survival than bortezomib, melphalan, and prednisone (VMP) in patients with NDMM. However, considering the high price of daratumumab, it is necessary to conduct further research on its efficacy and cost. This study evaluated the cost-effectiveness, from the US payer perspective, of D-VMP vs VMP in the first-line setting for patients with NDMM who are not eligible for autologous stem cell transplantation. METHODS: A Markov model was developed to estimate the lifetime cost and effectiveness of VMP with or without daratumumab as the first-line therapy for patients with NDMM. Univariable sensitivity analysis and probabilistic sensitivity analysis were performed to address the model robustness and uncertainty. Expected value of perfect information analysis was conducted to explore the uncertainty of decision-making and future costs. FINDINGS: D-VMP provides an additional 2.417 quality-adjusted life years (QALYs), at a cost of $30,893 per QALY. Sensitivity analysis revealed that the transition probability of progression-free survival in D-VMP strategy, the price of daratumumab, and body weight of the patient influenced the model results most strongly. Probabilistic sensitivity analysis showed that D-VMP versus VMP has a 90.8% probability of being cost-effective at the $150,000/QALY willingness-to-pay (WTP) threshold. The population expected value of perfect information was $2150 million at a WTP threshold of $50,000/QALY and $1481 million at $100,000/QALY. IMPLICATIONS: In this study, D-VMP was estimated to be cost-effective compared with VMP for patients with NDMM at a WTP threshold of $150,000/QALY.

Cost-Effectiveness of Lorlatinib as a First-Line Therapy for Untreated Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.

INTRODUCTION: Recently, a phase III CROWN trial compared the efficacy of two anaplastic lymphoma kinase (ALK) inhibitors and demonstrated that lorlatinib displayed clinical improvement over crizotinib for advanced non-small cell lung cancer (NSCLC) patients. Therefore, the aim of this study was to estimate the cost-effectiveness of lorlatinib as a first-line therapy for patients with advanced ALK-positive (+) NSCLC. MATERIALS AND METHODS: A cost-effectiveness analysis was performed using a microsimulation model from the US payer perspective and a lifetime horizon (30 years) in patients with previous untreated advanced ALK+ NSCLC. Based on the CROWN trial, patient characteristics were obtained, and the transition probabilities were estimated. All direct costs were derived from official sources and published literature. The main outcomes of the model were total costs, incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and life years (LYs). One-way and probabilistic sensitivity analyses and multiple scenario analyses were conducted to test the robustness of the model outcomes. RESULTS: In the base case analysis, in which 1 million patients were simulated, treatment with lorlatinib or crizotinib as the first-line treatment was related to a mean cost of $909,758 and $616,230 (incremental cost: $293,528) and a mean survival of 4.81 QALYs and 4.09 QALYs (incremental QALY: 0.72) per patient, respectively. The main drivers of cost effectiveness were drug price and subsequent cost. PAS indicated that lorlatinib has 90% cost-effectiveness when compared to crizotinib when the willingness-to-pay (WTP) threshold in increased to $448,000/QALY. Scenario analysis demonstrated that lorlatinib has 100% cost-effectiveness at a WTP threshold of 200,000/QALY compared to crizotinib treatment when the price of lorlatinib is decreased to 75% ($424.5) of its original price. CONCLUSIONS: In this study, lorlatinib was unlikely to be cost effective compared with crizotinib for patients with previously untreated advanced ALK+ NSCLC at a WTP threshold of 200,000/QALY.

Cost-Effectiveness of Baricitinib for Patients with Moderate-to-Severe Rheumatoid Arthritis After Methotrexate Failed in China.

INTRODUCTION: A phase 3 (RA-BEAM study) clinical trial reported that baricitinib (BCT) + methotrexate (MTX) had clinical improvement compared with adalimumab (ADA) + MTX as a first-line strategy in patients with rheumatoid arthritis (RA) who had inadequate responses to MTX monotherapy. However, from the perspective of the Chinese healthcare system, the cost-effectiveness of introducing BCT into current treatment for patients with RA unresponsive to MTX remains unclear. METHODS: A patient-level microsimulation model was used to extrapolate the lifetime incremental cost per quality-adjusted life-year (QALY) and other outcomes. This study compared treatment sequences with or without first-line BCT with current treatment sequences, including adalimumab, etanercept, tocilizumab, and palliative care. Effectiveness and physical function were assessed using the American College of Rheumatology (ACR) 20/50/70 response and Health Assessment Questionnaire (HAQ). The input parameters of the model, comprising patient characteristics (sex and age) and treatment efficacy (ACR responses and HAQ score), were derived from a phase III clinical trial and network meta-analysis. The total cost estimation included direct costs and indirect costs. Probabilistic and univariate sensitivity analyses were performed, as were a series of scenario analyses. RESULTS: The lifetime analysis revealed that adding BCT as a first-line treatment resulted in a QALY gain of 2.66 years; this gain would cost an incremental $26,662, leading to an incremental cost-effectiveness ratio of $10,036/QALY per patient compared with the current treatment sequence. Sensitivity and scenario analyses showed the results to be robust. CONCLUSIONS: From a Chinese payer perspective, the introduction of BCT into the current treatment sequence is projected to be a cost-effective option as first-, second-, third-, and fourth-line treatment for patients with moderate-to-severe RA.

Cost-effectiveness of Triple Therapy vs. Biologic Treatment Sequence as First-line Therapy for Rheumatoid Arthritis Patients after Methotrexate Failure.

INTRODUCTION: A clinical trial (RACAT) reported the noninferiority of triple therapy compared to biologic agents (etanercept + methotrexate), and previous studies confirmed that biologic disease-modifying antirheumatic drugs (bDMARDs) are more expensive but less beneficial than triple therapy for patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) fails. However, from the perspective of the Chinese healthcare system, the cost-effectiveness of triple therapy versus bDMARD treatment sequences as a first-line therapy for patients with RA is still unclear. METHODS: An individual patient simulation model was used to extrapolate the lifetime cost and health outcomes by tracing patients from initial treatment through switches to further treatment lines in a sequence. Therapeutic efficacy and physical function were evaluated using the American College of Rheumatology (ACR) response, 28-Joint Disease Activity Score (DAS28), and Health Assessment Questionnaire score. All input parameters in the model were derived from published studies, national databases, local hospitals, and experts' opinions. Both direct costs and indirect costs were taken into consideration. Probabilistic and one-way sensitivity analyses were performed to test the uncertainty of the model, as were multiple scenario analyses. RESULTS: The lifetime analysis demonstrated that triple therapy was associated with lower costs and quality-adjusted life years (QALYs) than bDMARD sequences. These resulted in incremental cost-effectiveness ratios (ICERs) ranging from $87,090/QALY to $104,032/QALY, higher than the willingness-to-pay (WTP) threshold in China ($30,950/QALY). The baseline DAS28 impacted the model outcomes the most. Scenario analyses indicated that adding triple therapy to bDMARD sequences as a first-, second-, third-, or fourth-line therapy is very cost-effective, at a WTP of $10,316/QALY. CONCLUSIONS: From a Chinese payer perspective, triple therapy as first-line treatment in treatment sequence could be regarded as cost-effectiveness option for patients who failed MTX, compared to bDMARDs as first-line treatment, and instead of prescribing triple therapy as a substitute for bDMARDs as a first-line treatment, adding triple therapy to the bDMARD treatment sequence is likely to be very cost-effective for patients with active RA compared to bDMARD sequences.

Cost-Effectiveness of ramucirumab plus paclitaxel as a second-line therapy for advanced gastric or gastro-oesophageal cancer in China.

AIM: That clinical trial (RAINBOW) showed that a 7.4 months overall survival benefit with the combination therapy with ramucirumab (RAM) and paclitaxel (PAC) as second-line therapy for patients with recurrent or metastatic gastric or gastro-oesophageal junction adenocarcinoma, compared with placebo (PLA) plus paclitaxel. We performed an analysis to assess the cost-effectiveness of RAM from a Chinese perspective and recognized the range of drug costs. METHODS: By building a Markov model to estimate quality-adjusted life-years (QALYs), life-years (LYs) and lifetime costs. Transition probabilities, costs and utilities were estimated for the published literature, Chinese health care system and local price setting. We performed threshold analyses and probabilistic sensitivity analyses to evaluate the uncertainty of the model. RESULTS: Compared with PLA strategy, RAM strategy provided an incremental survival benefit of 1.22 LYs and 0.64 QALYs. The probabilistic sensitivity analysis showed that when RAM costs less than $151 or $753 per 4 weeks, the incremental cost-effectiveness ratio (ICER) approximated the willingness-to-pay threshold (WTP), suggesting that there was 50% likelihood that the ICER for RAM + PAC would be less than $44528.4 per QALY or $48121 per QALY, respectively. CONCLUSIONS: For patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who fail first-line chemotherapy, our results are conducive to the multilateral drug price guidance negotiations of RAM in China.

Model-Based Cost-Effectiveness Analysis of Panitumumab Plus FOLFIRI for the Second-Line Treatment of Patients with Wild-Type Ras Metastatic Colorectal Cancer.

INTRODUCTION: The NCT00339183 trial demonstrated that adding panitumumab to fluorouracil, leucovorin and irinotecan (FOLFIRI) as a second-line therapy of wild-type RAS metastatic colorectal cancer (mCRC) increases the median progression-free survival (PFS). Nevertheless, panitumumab is not yet approved in China, and the costs and outcomes of the therapy are still unclear. We estimated the cost-effectiveness of this intervention from the perspective of Chinese health care systems by constructing two pricing scenarios for panitumumab. Scenario 1: Pricing is based on the price of a similar product (cetuximab) in China. Scenario 2: We estimated the value-based price. METHODS: A partitioned survival model was created based on the results of the NCT00339183 trial, which evaluated panitumumab plus FOLFIRI versus FOLFIRI. The model simulated the disease progression. We calculated medical costs from the perspectives of the Chinese health care systems. The primary outcome measures were costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: In scenario 1, compared with FOLFIRI alone, FOLFIRI with panitumumab arm had an ICER of ¥1,539,988/QALY. The most influential factors were the mean overall survival (OS), utility before progression and cost of panitumumab. The probability of panitumumab plus FOLFIRI being cost-effective in China was 0% when the willingness-to-pay (WTP) threshold was ¥193,932/QALY. In scenario 2, when the cost of panitumumab was assumed to be ¥4032.61 or ¥5218.96 per cycle, the ICERs approximated the WTP thresholds of ¥193,932/QALY or ¥420,633/QALY, respectively. In this value-based pricing scenario, panitumumab plus FOLFIRI is estimated to be cost-effective. CONCLUSION: We construct two pricing scenarios in China. In scenario 1, panitumumab plus FOLFIRI as a second-line therapy of mCRC provided an incremental benefit, but simultaneously increased costs (at the current price) even further. In scenario 2, when the value-based price was adopted, panitumumab plus FOLFIRI was estimated to be cost-effective. Our study establishes a pricing framework for new anticancer drugs to reflect the economics of drugs. TRIAL REGISTRATION NUMBER: NCT00339183.

Isolation and Identification of Subgroup J Avian Leukosis Virus Inducing Multiple Systemic Tumors in Parental Meat-Type Chickens.

Avian leukosis virus (ALV) continues evolving to obtain new genomic characters to enhance its pathogenicity. In the present study, an ALV-J strain LH20180301 was isolated from broiler breeder chickens that reached the speak of paralyzation before 20-week-old. The necropsy chickens showed subcutaneous and muscular hemorrhage, and developed tumors in multiple organs including bone, liver, spleen, and kidney. The complete provirus was then cloned and sequenced to investigate the molecular characteristics and oncogenicity etiology of this virus associated with the outbreak of disease. The genomic structure of the reported ALV-J strain LH20180301 was highly conservative with other ALVs. Recombination events between the virus with endogenous virus were identified in the viral genome. Compared with the ALV-J original HPRS-103 strain, the major recombination sites of the viral genome with ev-1 were located in 5' UTR-gag and 3' UTR regions. Phylogenetic analysis of group specific antigen gp85 encoding protein showed that the LH20180301 branched with ALV-J prevalent in "yellow chickens" of local breeds in South China. Nine amino acids (N58, D60, K70, A71, K108, N112, N113, N121, R272) in the gp85 were highly conserved among ALV-J isolates before 2012, but various mutations were found in the late isolates including LH20180301. In addition, the LH20180301 strain also had the same deletion pattern of 3' UTR with them. Therefore, LH20180301 might derive from the same ancestor with those viruses and may be the trend of ALV-J evolution in China. The defined new genomic characters in the gp85 and 3' UTR region of ALV-J might provide the molecular basis for its enhanced oncogenicity.

[In vitro evaluation, cellular uptake and anti-acute myocardial ischemia effect of puerarin PEG-PLGA micelles].

PUE@PEG-PLGA micelles has excellent characteristics such as small particle size, high drug loading and slow drug release. The results of TEM electron microscopy showed that PUE@PEG-PLGA micelles had obvious core-shell structure. The critical micelle concentration(CMC) of PEG-PLGA micelles determined by pyrene assay was about 4.8 mg·L~(-1). Laser confocal experiments showed that PEG-PLGA micelles can enhance the cellular uptake of coumarin-6 and aggregate around the mitochondria; quantitative results of extracellular drug residues also indirectly confirmed that PEG-PLGA micelles can promote cellular uptake of the drug. Acute ischemic myocardial model rats were prepared by coronary artery ligation, and then the model rats were randomly divided into six groups: Sham operation group, model group, puerarin(PUE) group, as well as low-, mid-, and high-dose PUE@PEG-PLGA micelles groups. Drugs were given by iv administration 5 min after the ligation. The ST segment changes in the electrocardiogram were monitored; serum creatine kinase(CK), lactate dehydrogenase(LDH), aspartate aminotransferase(AST), and malondialdehyde(MDA) levels were detected and myocardial infarct size was also measured. Both PUE and PUE@PEG-PLGA micelles can reduce the elevated ST segment, reduce serum CK, LDH, AST and MDA levels, and reduce myocardial infarct size. The efficacy of PUE@PEG-PLGA medium and high dose groups was significantly better than that in the PUE group, and the efficacy in PUE@PEG-PLGA low dose group was basically equivalent to that in the PUE group. PUE@PEG-PLGA micelles can greatly improve the cardiomyocytes uptake of PUE, enhance the anti-acute myocardial ischemia effect of drugs, and reduce its dosage.

Piperazine ferulate ameliorates the development of diabetic nephropathy by regulating endothelial nitric oxide synthase.

Diabetic nephropathy (DN) is among the most common complications of diabetes mellitus. The disorder is associated with a decrease in the activity of the nitric oxide synthase/nitric oxide system. Piperazine ferulate (PF) is widely used for the treatment of kidney disease in China. The aim of the present study was to examine the effects of PF on streptozotocin (STZ)­induced DN and the underlying mechanism of this process. STZ­induced diabetic mice were intragastrically administered PF (100, 200 and 400 mg/kg/body weight/day) for 12 weeks. At the end of the treatment period, the parameters of 24­h albuminuria and blood urea nitrogen, creatinine and oxidative stress levels were measured. Hematoxylin and eosin staining, periodic acid­Schiff staining and electron microscopy were used to evaluate the histopathological alterations. mRNA and protein expression of endothelial nitric oxide synthase (eNOS) were measured by quantitative polymerase chain reaction and western blotting, respectively. PF significantly decreased blood urea nitrogen and creatinine levels and 24­h albuminuria, and it alleviated oxidative stress, improved glomerular basement membrane thickness and caused an upregulation in eNOS expression and activity levels in diabetic mice. In addition, high glucose decreased eNOS expression levels, whereas PF caused a reversal in the nitric oxide (NO) levels of glomerular endothelial cells. The present results suggested that PF exhibited renoprotective effects on DN. The mechanism of its action was associated with the regulation of eNOS expression and activity.

Puerarin-loaded PEG-PE micelles with enhanced anti-apoptotic effect and better pharmacokinetic profile.

Puerarin (PUE) is the most abundant isoflavonoid in kudzu root. It is widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, the short elimination half-life, poor-bioavailability, and acute intravascular hemolysis of PUE are the main obstacles to its widespread clinical applications. Whereas PEG-PE micelles possess the ability to release medicine slowly, enhance the cellular uptake of drugs and improve their biocompatibility. Therefore, it was aim to fabricate puerarin-loaded PEG-PE (PUE@PEG-PE) micelles to improve the pharmaceutical properties of drugs. It can be observed from the TEM images that PUE@PEG-PE micelles appeared obvious core-shell structure and remained well-dispersed without aggregation and adhesion. PUE was successfully embedded in the core of PEG-PE micelles, which was confirmed by FT-IR and 1H NMR spectra. In vitro studies showed that PUE@PEG-PE micelles exhibited a sustained release behavior in pH 7.4 PBS buffer and decreased hemolysis rate of PUE. Compared with PUE, PUE@PEG-PE micelles showed a 3.2-fold increase in the half-life of PUE and a 1.58-fold increase in bioavailability. In addition, the PUE@PEG-PE micelles exerted enhanced protective effect against isoprenaline-induced H9c2 cells apoptosis compared with PUE, as evident by decreased percentage of Hoechst-positive cells, Caspase 3 activity, Bax expression, and increased Bcl-2 expression. Notably, the PEG-PE micelles exhibited favorable cellular uptake efficiency on H9c2 cells, and this may account for their enhanced anti-apoptotic effect of the incorporated drug. Altogether, the PUE@PEG-PE micelles were not only able to control the drug release but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of PUE.

In vitro and in vivo evaluation of puerarin-loaded PEGylated mesoporous silica nanoparticles.

Puerarin, which is extracted from Chinese medicine, is widely used in China and mainly used as a therapeutic agent for the treatment of cardiovascular diseases. Owing to its short elimination half-life in human beings, frequently intravenous administration of high doses of puerarin may be needed, which possibly leads to severe and acute side effects. The development of an effective sustained-release drug delivery system is urgently needed. In this study, PEGylated mesoporous silica nanoparticles (PEG-MSNs) had become a preferred way to prolong the half-life and improve the bioavailability of drugs. The release of puerarin from PEG-MSNs was pH dependent, and the release rate was much faster at lower pH than that at higher pH. Moreover, the PEG-MSNs exhibited improved blood compatibility over the MSNs in terms of low hemolysis, and it could also reduce the side effect of hemolysis induced by PUE. Compared with puerarin, PUE-loaded PEG-MSNs showed a 2.3-fold increase in half-life of puerarin and a 1.47-fold increase in bioavailability. Thus, the PEG-MSNs hold the substantial potential to be further developed as an effective sustained-release drug delivery system.

Economic outcomes of maintenance gefitinib for locally advanced/metastatic non-small-cell lung cancer with unknown EGFR mutations: a semi-Markov model analysis.

BACKGROUND: Maintenance gefitinib significantly prolonged progression-free survival (PFS) compared with placebo in patients from eastern Asian with locally advanced/metastatic non-small-cell lung cancer (NSCLC) after four chemotherapeutic cycles (21 days per cycle) of first-line platinum-based combination chemotherapy without disease progression. The objective of the current study was to evaluate the cost-effectiveness of maintenance gefitinib therapy after four chemotherapeutic cycle's stand first-line platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC with unknown EGFR mutations, from a Chinese health care system perspective. METHODS AND FINDINGS: A semi-Markov model was designed to evaluate cost-effectiveness of the maintenance gefitinib treatment. Two-parametric Weibull and Log-logistic distribution were fitted to PFS and overall survival curves independently. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the model designed. The model base-case analysis suggested that maintenance gefitinib would increase benefits in a 1, 3, 6 or 10-year time horizon, with incremental $184,829, $19,214, $19,328, and $21,308 per quality-adjusted life-year (QALY) gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was utility of PFS plus rash, followed by utility of PFS plus diarrhoea, utility of progressed disease, price of gefitinib, cost of follow-up treatment in progressed survival state, and utility of PFS on oral therapy. The price of gefitinib is the most significant parameter that could reduce the incremental cost per QALY. Probabilistic sensitivity analysis indicated that the cost-effective probability of maintenance gefitinib was zero under the willingness-to-pay (WTP) threshold of $16,349 (3 × per-capita gross domestic product of China). The sensitivity analyses all suggested that the model was robust. CONCLUSIONS: Maintenance gefitinib following first-line platinum-based chemotherapy for patients with locally advanced/metastatic NSCLC with unknown EGFR mutations is not cost-effective. Decreasing the price of gefitinib may be a preferential choice for meeting widely treatment demands in China.