A Randomized Controlled Dose-Escalation Study of LY06006, a Recombinant Humanized Monoclonal Antibody to RANKL, in Chinese Healthy Adults.

Background: This study was conducted to explore the safety, tolerance, pharmacokinetics, pharmacodynamics, and immunogenicity of LY06006, a recombinant humanized monoclonal antibody to RANKL, when administrated subcutaneously in Chinese healthy adults. Research design and methods: This was a randomized, double-blinded, placebo-controlled, single ascending dose study performed in 32 healthy Chinese adults, who were randomly assigned to receive a single injection dose of 18, 60, 120 mg study drug or placebo with a follow-up of 140-252 days. Results: No deaths or drug-related serious adverse events occurred. LY06006 was rapidly absorbed in the 60 mg group with a Tmax range of 120-480 h and serum LY06006 concentrations decreased slowly 11-13 days after dosing with a long mean (SD) half-life of 389.58 (63.44) h. The most frequent AEs were elevated serum parathyroid hormone (PTH) level (83.3%), hypocalcemia (54.2%), and hypophosphatemia (45.8%). None of the 32 subjects tested positive for anti-drug antibody during the trial. Conclusion: Single-dose subcutaneous administration of LY06006 was safe and well-tolerated in healthy Chinese adults. Cmax showed linear pharmacokinetic characteristics in the dose range of 18-120 mg based on dose-exposure proportionality analysis.

Incorporation of Laboratory Test Biomarkers Into Dual Antiplatelet Therapy Score Improves Prediction of Ischemic and Bleeding Events in Post-percutaneous Coronary Intervention Patients.

This study aimed to examine the performance of the dual antiplatelet therapy (DAPT) score in two retrospective cohorts of post-percutaneous coronary intervention (PCI) patients and to explore whether incorporating additional biomarkers could further improve the predictive power of the DAPT score. In a retrospective derivation cohort of 4,798 PCI patients, the validity of DAPT score for stratifying ischemic/bleeding risks was explored. Then, the association between the baseline status of 54 laboratory test biomarkers and ischemic/bleeding events was revealed while adjusting for the DAPT score. Combinations of individual laboratory test biomarkers that were significantly associated with ischemic/bleeding events were explored to identify the ones that improved discrimination of ischemic and bleeding events when incorporated into DAPT score. Finally, the impact of the combination of biomarkers with DAPT score was validated in an independent retrospective validation cohort of 1,916 PCI patients. Patients with a high DAPT score (DAPT score ≥ 2) had significantly higher risk of ischemic events and significantly lower risk of bleeding than patients with a low DAPT score (DAPT score < 2). Moreover, the addition of aspartate aminotransferase (AST) and red cell distribution width CV (RDW-CV) into the DAPT score further improved discrimination of ischemia and bleeding. Furthermore, the incremental predictive value of AST + RDW-CV maintained with measurements was updated at post-baseline time points. DAPT score successfully stratified the risks of ischemia/bleeding post PCI in the current cohorts. Incorporation of AST + RDW-CV into the DAPT score further improved prediction for both ischemic and bleeding events.

Effects of S1PR2 antagonist on blood pressure and angiogenesis imbalance in preeclampsia rats.

Preeclampsia (PE), a hypertensive multisystem disorder, can lead to increased maternal and fetal mortality and morbidity. Sphingosine­1­phosphate (S1P) plays various roles, depending on the cell type, by binding to S1P receptors (S1PR). The present study evaluated the changes of S1PRs and investigated the potential role of S1PRs in pregnancy­induced hypertension. PE rats were established by reduced uterine perfusion pressure. The involvement of S1PR2 was evaluated using JTE­013, a specific S1PR2 antagonist, in PE rats. After the treatment, inflammatory cytokines were evaluated using enzyme linked immunosorbent assay, and the expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) activation and endothelial nitric oxide synthase (eNOS) were evaluated by reverse transcription­quantitative PCR and western blotting. Results showed that S1PR2, but not S1PR1 and S1PR3, was significantly increased in the serum and placenta tissues of PE rats. Notably, JTE­013 significantly decreased blood pressure, attenuated infiltration of inflammatory cells and decreased inflammation, as indicated by the decreased expression of inflammatory cytokines, including tumor necrosis factor­α, interleukin­1ß (IL­1ß) and IL­6, in placental tissues. Mechanistic studies demonstrated that JTE­013 significantly increased the expression of VEGF and decreased the expression of fms­like tyrosine kinase 1 in placental tissue. Furthermore, JTE­013 prevented iNOS activation and increased eNOS in placental tissue. In summary, the present study demonstrated that S1PR2 contributed to hypertension and angiogenesis imbalance in PE rats.

A Randomized Study on the Bioequivalence of Desloratadine in Healthy Chinese Subjects and the Association of Different Metabolic Phenotypes With UGT2B10 and CYP2C8 Genotypes.

BACKGROUND: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. OBJECTIVE: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. METHODS: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. RESULTS: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. CONCLUSION: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.

Objectifying the level of incomplete revascularization by residual SYNTAX score and evaluating the impact of incomplete revascularization on exercise tolerance in patients with coronary atherosclerotic heart disease treated by percutaneous coronary intervention.

The prognostic impact of incomplete revascularization (ICR) on patients underwent percutaneous coronary intervention (PCI) was vague. Our research aimed to objectify the level of ICR by residual SYNTAX score (rSS) and evaluate the impact of ICR on exercise tolerance.We enrolled 87 patients who completed cardiopulmonary exercise testing (CPET) within 12 months after PCI, retrospectively. According to rSS, patients were divided into rSS = 0 group, 0 < rSS ≤ 8 group, and rSS > 8 group. The CPET variables--including peak metabolic equivalent (METpeak), percentages of predicting value of METpeak (METpeak%pred), MET at anaerobic threshold (AT), peak oxygen uptake (VO2peak), percentages of predicting value of VO2peak (VO2peak%pred), VO2 at AT--were collected and compared.Among rSS = 0, 0 < rSS ≤ 8 and rSS > 8 groups, patients with higher rSS had progressively lower METpeak, METpeak%pred, VO2peak%pred, VO2 at AT, and MET at AT, which indicate reduced exercise tolerance. And further multiple comparisons showed that there were no statistically significant differences between rSS = 0 and 0 < rSS ≤ 8 groups, while the aforementioned CPET variables were significantly lower in rSS > 8 group compared with rSS = 0 group. Logistic regression analysis showed that rSS was an independent risk factor for reduced exercise tolerance.

Predictive value of cardiopulmonary fitness parameters in the prognosis of patients with acute coronary syndrome after percutaneous coronary intervention.

OBJECTIVES: We aimed to determine the predictive value of cardiopulmonary exercise testing (CPX) in the prognosis of patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). METHODS: We conducted a retrospective study including patients who underwent CPX within 1 year of PCI between September 2012 and October 2017. Patients were followed-up until the occurrence of a major adverse cardiac event (MACE) or administrative censoring (September 2019). A Cox regression model was used to identify significant predictors of a MACE. Model performance was evaluated in terms of discrimination (C-statistic) and calibration (calibration-in-the-large). RESULTS: In total, 184 patients were included and followed-up for a median 51 months (interquartile range: 36-67 months) and 32 events occurred. Multivariable analysis revealed that body mass index and Gensini score were significant predictors of a MACE. Four CPX-related variables were found to be predictive of a MACE: premature CPX termination, peak oxygen uptake, heart rate reserve, and ventilatory equivalent for carbon dioxide slope. The final prediction model had a C-statistic of 0.92 and calibration-in-the-large 0.58%. CONCLUSION: CPX-related parameters may have high predictive value for poor outcomes in patients with ACS who undergo PCI, indicating a need for appropriate treatment and timely management.

Values of the Wells and revised Geneva scores combined with D-dimer in diagnosing elderly pulmonary embolism patients.

BACKGROUND: Pulmonary embolism (PE) can be difficult to diagnose in elderly patients because of the coexistent diseases and the combination of drugs that they have taken. We aimed to compare the clinical diagnostic values of the Wells score, the revised Geneva score and each of them combined with D-dimer for suspected PE in elderly patients. METHODS: Three hundred and thirty-six patients who were admitted for suspected PE were enrolled retrospectively and divided into two groups based on age (≥65 or <65 years old). The Wells and revised Geneva scores were applied to evaluate the clinical probability of PE, and the positive predictive values of both scores were calculated using computed tomography pulmonary arteriography as a gold standard; overall accuracy was evaluated by the area under the curve (AUC) of receiver operator characteristic curve; the negative predictive values of D-dimer, the Wells score combined with D-dimer, and the revised Geneva score combined with D-dimer were calculated. RESULTS: Ninety-six cases (28.6%) were definitely diagnosed as PE among 336 cases, among them 56 cases (58.3%) were ≥65 years old. The positive predictive values of Wells and revised Geneva scores were 65.8% and 32.4%, respectively (P < 0.05) in the elderly patients; the AUC for the Wells score and the revised Geneva score in elderly was 0.682 (95% confidence interval [CI]: 0.612-0.746) and 0.655 (95% CI: 0.584-0.722), respectively (P = 0.389). The negative predictive values of D-dimer, the Wells score combined with D-dimer, and the revised Geneva score combined with D-dimer were 93.7%, 100%, and 100% in the elderly, respectively. CONCLUSIONS: The diagnostic value of the Wells score was higher than the revised Geneva score for the elderly cases with suspected PE. The combination of either the Wells score or the revised Geneva score with a normal D-dimer concentration is a safe strategy to rule out PE.

[Association of QT dispersion, ST/heart rate slope and ST-segment depression in exercise test to evaluate restenosis after percutaneous coronary intervention].

OBJECTIVE: To evaluate the sensitivity and specificity of QT dispersion (QTd) and ST/heart rate slope (ST/HRs) at the end of ECG exercise test plus ST-segment depression on diagnosing restenosis after percutaneous coronary intervention (PCI). METHODS: Between November 2001 and December 2003, 129 patients underwent PCI successfully, and they were examined 3-6 months later. At the end of treadmill exercise, QTd and ST/HRs were measured. All patients also accepted coronary angiography to ascertain whether he/she had restenosis. The results of QTd and ST/HRs plus ST-segment depression were then evaluated. RESULTS: The sensitivity and specificity of QTd and ST/HRs plus ST-segment depression were 84.6% and 80.4% respectively. Both of them were significantly higher than conventional ST-segment depression standard (sensitivity was 53.3% and specificity was 66.7%, P<0.05). CONCLUSION: Measuring QTd and ST/HRs at the end of ECG treadmill exercise test plus ST-segment depression can be used for the diagnosis of restenosis after PCI.

[The effects of gender on heart rate adjustment of ST segment depression for identifying coronary arteriosclerosis disease].

OBJECTIVE: To assess the effects of gender on heart rate adjustment of ST segment depression (ST/HR) for identifying coronary arteriosclerotic disease. METHODS: One hundred and seventy three patients with suspected coronary disease (CAD) were referred for a routine treadmill exercise electrocardiogram and subsequently they underwent selective coronary angiography within 3 weeks. The magnitude of ST segment depression, ST/HR slope and calculated ST/HR index are performed by a computerized ECG system; exercise was performed according to the cornell protocol. CAD was defined by coronary angiography. We divided the patients into two groups by gender. RESULTS: Sensitivity and specificity for identifying CAD with ST/HR slope and ST/HR index were all significantly greater than that of standard electrocardiographic test criteria (P <0.05). Compared with standard criteria, the sensitivity for identifying CAD of ST/HR slope and ST/HR index increased 23% and 16% in men, 50% and 42% in women respectively; all difference were statistically significant (P <0.05). The specificity for identifying CAD with ST/HR slope and ST/HR index increased 58% and 50% in women, with no increase in men. CONCLUSIONS: It is suggested that sensitivity and specificity for identifying CAD with ST/HR slope and ST/HR index were all significantly higher than those with standard electrocardiographic test criteria in selected women patients. Sensitivity were significantly increased in selected men patients, with no significant change in specificity.