Cost-effectiveness analysis of mecapegfilgrastim and recombinant human granulocyte stimulating factor for primary prophylaxis of chemotherapy-induced neutropenia in non-small cell lung cancer.

OBJECTIVE: To evaluate the efficacy, safety, and economics of mecapegfilgrastim and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the primary prevention of chemotherapy-related neutropenia in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Data from 181 patients with NSCLC who received intermediate risk chemotherapy were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with mecapegfilgrastim (n = 91) and those treated with rhG-CSF (n = 90). The clinical efficacy rates of neutropenia prevention were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. RESULTS: There was no statistical difference between the mecapegfilgrastim and rhG-CSF groups in clinical efficacy rates (98.9 vs. 97.8%). However, the total cost in the mecapegfilgrastim group was significantly higher than that in the rhG-CSF group (16,341.6 CNY vs. 14,371.1 CNY, p = 0.03). The cost-minimization analysis shows that mecapegfilgrastim is not cost-effective. The sensitivity analyses confirm that these results are robust. CONCLUSION: Compared with rhG-CSF, mecapegfilgrastim is not a cost-effective strategy for NSCLC patients in neutropenia prevention in China.

Neuroprotection of rhGLP-1 in diabetic rats with cerebral ischemia/reperfusion injury via regulation of oxidative stress, EAAT2, and apoptosis.

Preclinical Research & Development The purpose of the present study is to evaluate the neuroprotective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) as well as to explore corresponding mechanisms in diabetic rats with cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion (MCAO). Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. The rats were pretreated with rhGLP-1 (20 µg/kg intraperitoneally, thrice a day) for 14 days. Thereafter, the rats were subjected to MCAO 90 min/reperfusion 24 hr. At 2 and 24 hr of reperfusion, the rats were assessed for neurological deficits and subsequently executed for the evaluation of cerebral infarct volume, oxidative stress parameters, and the expression of excitatory amino acid transporter 2 (EAAT2) and apoptotic markers. Results indicate that rhGLP-1 significantly ameliorated neurological deficits and reduced cerebral infarct volume in diabetic MCAO rats. In addition, oxidative stress parameters in ischemic penumbra were significantly alleviated in rhGLP-1-pretreated diabetic MCAO rats. rhGLP-1 significantly upregulated the ratio of Bcl-2/Bax and EAAT2 expression and downregulated cleaved caspase-3 expression in ischemic penumbra of diabetic MCAO rats. Our results suggest that rhGLP-1 could significantly ameliorate neurological deficits and reduce cerebral infarct volume in diabetic MCAO rats, which may be due to the inhibition of oxidative stress and apoptosis and the promotion of EAAT2 expression.

RhGLP-1 (7-36) protects diabetic rats against cerebral ischemia-reperfusion injury via up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.

The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7-36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low-dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7-36) (10, 20, 40 µg/kg i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7-36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7-36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7-36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.

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

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

Neuroprotective Effects of rhGLP-1 in Diabetic Rats with Cerebral Ischemia/Reperfusion Injury.

Preclinical Research The aim of the present study was to evaluate the neuroprotective benefits of rhGLP-1 in diabetic rats subjected to acute cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Streptozotocin (STZ)-induced diabetic rats were pretreated with rhGLP-1 (10, 20, or 40 µg/kg ip, tid) for 14 days. During this time, body weight and fasting blood glucose levels were assessed. Rats were then subjected to MCAO 90 min/R 24 h. At 2 and 24 h of reperfusion, rats were evaluated for neurological deficits and blood samples were collected to analyze markers of brain injury. Rats were then sacrificed to assess the infarction volume. rhGLP-1 pretreatment lowered blood glucose levels, improved neurological scores, attenuated infarct volumes, and reduced the blood levels of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and myelin basic protein (MBP). rhGLP-1 has neuroprotective benefits in diabetic rats with cerebral ischemia/reperfusion injury and could potentially be used as a prophylatic neuroprotectant in diabetic patients at high risk of ischemic stroke. Drug Dev Res 77 : 124-133, 2016. © 2016 Wiley Periodicals, Inc.

To Estimate Performance of Artificial Neural Network Model Based on Terahertz Spectrum: Gelatin Identification as an Example.

It is a necessity to determine significant food or traditional Chinese medicine (TCM) with low cost, which is more likely to achieve high accurate identification by THz-TDS. In this study, feedforward neural networks based on terahertz spectra are employed to predict the animal origin of gelatins, whose adaption to the mission is examined by parallel models built by random sample partition and initialization. It is found that the generalization performance of feedforward ANNs in original data is not satisfactory although prediction on trained samples can be accurate. A multivariate scattering correction is conducted to enhance prediction accuracy, and 20 additional models verify the effectiveness of such dispose. A special partition of total dataset is conducted based on statistics of parallel models, whose influence on ANN performance is investigated with another 20 models. The performance of the models is unsatisfactory because of notable differences in training and test sets according to principal component analysis. By comparing the distribution of the first two principal components before and after multivariate scattering correction, we found that the reciprocal of the minimum number of line segments required for error-free classification in 2-D feature space can be viewed as an index to describe linear separability of data. The rise of proposed linear separability would have a lower requirement for harsh parameter tuning of ANN models and tolerate random initialization. The difference in principal components of samples between a training set and a data set determines whether partition is acceptable or whether a model would have generality. A rapid way to estimate the performance of an ANN before sufficient tuning on a classification mission is to compare differences between groups and differences within groups. Given that a representative peak missing curve is discussed in this article, an analysis based on gelatin THz spectra may be helpful for studies on some other feature-less species.

A real-world cost-effectiveness analysis of nebulized budesonide and intravenous methylprednisolone in acute exacerbation of chronic obstructive pulmonary disease.

Objective: To assess the cost-effectiveness of nebulized budesonide and intravenous methylprednisolone in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a real-world setting. Materials and methods: Data from 291 patients with AECOPD were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with nebulized budesonide (n = 148) and those treated with intravenous methylprednisolone (n = 143). Clinical efficacy and the rate of no readmission within 1 year after discharge were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. Results: There was no statistical difference between the budesonide and methylprednisolone groups in clinical efficacy rates (94.6% vs. 93.7%). The cost-minimization analysis shows that budesonide is not cost-effective owing to higher total cost. In terms of readmission rates, budesonide was again not cost-effective, with an incremental cost-effectiveness ratio (ICER) of 22276.62 CNY, which is higher than the willingness to pay (WTP) of 20206.20 CNY, the mean per admission expenditure in China. The sensitivity analyses confirm that these results are robust. Conclusion: Compared with intravenous methylprednisolone, nebulized budesonide is not a cost-effective strategy for AECOPD patients in China.

Safety and tolerability of a humanized rabbit monoclonal antibody (SSS07) in healthy adults: Randomized double-blind placebo-controlled single ascending dose trial.

BACKGROUND/OBJECTIVE: SSS07, a humanized rabbit monoclonal antibody, can selectively block human tumor necrosis factor-α (TNF-α). The objective of this study was to assess the safety, tolerability, and relative immunogenicity of SSS07 after multiple single subcutaneous (SC) doses in healthy volunteers. METHODS: A total of 71 healthy volunteers were randomized to six sequential ascending-dose groups (5, 15, 30, 50, 75, and 100 mg), and except for the 100 mg group that only had one subject who received a placebo, all of the other groups included two placebo-control subjects. Safety, tolerability, and immunogenicity were assessed by physical examinations, vital signs, electrocardiography (ECG), clinical laboratory tests, and plasma anti-drug antibody (ADA) over 28 days for each group. Their concentrations of TNF-α were also analyzed. Only after safety and tolerance were determined in the lower-dose groups was the next dose group initiated. The dose increments did not exceed 100 mg. RESULTS: No serious adverse events or dose-limited toxicity (DLT) were observed, so 100 mg was defined as the maximum tolerated dose (MTD). Overall, 71 AEs and 59 treatment-related adverse events (TRAEs) were reported in 36 (60.0%) and 30 (50.0%) volunteers, respectively, who received SSS07. All AEs and TRAEs were mild or moderate and expected based on previous results with similar types of drugs, without new safety concerns. Except for infections and administration site reactions, the frequency and intensity of the other TRAEs were similar for SSS07 and placebo. No severe acute immune reactions occurred. The lower dose's immunogenicity was stronger than the higher doses. The highest ADA titer was observed 3 to 6 months after administration. CONCLUSION: SSS07 was generally safe and well tolerated in healthy Chinese volunteers. Higher immunogenicity was observed at low SSS07 concentration levels. The infections and administration site conditions might have been related to the immunogenicity and the degree of inhibition of TNF-α. However, the existence of ADA did not appear to affect the safety of the subjects throughout the follow-up period. These findings could support further investigations of treatments with humanized monoclonal antibodies.

A randomized controlled dose-escalation study of SSS07, a humanized rabbit anti-human TNF alpha antibody, in healthy Chinese adults.

AIMS: SSS07 is a rabbit derived humanized anti-human TNF-α antibody. This study aimed to explore the pharmacokinetics, safety, and immunogenicity of SSS07 when administrated subcutaneously in healthy adults. METHODS: This was a double-blind, dose-escalation study of SSS07 in 71 adults. Dose cohorts were set to 5 mg, 15 mg, 30 mg, 50 mg, 75 mg, and 100 mg. In each dosage group, other than 100 mg, twelve healthy participants were randomly assigned to receive a single dose of SSS07 (n = 10) or placebo (n = 2). Blood samples were taken for pharmacokinetics and immunogenicity analysis. RESULTS: No deaths, serious adverse events or drug-related withdrawals occurred in this trial. No drug limited toxicity appeared. After subcutaneous injection, SSS07 was absorbed slowly with Tmax ranging from 60 to 264 h but eliminated quickly with a short half-life ranging from 21.69 to 78.4 h (1-3 days). From 5 mg to 100 mg, dose-exposure proportionality analysis found a 90% confidence interval (CI) of ß of Cmax (1.015-1.193), AUC0-t (1.096-1.263) and AUC0-∞ (0.999-1.174) partially within the range 0.926-1.074. The plasma concentration of TNF-α decreased significantly post-dose, but a few days later, levels of TNF-α elevated rapidly and exceeded its baseline value. All participants receiving SSS07 were found to be anti-drug antibody positive during the study. CONCLUSIONS: A single-dose injection of SSS07 was safe and well-tolerated in healthy adults. Doses of SSS07 from 5 mg to 100 mg could not be regarded as nonlinear, based on dose-exposure proportionality analysis. A high incidence of anti-drug antibodies indicated strong immunogenicity, which may influence the pharmacokinetics profile and interfere with the TNF-α inhibition capability of SSS07.