-
1.
Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study.
van Groenendael, R, Beunders, R, Hemelaar, P, Hofland, J, Morshuis, WJ, van der Hoeven, JG, Gerretsen, J, Wensvoort, G, Kooistra, EJ, Claassen, WJ, et al
Critical care medicine. 2021;(5):790-803
-
-
Free full text
-
Abstract
OBJECTIVES To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies. DESIGN Double-blinded, placebo-controlled, randomized study. SETTING Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands. PATIENTS One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery. INTERVENTIONS Ninety mg/kg/hr EA-230 or placebo administered during surgery. MEASUREMENTS AND MAIN RESULTS During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL × hr [1,968-3,760] vs 2,680 pg/mL × hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean ± sem increase in the EA-230 vs placebo groups: glomerular filtration rateiohexol measured using iohexol plasma clearance: 19 ± 2 vs 16 ± 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 ± 1 vs 2 ± 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 ± 108 vs 605 ± 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11] vs 10 d [8-12]; p = 0.001). Efficacy results were more pronounced in patients that had longer duration of surgery and thus longer duration of study drug infusion. CONCLUSIONS EA-230 was safe in patients undergoing on-pump cardiac surgery. It did not modulate interleukin-6 plasma concentrations but appeared to exert beneficial renal and cardiovascular effects and shortened in-hospital length of stay.
-
2.
Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men.
Rubinow, KB, Vaisar, T, Chao, JH, Heinecke, JW, Page, ST
Journal of clinical lipidology. 2018;(4):1072-1082
-
-
Free full text
-
Abstract
BACKGROUND Exogenous testosterone decreases serum concentrations of high-density lipoprotein cholesterol (HDL-C) in men, but whether this alters cardiovascular risk is uncertain. OBJECTIVE To investigate the effects of testosterone and estradiol on HDL particle concentration (HDL-Pima) and metrics of HDL function. METHODS We enrolled 53 healthy men, 19 to 55 years of age, in a double-blinded, placebo-controlled, randomized trial. Subjects were rendered medically castrate using the GnRH receptor antagonist acyline and administered either (1) placebo gel, (2) low-dose transdermal testosterone gel (1.62%, 1.25 g), (3) full replacement dose testosterone gel (1.62%, 5 g) or (4) full replacement dose testosterone gel together with an aromatase inhibitor for 4 weeks. At baseline and end of treatment, serum HDL total macrophage and ABCA1-specific cholesterol efflux capacity (CEC), HDL-Pima and size, and HDL protein composition were determined. RESULTS Significant differences in serum HDL-C were observed with treatment across groups (P = .01 in overall repeated measures ANOVA), with increases in HDL-C seen after both complete and partial testosterone deprivation. Medical castration increased total HDL-Pima (median [interquartile range] 19.1 [1.8] nmol/L at baseline vs 21.3 [3.1] nmol/L at week 4, P = .006). However, corresponding changes in total macrophage CEC and ABCA1-specific CEC were not observed. Change in serum 17β-estradiol concentration correlated with change in total macrophage CEC (β = 0.33 per 10 pg/mL change in serum 17β-estradiol, P = .03). CONCLUSIONS Testosterone deprivation in healthy men leads to a dissociation between changes in serum HDL-C and HDL CEC. Changes in serum HDL-C specifically due to testosterone exposure may not reflect changes in HDL function.
-
3.
Lactotripeptides Supplementations Alleviate the Decrease in Maximal Isometric Force After High-Intensity Eccentric Exercise: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.
Tagawa, K, Ra, SG, Choi, Y, Maeda, S
American journal of physical medicine & rehabilitation. 2018;(5):370-374
Abstract
OBJECTIVE The aim of the study was to investigate whether lactotripeptides supplementations alleviate the decrease in the maximal isometric force, an indirect marker of muscle damage, after eccentric exercise (ECC). DESIGN Twenty-two young men performed 50 ECC of the elbow flexors using an isokinetic dynamometer. The subjects were randomly assigned to either the placebo or lactotripeptides group and were each given a 4.5 mg/d placebo or lactotripeptides thrice on the exercise day and the day after. Maximal isometric force and brachial arterial diameter were assessed before and 2 days after the ECC. RESULTS The interaction of time and group on maximal isometric force was significant (P < 0.05); maximal isometric force was significantly decreased in both groups after ECC (P < 0.005). The interaction of brachial arterial diameter was significant (P < 0.05); brachial arterial diameter was significantly increased in only the lactotripeptides group (P < 0.005). In addition, the change in maximal isometric force was significantly related to the change in brachial arterial diameter after adjusting for body weight and change in range of motion (P < 0.05). CONCLUSIONS The present results suggest that lactotripeptides supplementation alleviates the decrease in the maximal isometric force via an increase in brachial arterial diameter after ECC.
-
4.
Effect of Lactotripeptides (Isoleucine-Proline-Proline/Valine-Proline-Proline) on Blood Pressure and Arterial Stiffness Changes in Subjects with Suboptimal Blood Pressure Control and Metabolic Syndrome: A Double-Blind, Randomized, Crossover Clinical Trial.
Cicero, AF, Colletti, A, Rosticci, M, Cagnati, M, Urso, R, Giovannini, M, Borghi, C, D'Addato, S
Metabolic syndrome and related disorders. 2016;(3):161-6
Abstract
BACKGROUND Lactotripeptides (LTPs) have a mild antihypertensive effect in hypertensive subjects. The main aim of our clinical trial was to test if LTPs could have some influence on blood pressure (BP) and related hemodynamic parameters in a sample of outpatients affected by metabolic syndrome. METHODS A randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in a group of 40 nonsmoking volunteers with metabolic syndrome. The treatment periods were 4 weeks long and were separated by a 4-week washout period. The dietary supplementation was made by daily administration of LTPs from casein, 10.2 mg/day, and compared with placebo. RESULTS During the LTP treatment, patients experienced a significant mean decrease in systolic BP (SBP; -3.4 ± 4.4 mmHg, P = 0.041), diastolic BP (DBP; -3.1 ± 3.2 mmHg, P = 0.049), and pulse wave velocity (PWV; -0.7 ± 0.3 m/sec, P = 0.001). After LTP treatment, delta SBP, DBP, and PP were all significantly improved (P < 0.01 for all) compared with placebo. PWV also improved significantly after LTP treatment with respect to the end of the treatment with placebo (-0.8 ± 0.4 vs. -0.1 ± 0.3 m/sec, P = 0.009). The square root of the ratio of peak:baseline pulse volume during hyperemia (√V2/V1) improved after LTP treatment only (1.2 ± 0.4 vs. 1.4 ± 0.5, P = 0.04). Through the evaluation of the hemodynamic parameters that were measured by the 24-hr ambulatory monitoring, we observed that SBP, MBP, and the percentage of time with SBP over the normal were significantly reduced only after the LTP treatment (P < 0.05). These parameters were also significantly improved when compared with the ones measured after the placebo treatment (P < 0.05). CONCLUSION In our trial, during LTP treatment, patients affected by metabolic syndrome experienced a mild but significant improvement in office and 24-hr BP, PWV, and endothelial function compared with placebo treatment.
-
5.
Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers.
Nelson, AD, Camilleri, M, Acosta, A, Busciglio, I, Linker Nord, S, Boldingh, A, Rhoten, D, Ryks, M, Burton, D
Neurogastroenterology and motility. 2016;(11):1705-1713
-
-
Free full text
-
Abstract
BACKGROUND Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis. AIM: To measure pharmacological effects of relamorelin on gastric accommodation, distal antral motility, and satiation in healthy volunteers. METHODS In a placebo-controlled, double-blind, randomized study of 16 healthy volunteers, we compared effects of 30 μg subcutaneous (s.c.) relamorelin to placebo on: (i) gastric volumes measured by single photon emission computed tomography, (ii) 1-h postprandial distal antral motility index (MI) by 15-lumen perfusion gastroduodenal manometry, and (iii) satiation tested by Ensure nutrient drink test. Primary endpoints were: fasting and postprandial gastric volumes, distal antral phasic pressure activity (number of contractions, mean amplitude, and MI), and maximum tolerated volume. Results were normally distributed and the two treatment groups were compared using t-test. KEY RESULTS Relamorelin, 30 μg s.c., significantly increased the number of contractions in the distal antrum during 0-60 min postmeal when compared to placebo (p = 0.022); this was also observed in the first two 15-min periods (p = 0.005 and 0.015 for number of contractions 0-15 and 16-30). There was borderline increase in MI0-15 (p = 0.055) and numerically increased MI0-60 (p = 0.139) and MI16-30 (p = 0.116). The amplitude of contractions was not significantly increased. Relamorelin did not significantly alter fasting or postprandial gastric volumes, gastric accommodation, or satiation volumes and symptoms. CONCLUSIONS & INFERENCES Relamorelin increases frequency of distal antral motility contractions without significant effects on amplitude of contractions. The lack of inhibition of accommodation and absence of increase in satiation symptoms support relamorelin for the treatment of symptomatic gastroparesis (ClinicalTrials.gov NCT02466711).
-
6.
A comparative study on the efficacies of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist in neoadjuvant androgen deprivation therapy combined with transperineal prostate brachytherapy for localized prostate cancer.
Miki, K, Sasaki, H, Kido, M, Takahashi, H, Aoki, M, Egawa, S
BMC cancer. 2016;(1):708
Abstract
BACKGROUND Neoadjuvant androgen deprivation therapy (ADT) has been suggested to confer several clinical benefits in patients with prostate cancer (PCa) undergoing transperineal prostate brachytherapy (TPPB). Unlike gonadotropin-releasing hormone (GnRH) receptor agonists, a GnRH antagonist such as degarelix can achieve castrate levels of testosterone without testosterone flare. However, normalization of serum testosterone levels following completion of neoadjuvant ADT in either form of treatment has never been compared in clinical trials. METHODS/DESIGN This is a single-center, open-label, randomized controlled study that will compare the efficacy and safety of degarelix with those of existing GnRH agonists combined with (125)I-TPPB. A total of 56 patients with low/intermediate-risk clinically localized PCa will be enrolled and randomized to one of two treatment groups: the GnRH agonist group and the degarelix group. Patients in the GnRH agonist group will receive leuprorelin acetate or goserelin acetate, and those in the degarelix group will receive the initial dose of 240 mg as 2 subcutaneous injections of 120 mg each, and then 80 mg of maintenance doses every 4 weeks for 12 weeks. Those randomly assigned to the 12-week intervention period will subsequently undergo 48-weeks of follow-up after (125)I-TPPB. The primary endpoint is defined as normalization of serum testosterone levels (>50 ng/dL) following completion of neoadjuvant ADT. All patients will be assessed every 4 weeks for the first 24 weeks, then every 12 weeks for the next 36 weeks after administrations of these drugs. Secondary endpoints are the proportion of normalized serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the percent reduction in prostate specific antigen (PSA) compared with pretreatment levels, the percent reduction in total prostate volume (TPV) during neoadjuvant ADT, the percent increase in TPV after (125)I-TPPB, the percent reduction in hemoglobin, serum alkaline phosphatase (ALP), changes in free testosterone and bone mineral content measurement, the proportion of patients who have serum testosterone levels over 50 ng/dL at 12 weeks following completion of neoadjuvant ADT, and the improvement of quality of life (QOL). DISCUSSION The present study will provide additional insight regarding the benefit and potency of degarelix and will examine its potential as a new option for administration in neoadjuvant ADT. TRIAL REGISTRATION Identification number: UMIN000015519 . Registration date: October 24, 2014.
-
7.
Relation of Left Ventricular Mass and Infarct Size in Anterior Wall ST-Segment Elevation Acute Myocardial Infarction (from the EMBRACE STEMI Clinical Trial).
Daaboul, Y, Korjian, S, Weaver, WD, Kloner, RA, Giugliano, RP, Carr, J, Neal, BJ, Chi, G, Cochet, M, Goodell, L, et al
The American journal of cardiology. 2016;(5):625-31
Abstract
Biomarker measures of infarct size and myocardial salvage index (MSI) are important surrogate measures of clinical outcomes after a myocardial infarction. However, there is variability in infarct size unaccounted for by conventional adjustment factors. This post hoc analysis of Evaluation of Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events (EMBRACE) ST-Segment Elevation Myocardial Infarction (STEMI) trial evaluates the association between left ventricular (LV) mass and infarct size as assessed by areas under the curve for creatine kinase-MB (CK-MB) and troponin I release over the first 72 hours (CK-MB area under the curve [AUC] and troponin I [TnI] AUC) and the MSI. Patients with first anterior STEMI, occluded left anterior descending artery, and available LV mass measurement in EMBRACE STEMI trial were included (n = 100) (ClinicalTrials.govNCT01572909). MSI, end-diastolic LV mass on day 4 cardiac magnetic resonance, and CK-MB and troponin I concentrations were evaluated by a core laboratory. After saturated multivariate analysis, dominance analysis was performed to estimate the contribution of each independent variable to the predicted variance of each outcome. In multivariate models that included age, gender, body surface area, lesion location, smoking, and ischemia time, LV mass remained independently associated with biomarker measures of infarct size (CK-MB AUC p = 0.02, TnI AUC p = 0.03) and MSI (p = 0.003). Dominance analysis demonstrated that LV mass accounted for 58%, 47%, and 60% of the predicted variances for CK-MB AUC, TnI AUC, and MSI, respectively. In conclusion, LV mass accounts for approximately half of the predicted variance in biomarker measures of infarct size. It should be considered as an adjustment variable in studies evaluating infarct size.
-
8.
Faldaprevir and pegylated interferon α-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV.
Dieterich, D, Nelson, M, Soriano, V, Arastéh, K, Guardiola, JM, Rockstroh, JK, Bhagani, S, Laguno, M, Tural, C, Ingiliz, P, et al
AIDS (London, England). 2015;(5):571-81
Abstract
OBJECTIVE Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon α-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. DESIGN A phase 3 open-label study (NCT01399619). METHODS Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. CONCLUSIONS High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.
-
9.
Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.
Berger, KL, Scherer, J, Ranga, M, Sha, N, Stern, JO, Quinson, AM, Kukolj, G
Antimicrobial agents and chemotherapy. 2015;(10):6017-25
-
-
Free full text
-
Abstract
Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.
-
10.
Effect of fermented milk product containing lactotripeptides and plant sterol esters on haemodynamics in subjects with the metabolic syndrome--a randomised, double-blind, placebo-controlled study.
Hautaniemi, EJ, Tikkakoski, AJ, Tahvanainen, A, Nordhausen, K, Kähönen, M, Mattsson, T, Luhtala, S, Turpeinen, AM, Niemelä, O, Vapaatalo, H, et al
The British journal of nutrition. 2015;(3):376-86
Abstract
We investigated the effects of fermented milk product containing isoleucine-proline-proline, valine-proline-proline and plant sterol esters (Pse) on plasma lipids, blood pressure (BP) and its determinants systemic vascular resistance and cardiac output. In a randomised, double-blind, placebo-controlled study, 104 subjects with the metabolic syndrome (MetS) were allocated to three groups in order to receive fermented milk product containing (1) 5 mg/d lactotripeptides (LTP) and 2 g/d plant sterols; (2) 25 mg/d LTP and 2 g/d plant sterols; (3) placebo for 12 weeks. Plasma lipids and home BP were monitored. Haemodynamics were examined in a laboratory using radial pulse wave analysis and whole-body impedance cardiography in the supine position and during orthostatic challenge. There were no differences between the effects of the two treatments and placebo on the measurements of BP at home or on BP, systemic vascular resistance index and cardiac index in the laboratory, neither in the supine nor in the upright position. The changes in plasma LDL-cholesterol concentration were - 0.1 (95% CI - 0.3, 0.1 and - 0.3, 0.0) mmol/l in the 5 and 25 mg/d LTP groups, respectively, and +0.1 (95% CI - 0.1, 0.3) mmol/l during placebo (P= 0.024). Both at baseline and at week 12, the increase in systemic vascular resistance during head-up tilt was lower in the 25 mg/d LTP group than in the 5 mg/d LTP group (P< 0.01), showing persistent differences in cardiovascular regulation between these groups. In subjects with the MetS, intake of LTP and Pse in fermented milk product showed a lipid-lowering effect of borderline significance, while no antihypertensive effect was observed at home or in the laboratory.