Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure.

BACKGROUND: Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily. OBJECTIVES: This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF. METHODS: Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32. RESULTS: We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm. CONCLUSIONS: The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082).

Efficacy of the Oral Administration of Maltodextrin Fructose Before Major Abdominal Surgery: A Prospective, Multicenter Clinical Study.

BACKGROUND: To study the efficacy of the oral administration of maltodextrin and fructose before major abdominal surgery (MAS). METHODS: This prospective, multicenter, parallel-controlled, double-blind study included patients aged 45-70 years who underwent elective gastrectomy, colorectal resection, or duodenopancreatectomy. The intervention group (IG) was given 800 mL and 400 mL of a maltodextrin and fructose beverage at 10 h and 2 h before MAS, respectively, and the control group (CG) received water under the same experimental conditions. The primary endpoint was insulin resistance index (IRI), and the secondary endpoints were fasting blood glucose, fasting insulin, insulin secretion index, insulin sensitivity index, intraoperative blood glucose, subjective comfort score, and clinical outcome indicators. RESULTS: A total of 240 cases were screened, of which 231 cases were randomly divided into two groups: 114 in the IG and 117 in the CG. No time-treatment effect was detected for any endpoint. The IRI and fasting insulin were significantly lower in the IG than CG after MAS (p = 0.02 & P = 0.03). The scores for anxiety, appetite, and nausea were significantly lower in the IG than CG at 1 h before MAS. Compared with baseline, the scores for appetite and nausea decreased in the IG but increased in the CG. CONCLUSION: The oral administration of maltodextrin and fructose before MAS can improve preoperative subjective well-being and reduce postoperative insulin resistance without increasing the risk of gastrointestinal discomfort.

Using Buck's Fascia as an Integral Covering in Urethroplasty to Restore the Anatomical Structure of the Penis in One-Stage Hypospadias Repair: A Multicenter Chinese Study Comprising 1,386 Surgeries.

Objectives: The objective of the study is to investigate the feasibility and efficacy of urethroplasty with a Buck's fascia integral-covering technique (BFIC) to wrap and restore the normal anatomical structure of the penis in one-stage hypospadias surgery. Methods: One-stage surgeries for hypospadias management were performed using BFIC from January 2016 to September 2020 at four high-volume medical centers in China. The technique integrates Buck's fascia with glans wings to mobilize and wrap the urethra and restore penile anatomical relationships. The clinical data, postoperative follow-up data, and complications were recorded, and the results were analyzed. Results: A total of 1,386 patients were included in the study: 1,260 cases of primary hypospadias and 126 cases of re-operations; distal in 382 cases (27.6%), mid-shaft in 639 (46.1%), proximal in 365 (26.3%); tubularized incised plate (TIP) in 748 cases, inlay-graft in 124, onlay-graft in 49, Mathieu in 28, free-tube graft urethroplasty in 406, and 31 of hybrid procedures. One thousand one hundred forty-two patients (82.4%) were found to have penile curvature (>10°) after artificial erection and all corrected by dorsal plication/s or transection of the urethra plate (UP) simultaneously. The median followed-up time was 27 months (6-62). A total of 143 (10.3%) complications were recorded: 114 (9.0%) in the primary operations and 29 (23%) in the re-operations, 15 (3.9%) in distal hypospadias, 61 (9.5%) in mid-shaft, and 67 (18.4%) in proximal. The complication rate in UP preservation and transection was 10.1 and 10.8%, respectively. Of all case complications, there were 73 (5.2%) of fistula, 10 (0.6%) of dehiscence, 22 (1.6%) of meatal stenosis, 21 (1.5%) of stricture, 6 (0.7%) of diverticulum, and resident curvature in 11 cases (1.2%). The overall complication rate in TIP and free-tube procedure was 9.8 and 9.9%, respectively, and fistula occurred in primary TIP of 33 cases (4.9%). Conclusions: Buck's fascia with the glans can be used as an integral covering technique in one-stage distal to proximal hypospadias and primary or re-operative hypospadias repair. It is safe, feasible, and effective for the repair of hypospadias.

Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.

BACKGROUND: This study aimed to evaluate the efficacy and safety of anlotinib as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC). METHODS: We conducted this Phase 2 trial at 11 institutions in China. Patients with pathologically confirmed SCLC who failed at least two lines of chemotherapy were enrolled. Subjects were randomly assigned in a 2:1 ratio to receive either anlotinib 12 mg orally once daily for 14 days every 3 weeks or placebo. The primary endpoint was progression-free survival (PFS). RESULTS: Between March 30, 2017 and June 8, 2018, a total of 82 and 38 patients were randomly assigned to receive anlotinib and placebo. The median PFS was significantly longer in the anlotinib group compared with the placebo group (4.1 months [95% confidence interval (CI), 2.8-4.2] vs 0.7 months [95% CI, 0.7-0.8]; hazard ratio (HR) 0.19 [95% CI, 0.12-0.32], p < 0.0001). Overall survival (OS) was significantly longer with anlotinib than placebo (7.3 months [95% CI, 6.1-10.3] vs 4.9 months [95% CI, 2.7-6.0]; HR 0.53 [95% CI, 0.34-0.81], p = 0.0029). CONCLUSIONS: Anlotinib as a third-line or subsequent treatment for Chinese patients with SCLC showed improved PFS and OS than placebo with favourable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT03059797.

Fixed combination of tazarotene and betamethasone dipropionate for treatment of psoriasis vulgaris: The result of a phase 3, multicenter, randomized controlled trial.

Long-term use of corticosteroids or local use of tazarotene (TAZ) alone for the treatment of psoriasis cause safety issues and low compliance rates. Combining these two may optimize their efficacy and minimize safety concerns. This study aimed to evaluate the clinical efficacy and safety of a fixed combination of TAZ 0.05% and betamethasone dipropionate 0.05% (BM) for psoriasis vulgaris. A multicenter, randomized, single-blinded, controlled phase 3 clinical trial was conducted. A total of 600 Chinese subjects with psoriasis vulgaris were randomized (3:1:1) to TAZ/BM cream, TAZ gel or BM cream groups for 6 weeks with an 8-week follow up. The primary efficacy assessment end-point was 75% improvement in Psoriasis Area and Severity Index (PASI-75) at 6 weeks. Secondary outcome assessments included PASI-90, percentage of PASI decrease and so forth. Safety and treatment-related adverse events were monitored throughout the study. Our results demonstrated that the TAZ/BM group exhibited statistically significant superiority in PASI-75 over TAZ (6.74% vs 1.67%) within 2 weeks. After 6 weeks of treatment, PASI-75 was 44.94% in the TAZ/BM group while 19.17% and 35.00% in the TAZ and BM group, respectively. At the 8-week follow up, the relapse rate of the TAZ/BM group was significantly lower than the BM group (10.62% vs 29.63%, P = 0.0269) though comparable with the TAZ group (10.00%). The most frequently reported treatment-related adverse event was mild to moderate level of skin irritation events. TAZ/BM combination has significant advantages over TAZ, including satisfying efficacy, rapid onset and reduced local stimulation. Meanwhile, compared with BM, it has the advantages of longer relief time and reduced clinical relapse rate. The TAZ/BM combination drug provides psoriatic patients an alternative drug with high efficacy and low relapse rate and safety concerns.

Progression-free survival as a surrogate endpoint for overall survival in patients with third-line or later-line chemotherapy for advanced gastric cancer.

BACKGROUND: The correlation between overall survival (OS) and progression-free survival (PFS) has been evaluated in patients with metastatic or advanced gastric cancer who have received first-line and/or second-line chemotherapy. However, no corresponding analysis has been done for patients who have undergone third-line or later-line chemotherapy. METHODS: A total of 303 patients from the Phase II/III studies of apatinib were pooled (the Phase II study as a training data set, the Phase III study as a testing data set). Landmark analyses of PFS at 2 months from randomization were performed to minimize lead time bias. The Cox proportional hazard model was used to test for the significance effect of PFS rate at 2 months in predicting OS. Additionally, the PFS/OS correlations were evaluated by the normal induced copula (National Institute for Health and Care Excellence) estimation model. RESULTS: The median OS was 3.37 months (95% confidence interval 2.63-3.80) in patients who experienced progression at 2 months and 5.67 months in patients who did not (95% confidence interval 4.83-6.67; P<0.0001). Compared with patients who did not progress at 2 months, the adjusted hazard ratio for death was 3.39 (95% confidence interval 1.79-6.41; P<0.0001) for patients who experienced progression at 2 months. Moreover, the correlation of PFS/OS was 0.84 (95% confidence interval 0.74-0.90). Similar results were found in the testing data set. CONCLUSION: These results indicate that PFS correlates strongly with OS, suggesting PFS may be a useful early endpoint for patients with advanced gastric cancer who have undergone third-line or later-line chemotherapy. These observations require prospective validation.

Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib.

PURPOSE: To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib L-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer. METHODS: Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks. RESULTS: Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.7-33.8 and 41.3-47.7 h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage. CONCLUSIONS: Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg.

[The reliability of dento-maxillary models created by cone-beam CT and rapid prototyping:a comparative study].

PURPOSE: To analyze the reliability of the dento-maxillary models created by cone-beam CT and rapid prototyping (RP). METHODS: Plaster models were obtained from 20 orthodontic patients who had been scanned by cone-beam CT and 3-D models were formed after the calculation and reconstruction of software. Then, computerized composite models (RP models) were produced by rapid prototyping technique. The crown widths, dental arch widths and dental arch lengths on each plaster model, 3-D model and RP model were measured, followed by statistical analysis with SPSS17.0 software package. RESULTS: For crown widths, dental arch lengths and crowding, there were significant differences(P<0.05) among the 3 models, but the dental arch widths were on the contrary. Measurements on 3-D models were significantly smaller than those on other two models(P<0.05). Compared with 3-D models, RP models had more numbers which were not significantly different from those on plaster models(P>0.05). The regression coefficient among three models were significantly different(P<0.01), ranging from 0.8 to 0.9. But between RP and plaster models was bigger than that between 3-D and plaster models. CONCLUSIONS: There is high consistency within 3 models, while some differences were accepted in clinic. Therefore, it is possible to substitute 3-D and RP models for plaster models in order to save storage space and improve efficiency.

[Introduction on "case-sibling control design"].

OBJECTIVE: To introduce the design and statistical methods of case-sibling control design and to analyze the published data. METHODS: Data from an association study between the coronary heart disease and methylenetetrahydrofolate reductase gene C677T polymorphism was analyzed by the sib transmission/disequibrium test (s-TDT) and the sibship disequilibrium (SDT) methods. RESULTS: Using s-TDT method, Z value was 0.27 with P > 0.05. The result of SDT method showed that chi-square was 0.31 with 1 df, P > 0.05. All results suggested that neither s-TDT nor SDT showed significant difference between the transmitted and untransmitted methylenetetrahydrofolate reductase gene C677T allele distributions. CONCLUSION: Case-sibling control design might avoid population stratification by using siblings as controls thus might be used to test association and linkage between genes and disease.